Livia Archibugi

Exocrine Pancreatic Insufficiency in Diabetic Patients: Prevalence, Mechanisms, and Treatment

Pancreas is a doubled-entity organ, with both an exocrine and an endocrine component, reciprocally interacting in a composed system whose function is relevant for digestion, absorption, and homeostasis of nutrients. Thus, it is not surprising that disorders of the exocrine pancreas also affect the endocrine system and vice versa. It is well-known that patients with chronic pancreatitis develop a peculiar form of diabetes (type III), caused by destruction and fibrotic injury of islet cells. However, less is known on the influence of diabetes on pancreatic exocrine function. Pancreatic exocrine insufficiency (PEI) has been reported to be common in diabetics, with a prevalence widely ranging, in different studies, in both type I (25–74%) and type II (28–54%) diabetes. A long disease duration, high insulin requirement, and poor glycemic control seem to be risk factors for PEI occurrence. The impact of pancreatic exocrine replacement therapy on glycemic, insulin, and incretins profiles has not been fully elucidated. The present paper is aimed at reviewing published studies investigating the prevalence of PEI in diabetic patients and factors associated with its occurrence.

Systematic review and meta-analysis: Small intestinal bacterial overgrowth in chronic pancreatitis

Background Evidence on small intestinal bacterial overgrowth (SIBO) in patients with chronic pancreatitis (CP) is conflicting. Aim The purpose of this study was to perform a systematic review and meta-analysis on the prevalence of SIBO in CP and to examine the relationship of SIBO with symptoms and nutritional status. Methods Case-control and cross-sectional studies investigating SIBO in CP patients were analysed. The prevalence of positive tests was pooled across studies, and the rate of positivity between CP cases and controls was calculated. Results In nine studies containing 336 CP patients, the pooled prevalence of SIBO was 36% (95% confidence interval (CI) 17–60%) with considerable heterogeneity (I2u2009=u200991%). A sensitivity analysis excluding studies employing lactulose breath test gave a pooled prevalence of 21.7% (95% CI 12.7–34.5%) with lower heterogeneity (I2u2009=u200956%). The odds ratio for a positive test in CP vs controls was 4.1 (95% CI 1.6–10.4) (I2u2009=u200959.7%). The relationship between symptoms and SIBO in CP patients varied across studies, and the treatment of SIBO was associated with clinical improvement. Conclusions One-third of CP patients have SIBO, with a significantly increased risk over controls, although results are heterogeneous, and studies carry several limitations. The impact of SIBO and its treatment in CP patients deserve further investigation.

Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors.

Over the past few years, knowledge regarding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs) has increased substantially, and a number of targeted agents have been tested in clinical trials in this tumor type. For some of these agents there is a strong biological rationale. Among them, the mammalian target of rapamycin inhibitor Everolimus and the antiangiogenic agent Sunitinib have both been approved for the treatment of PNETs. However, there is lack of knowledge regarding biomarkers able to predict their efficacy, and mechanisms of resistance. Other angiogenesis inhibitors, such as Pazopanib, inhibitors of Src, Hedgehog or of PI3K might all be useful in association or sequence with approved agents. On the other hand, the clinical significance, and potential for treatment of the most common mutations occurring in sporadic PNETs, in the MEN‐1 gene and in ATRX and DAXX, remains uncertain. The present paper reviews the main molecular changes occurring in PNETs and how they might be linked with treatment options.

The Neutrophil/Lymphocyte Ratio at Diagnosis Is Significantly Associated with Survival in Metastatic Pancreatic Cancer Patients

Different inflammation-based scores such as the neutrophil/lymphocyte ratio (NLR), the Odonera Prognostic Nutritional Index (PNI), the Glasgow Prognostic Score, the platelet/lymphocyte ratio, and the C-reactive protein/albumin ratio have been found to be significantly associated with pancreatic cancer (PDAC) prognosis. However, most studies have investigated patients undergoing surgery, and few of them have compared these scores. We aimed at evaluating the association between inflammatory-based scores and PDAC prognosis. In a single center cohort study, inflammatory-based scores were assessed at diagnosis and their prognostic relevance as well as that of clinic-pathological variables were evaluated through multiple logistic regression and survival probability analysis. In 206 patients, age, male sex, tumor size, presence of distant metastasis, access to chemotherapy, and an NLR > 5 but not other scores were associated with overall survival (OS) at multivariate analysis. Patients with an NLR < 5 had a median survival of 12 months compared to 4 months in those with an NLR > 5. In the 81 patients with distant metastasis at diagnosis, an NLR > 5 resulted in the only variable significantly associated with survival. Among patients with metastatic disease who received chemotherapy, the median survival was 3 months in patients with an NLR > 5 and 7 months in those with an NLR < 5. The NLR might drive therapeutic options in PDAC patients, especially in the setting of metastatic disease.

