Pain resolution and glucose control in pediatric patients with chronic pancreatitis after total pancreatectomy with islet auto-transplantation.

BACKGROUND: Chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) in pediatric patients are strongly associated with genetic mutations and lead to pan-parenchymal disease refractory to medical and endoscopic treatment. Our aim was to assess pain resolution and glucose control in patients with CP and ARP following total pancreatectomy with islet auto-transplantation (TPIAT). METHODS: We retrospectively analyzed prospectively collected clinical data of 12 children who developed CP and ARP and underwent TPIAT when 21 years old or younger at the University of Chicago between December 2009 and June 2020. Patients with recurrent or persistent abdominal pain attributed to acute or chronic pancreatic inflammation and a history of medical interventions attempted for the relief of pancreatic pain were selected by a multi-disciplinary team for TPIAT. We followed patients post-operatively and reported data for pre-TPIAT, post-operative day 75, and yearly post-TPIAT. RESULTS: All 12 patients experienced complete resolution of pancreatic pain. The overall insulin-independence rate after 1 year was 66% (8/12) and 50% (3/6) at 4 years. Shorter duration of CP/ARP pre-TPIAT, higher mass of islets infused, and lower BMI, BMI percentile, and BSA were associated with insulin-independence post-TPIAT. CONCLUSIONS: TPIAT is a viable treatment option for pediatric patients with CP and ARP. Pediatric patients undergoing TPIAT for CP achieved resolution of pancreatic-type pain and reduced opioid requirements. The majority were able to achieve insulin-independence which was associated with lower pre-TPIAT BMI and higher islet mass transplanted (i.e., over 2000 IEQ/kg), the latter of which can be achieved by earlier TPIAT. LEVEL OF EVIDENCE: Treatment study, Level IV.

Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: Identifying metabolic abnormalities that occur before pancreatic ductal adenocarcinoma (PDAC) diagnosis could increase chances for early detection. We collected data on changes in metabolic parameters (glucose, serum lipids, triglycerides; total, low-density, and high-density cholesterol; and total body weight) and soft tissues (abdominal subcutaneous fat [SAT], adipose tissue, visceral adipose tissue [VAT], and muscle) from patients 5 years before the received a diagnosis of PDAC. METHODS: We collected data from 219 patients with a diagnosis of PDAC (patients) and 657 healthy individuals (controls) from the Rochester Epidemiology Project, from 2000 through 2015. We compared metabolic profiles of patients with those of age- and sex-matched controls, constructing temporal profiles of fasting blood glucose, serum lipids including triglycerides, cholesterol profiles, and body weight and temperature for 60 months before the diagnosis of PDAC (index date). To construct the temporal profile of soft tissue changes, we collected computed tomography scans from 68 patients, comparing baseline (>18 months before diagnosis) areas of SAT, VAT, and muscle at L2/L3 vertebra with those of later scans until time of diagnosis. SAT and VAT, isolated from healthy individuals, were exposed to exosomes isolated from PDAC cell lines and analyzed by RNA sequencing. SAT was collected from KRAS+/LSLG12D P53flox/flox mice with PDACs, C57/BL6 (control) mice, and 5 patients and analyzed by histology and immunohistochemistry. RESULTS: There were no significant differences in metabolic or soft tissue features of patients vs controls until 30 months before PDAC diagnosis. In the 30 to 18 months before PDAC diagnosis (phase 1, hyperglycemia), a significant proportion of patients developed hyperglycemia, compared with controls, without soft tissue changes. In the 18 to 6 months before PDAC diagnosis (phase 2, pre-cachexia), patients had significant increases in hyperglycemia and decreases in serum lipids, body weight, and SAT, with preserved VAT and muscle. In the 6 to 0 months before PDAC diagnosis (phase 3, cachexia), a significant proportion of patients had hyperglycemia compared with controls, and patients had significant reductions in all serum lipids, SAT, VAT, and muscle. We believe the patients had browning of SAT, based on increases in body temperature, starting 18 months before PDAC diagnosis. We observed expression of uncoupling protein 1 (UCP1) in SAT exposed to PDAC exosomes, SAT from mice with PDACs, and SAT from all 5 patients but only 1 of 4 controls. CONCLUSIONS: We identified 3 phases of metabolic and soft tissue changes that precede a diagnosis of PDAC. Loss of SAT starts 18 months before PDAC identification, and is likely due to browning. Overexpression of UCP1 in SAT might be a biomarker of early-stage PDAC, but further studies are needed.

Pancreatic ductal adenocarcinoma is associated with a unique endocrinopathy distinct from type 2 diabetes mellitus.

INTRODUCTION: The majority of patients with pancreatic ductal adenocarcinoma (PC) display either impaired fasting glucose/glucose intolerance or overt diabetes. However, the pathophysiologic basis of this association remains largely unexplained. METHODS: In this case-control study we aimed to study the morphological changes in the islets of patients with PC, compared to control patients with and without type 2 diabetes mellitus (T2DM). T2DM controls and PC cases had a lower ß-cell area and average islet size and density compared to non-T2DM controls (p < 0.05). RESULTS: Compared to both T2DM and non-T2DM controls, mean α-cell area was significantly lower and ß/α-ratio was higher in PC cases (p < 0.05). Furthermore, whereas islets in T2DM controls were characterized by disrupted islet architecture and presence of islet amyloid aggregates, islet composition in PC islets was not significantly different compared to non-T2DM controls (p > 0.05 vs. Control). CONCLUSIONS: Our data shows that PC is associated with a unique pattern of islet pathology characterized by preserved architecture, absence of amyloid aggregates, and relative α-cell loss indicating that distinct mechanisms are likely involved in the pathophysiology of islet failure in PC-induced DM. Insights into the mechanisms mediating ß-cell failure in PC can be important for our understanding of pathophysiology of PC.

Model to Determine Risk of Pancreatic Cancer in Patients With New-Onset Diabetes.

BACKGROUND & AIMS: Of patients with new-onset diabetes (NOD; based on glycemic status) older than 50 years, approximately 1% are diagnosed with pancreatic cancer (PC) within 3 years. We aimed to develop and validate a model to determine risk of PC in patients with NOD. METHODS: We retrospectively collected data from 4 independent and nonoverlapping cohorts of patients (N = 1,561) with NOD (based on glycemic status; data collected at date of diagnosis and 12 months previously) in the Rochester Epidemiology Project from January 1, 2000 through December 31, 2015 to create our model. The model weighed scores for 3 factors identified in the discovery cohort to be most strongly associated with PC (64 patients with PC and 192 with type 2 diabetes): change in weight, change in blood glucose, and age at onset of diabetes. We called our model Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC). We validated the locked-down model and cutoff score in an independent population-based cohort of 1,096 patients with diabetes; of these, 9 patients (82%) had PC within 3 years of meeting the criteria for NOD. RESULTS: In the discovery cohort, the END-PAC model identified patients who developed PC within 3 years of diabetes onset (area under receiver operating characteristic curve 0.87); a score of at least 3 identified patients who developed PC with 80% sensitivity and specificity. In the validation cohort, a score of at least 3 identified 7 of 9 patients with PC (78%) with 85% specificity; the prevalence of PC in patients with a score of at least 3 (3.6%) was 4.4-fold greater than in patients with NOD. A high END-PAC score in patients who did not have PC (false positives) was often due to such factors as recent steroid use or different malignancy. An ENDPAC score no higher than 0 (in 49% of patients) meant that patients had an extremely low risk for PC. An END-PAC score of at least 3 identified 75% of patients in the discovery cohort more than 6 months before a diagnosis of PC. CONCLUSIONS: Based on change in weight, change in blood glucose, and age at onset of diabetes, we developed and validated a model to determine risk of PC in patients with NOD based on glycemic status (END-PAC model). An independent prospective study is needed to further validate this model, which could contribute to early detection of PC.

High-Grade Dysplasia in Resected Main-Duct Intraductal Papillary Mucinous Neoplasm (MD-IPMN) is Associated with an Increased Risk of Subsequent Pancreatic Cancer.

BACKGROUND: There is lack of consensus on post-operative surveillance for resected non-invasive intraductal papillary neoplasms (IPMNs). In this study we explored risk factors for subsequent PC in patients with MD-IPMN undergoing partial pancreatectomy. METHODS: We searched the Mayo Clinic surgical pathology database for all cases of resected MD-IPMN between 1997 and 2014. Cases with histologically confirmed main pancreatic duct involvement either isolated or in a mixed pattern with branch-duct involvement were included. Outcomes of PC in the remnant pancreas, and death related to MD-IPMN were assessed with survival analyses (Kaplan-Meier and Cox regression). RESULTS: Among the 179 patients with resected MD-IPMN the incidence of concomitant PC and high-grade dysplasia (HGD) in the resected specimen was 23 and 14%, respectively. The mean duration of follow-up was 4.31 years (range 0.12-13.5 years). Excluding 28 subjects who either underwent initial total pancreatectomy or partial pancreatectomy with surgical margins positive for PC/HGD, the 5-year incidence of subsequent PC was 12%, including 60.6% and 15.6% in those with initial PC and HGD, respectively. The 10-year incidence of PC was 21.2% overall, 60.6% for PC, 38.3% for HGD, and 3.0% for LGD. Risk of subsequent PC was significantly higher for those with initial PC compared with HGD (HR = 4.95, 95% CI: 1.63-15.03, p = 0.005 and for HGD compared with LGD (HR = 11.30, 95% CI: 1.55-82.26, p = 0.017). CONCLUSIONS: Patients with MD-IPMN with PC or HGD undergoing segmental pancreatectomy are at higher risk of subsequent PC and may benefit from post-operative surveillance. The post-operative surveillance intervals in resected MD-IPMNs need to be tailored based on dysplasia grade.