Early onset pancreatic cancer: Risk factors, presentation and outcome

BACKGROUNDnAbout 10% of pancreatic cancer patients are aged ≤50 at diagnosis and defined as Early Onset Pancreatic Cancer (EOPC). There is limited information regarding risk factors for EOPC occurrence and their outcome.nnnAIMnTo investigate risk factors, presentation features and outcome of EOPC patients.nnnMETHODSnConsecutive, histologically confirmed, pancreatic cancer patients enrolled. Data regarding environmental and genetic risk factors, clinical and pathological information, treatment and survival were recorded. EOPC patients (aged ≤50 at diagnosis) were compared to older subjects.nnnRESULTSnTwenty-five of 293 patients (8.5%) had EOPC. There was no difference regarding sex distribution, medical conditions and alcohol intake between EOPC and older subjects. EOPC patients were more frequently current smokers (56% vs 28% pxa0=xa00.001) and started smoking at a significantly lower mean age (19.8 years, 95%CI 16.7-22.9) as compared to older patients (26.1, 95%CI 24.2-28) (pxa0=xa00.001). Current smoking (OR 7.5; 95%CI 1.8-30; pxa0=xa00.004) and age at smoking initiation (OR 0.8 for every increasing year; 95%CI 0.7-0.9; pxa0=xa00.01) were significant and independent risk factors for diagnosis of EOPC. There were no differences regarding genetic syndromes and pancreatic cancer family history. EOCP presented less frequently with jaundice (16% vs 44%, pxa0=xa00.006) and had a higher rate of unresectable disease, albeit not significantly (84% vs 68%, pxa0=xa00.1). EOPC patients were more frequently fit for surgery or chemotherapy than their counterpart, resulting in similar stage-specific survival probability.nnnCONCLUSIONnEOPC seems related to active and early smoking but not to familial syndromes. Young patients display aggressive disease but not worse outcome.

Exclusive and Combined Use of Statins and Aspirin and the Risk of Pancreatic Cancer: a Case-Control Study

Data on the association between aspirin and statin use and Pancreatic Ductal AdenoCarcinoma (PDAC) risk are conflicting. These drugs are often co-prescribed, but no studies evaluated the potential combined or confounding effect of the two at the same time. We aimed to investigate the association between aspirin and statin exclusive and combined use and PDAC occurrence. Data on environmental factors, family and medical history were screened in a case-control study. PDAC cases were matched to controls for age and gender. Power calculation performed ahead. Odds ratios (OR) and 95% confidence intervals(CI) were obtained from multivariable logistic regression analysis. In 408 PDAC patients and 816 matched controls, overall statin (OR 0.61; 95%CI,0.43–0.88), but not aspirin use was associated to reduced PDAC risk. Compared to non-users, exclusive statin (OR 0.51; 95%CI,0.32–0.80) and exclusive aspirin users (OR 0.64; 95%CI,0.40–1.01) had reduced PDAC risk. Concomitant statin and aspirin use did not further reduce the risk compared with statin use alone and no interaction was evident. Statin protective association was dose-dependent, and consistent in most subgroups, being stronger in smokers, elderly, obese and non-diabetic patients. The present study suggests that statin use is associated to reduced PDAC risk, supporting a chemopreventive action of statins on PDAC.