Clinical spectrum of adult patients with annular pancreas: Findings from a large single institution cohort.

BACKGROUND AND AIMS: Annular pancreas (AnnP) is a rare congenital abnormality that results from the presence of a complete or partial ring of pancreatic tissue surrounding the descending portion of the duodenum. While the clinical presentation and management of AnnP in neonates and infants has been well described, the complete spectrum of clinical presentation of AP in adults is not very clear. We aimed to describe the clinical spectrum of presentation and management of adult patients with AnnP. METHODS: Using the electronic medical record, we identified 198 patients with radiologically and/or surgically confirmed AnnP evaluated at Mayo Clinic between 1995 and 2017. RESULTS: The mean age of the study population at diagnosis was 55.1 (±18.3) years (60% female). 60% of patients did not have symptoms attributable to pancreatic disease at the time of diagnosis and were diagnosed incidentally. Computed tomography (CT) was the most common modality (64%) of diagnosis. Among symptomatic patients, abdominal pain (50%), duodenal obstruction (31%) and acute pancreatitis (16%) were the most common symptoms (non-exclusive). While most patients with duodenal obstruction required surgery, all patients with acute pancreatitis could be managed conservatively in the absence of competing indications for intervention. CONCLUSION: AnnP may remain asymptomatic well into adulthood and be incidentally detected on abdominal imaging done for other indications. While surgery remains the mainstay of treatment in patients presenting with duodenal obstruction, a majority of these adult symptomatic patients with AnnP, including those with acute pancreatitis require no further treatment.

Dissemination of Information on Neutropenic Diet by Top US Cancer Centers: In-line with the Evidence?

Aim: The neutropenic diet is commonly prescribed to cancer patients with neutropenia with the goal of reducing infections. However, multiple randomized trials have proved no benefit with neutropenic diets compared to less restricted diets with regards to reducing infectious risk. We aimed to ascertain if top cancer centers recommended for or against the use of neutropenic diets on their official websites. Methods: We reviewed the websites of the top 20 hospitals in the 2017 US News Best Hospitals for Cancer©, and ascertained recommendations for neutropenic diet (for, against, equivocal, or not addressed). Results: Seven websites (35%) made recommendations for, four (20%) against, and nine (45%) did not address the neutropenic diet. Only five (25%) backed any of their recommendations with evidence (four against, one for), including two (10%) links to abstracts (both against), whereas seven mentioned the FDA safe food handling guidelines (non-exclusive). Type of recommendation made (for or against) did not depend on US News rank (top vs bottom 10; p = 1.00.). Conclusion: The neutropenic diet continues to be recommended on many (35%) websites of top US cancer centers, despite strong evidence against its use. The website content of major US cancer centers should be updated to better guide patients regarding neutropenic diets.

Autoimmune Pancreatitis.

Over the course of the last 2 decades our knowledge of autoimmune pancreatitis has increased exponentially. In this review, we summarize the clinical presentation, diagnosis and treatment of AIP, to better allow general gastroenterologists and primary care providers to consider AIP as a as a rare but important cause of painless obstructive jaundice and recurrent acute pancreatitis. While steroids remain the mainstay of first line therapy, a number of patients with type 1 AIP require immunomodulators or rituximab to maintain remission; recommendations on the management of relapses continue to evolve.

Metachronous colon polyps in younger versus older adults: a case-control study.