Acute pancreatitis patient registry to examine novel therapies in clinical experience (APPRENTICE): an international, multicenter consortium for the study of acute pancreatitis

Background We have established a multicenter international consortium to better understand the natural history of acute pancreatitis (AP) worldwide and to develop a platform for future randomized clinical trials. Methods The AP patient registry to examine novel therapies in clinical experience (APPRENTICE) was formed in July 2014. Detailed web-based questionnaires were then developed to prospectively capture information on demographics, etiology, pancreatitis history, comorbidities, risk factors, severity biomarkers, severity indices, health-care utilization, management strategies, and outcomes of AP patients. Results Between November 2015 and September 2016, a total of 20 sites (8 in the United States, 5 in Europe, 3 in South America, 2 in Mexico and 2 in India) prospectively enrolled 509 AP patients. All data were entered into the REDCap (Research Electronic Data Capture) database by participating centers and systematically reviewed by the coordinating site (University of Pittsburgh). The approaches and methodology are described in detail, along with an interim report on the demographic results. Conclusion APPRENTICE, an international collaboration of tertiary AP centers throughout the world, has demonstrated the feasibility of building a large, prospective, multicenter patient registry to study AP. Analysis of the collected data may provide a greater understanding of AP and APPRENTICE will serve as a future platform for randomized clinical trials.

The Use of Complementary and Alternative Medicine is Frequent in Patients With Pancreatic Disorders.

Background: Herbal remedies and other complementary and alternative medicine (CAM) are used by 30% of the patients with liver and inflammatory bowel diseases. However, there are no data regarding CAM use in patients with pancreatic disorders, including potential pancreatotoxicity. Aim of the Study: The aim of the study was to assess the prevalence of CAM use in patients with pancreatic disorders and screen for pancreatotoxicity. Materials and Methods: This was a cross-sectional survey of consecutive outpatients seen at a Pancreas Center. Data were collected in a specific questionnaire. Descriptive statistics were used to analyze the prevalence and the patterns of CAM use. Characteristics associated with CAM use were analyzed by appropriate statistics. Results: Of 108 patients (52% male; mean age, 65±13 years), 47 (43.5%) used CAM. The use of CAM was more frequent among patients with previous acute pancreatitis (47%). Reported reasons for the use of CAM were to help standard therapies and for an overall better feeling. About 61% of the patients reported advantages with treatment. As compared with nonusers, CAM users were more often female (55% vs. 42%), with a higher school degree (43% vs. 36%), more frequently performing physical activity (51% vs. 41%), and reporting anxiety (45% vs. 31%). However, none of these differences were statistically significant. Three patients with previous acute pancreatitis reported the use of Serenoa repens that is potentially pancreatotoxic. Discussion: The rate of CAM use in patients with pancreatic disorders is similar to those reported for other digestive diseases. CAM use seems to be more frequent in women with a higher education level and a “healthier lifestyle.” Patients might not be aware of the potential pancreatotoxicity of CAM, which should be carefully considered by physicians.

Meta‐analysis of mortality in patients with high‐risk intraductal papillary mucinous neoplasms under observation

Although consensus guidelines suggest that patients with high‐risk intraductal papillary mucinous neoplasms (IPMNs) should have surgery, a non‐operative strategy is often selected in patients who are poor surgical candidates. The aim was to determine the risk of disease‐related death from IPMN in patients with worrisome features or high‐risk stigmata who were kept under observation.

Prevalence of chronic pancreatitis: Results of a primary care physician-based population study

BACKGROUNDnData on chronic pancreatitis prevalence are scanty and usually limited to hospital-based studies.nnnAIMnInvestigating chronic pancreatitis prevalence in primary care.nnnMETHODSnParticipating primary care physicians reported the prevalence of chronic pancreatitis among their registered patients, environmental factors and disease characteristics. The data were centrally reviewed and chronic pancreatitis cases defined according to M-ANNHEIM criteria for diagnosis and severity and TIGAR-O classification for etiology.nnnRESULTSnTwenty-three primary care physicians participated in the study. According to their judgment, 51 of 36.401 patients had chronic pancreatitis. After reviewing each patient data, 11 turned out to have definite, 5 probable, 19 borderline and 16 uncertain disease. Prevalence was 30.2/100.000 for definite cases and 44.0/100.000 for definite plus probable cases. Of the 16 patients with definite/probable diagnosis, 8 were male, with mean age of 55.6 (±16.7). Four patients had alcoholic etiology, 5 post-acute/recurrent pancreatitis, 6 were deemed to be idiopathic. Four had pancreatic exocrine insufficiency, 10 were receiving pancreatic enzymes, and six had pain. Most patients had initial stage and non-severe disease.nnnCONCLUSIONSnThis is the first study investigating the prevalence of chronic pancreatitis in primary care. Results suggest that the prevalence in this context is higher than in hospital-based studies, with specific features, possibly representing an earlier disease stage.