BACKGROUND AND AIMS: The incidence of colorectal cancer in the United States has decreased substantially in individuals aged 50 and older. In contrast, it is increasing in young adults. The polyp characteristics on baseline and follow-up colonoscopy in young adults are not well characterized. We describe the polyp characteristics on baseline and follow-up colonoscopy in adults <40 years and determined factors associated with the occurrence of metachronous, advanced neoplasia or high-risk (HR) polyp features. We compared the occurrence of metachronous advanced neoplasia in young adults with those 50 years and older to assess whether postpolypectomy surveillance guidelines seem appropriate for polyp-bearing adults less than age 40 years. METHODS: Patients <40 years of age with >1 polyp removed on colonoscopy followed by a postpolypectomy colonoscopy were eligible. The primary outcome was the occurrence of advanced neoplasia or HR polyp features on follow-up colonoscopy. Secondary endpoints included factors associated with metachronous advanced neoplasia in young adults. The occurrence of metachronous advanced neoplasia in young adults was compared with a cohort of patients aged 50 years and older. RESULTS: Included were 128 patients with a mean age of 34.9 years; 124 patients (97%) had adenomas and 7% had sessile serrated polyps (SSPs). Advanced neoplasia was seen in 35% of patients at baseline. The median follow-up time was 33.6 months. Metachronous advanced neoplasia was identified in 7% of patients on follow-up colonoscopy. Baseline factors associated with metachronous advanced neoplasia included the presence of an SSP (hazard ratio, 7.8; 95% CI, 1.09-56.3; P = .041) with a trend in those with advanced neoplasia (hazard ratio, 3.4; 95% confidence interval, .89-12.8; P = .072). The occurrence of metachronous advanced neoplasia did not differ between the young and older cohorts (7% vs 12.2%, P = .58); however, young adults were less likely to have HR polyp features on follow-up (8.6% vs 20.3%, P = .008). CONCLUSIONS: More than 1 in 3 adults <40 years old undergoing colonoscopy had advanced neoplasia on baseline colonoscopy. The occurrence of metachronous advanced neoplasia in young adults is similar to older adults and appears to be associated with the size, pathology, and number of baseline polyps. Our data suggest young polyp-bearing adults may undergo postpolypectomy colonoscopy at intervals currently recommended by national guidelines. Confirmation in larger studies is warranted.

Portal Hypertension Complications Are Frequently the First Presentation of NAFLD in Patients Undergoing Liver Transplantation Evaluation.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is likely to replace Hepatitis C as the leading cause of cirrhosis resulting in liver transplantation (LT) within a few years. Unfortunately, due to the lack of established guidelines for the screening of NAFLD in high-risk populations, many patients present with portal hypertension complications as their first manifestation of NAFLD require a LT evaluation. We aimed to investigate what proportion of patients who underwent LT for NAFLD-cirrhosis had knowledge of their liver disease prior to presenting with portal hypertension complications and to identify differences in clinical parameters between those with and without knowledge of preexisting NAFLD. METHODS: Consecutive patients who underwent LT for NAFLD-cirrhosis at a tertiary referral center were included in the study. Demographic and clinical data at the time of the first LT evaluation visit were collected, and patient knowledge of previous NAFLD was documented. Ascites, variceal bleeding, hepatic encephalopathy, and thrombocytopenia leading to diagnosis of underlying cirrhosis were considered as the presenting symptoms of portal hypertension. A p < 0.05 was considered statistically significant. RESULTS: A total of 124 subjects who received LT for NAFLD-cirrhosis were included, 58 % (n = 72) were male. At the time of the first LT evaluation visit, 60 % had diabetes, the mean body mass index was 33.2 [28.6, 37.6] kg/m(2), and the mean Model for End-Stage Liver Disease (MELD) score was 14.0 [11.0, 19.0]. More importantly, 85/124 patients (68.5 %) had no knowledge of preexisting NAFLD prior to presentation with symptoms of portal hypertension. The presenting symptoms were new-onset ascites in 61 %, hepatic encephalopathy in 25 %, variceal bleeding in 18 %, thrombocytopenia in 9 %, and other in 9 % (non-exclusive). Patients with no prior knowledge of NAFLD were less likely to have a diagnosis of hypercholesterolemia (30 vs. 50 %, p = 0.035) and had a trend toward having higher MELD scores at the time of the first LT evaluation visit (15 vs. 13.5, p = 0.05) and presenting with encephalopathy (25 vs. 10 %, p = 0.06) compared to those with previous knowledge of NAFLD diagnosis. CONCLUSION: The majority of patients undergoing liver transplant evaluation for NAFLD-cirrhosis are not aware of underlying NAFLD until they present with features of portal hypertension. New guidelines should consider screening for NAFLD in certain high-risk groups as more effective treatments for NAFLD are emerging.

Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has been associated with an increased risk of nonmelanoma skin cancer, particularly among patients treated with thiopurines. It is unclear whether IBD affects risk for melanoma. We performed a systematic review and meta-analysis of cohort studies to determine the risk of melanoma in patients with IBD. METHODS: We conducted a systematic search of bibliographic databases through March 2013. Cohort studies reporting incident melanoma after IBD diagnosis and an estimate of incidence rate ratio or standardized incidence rate were included in the analysis. Pooled relative risk (RR) estimates with 95% confidence intervals (CIs) were calculated using the random-effects model. RESULTS: Our analysis included 12 studies, comprising a total of 172,837 patients with IBD; 179 cases of melanoma were reported from 1940 to 2009. The pooled crude incidence rate of melanoma in patients with IBD was 27.5 cases/100,000 person-years (95% CI, 19.9-37.0). Overall, IBD was associated with a 37% increase in risk of melanoma (12 studies: RR, 1.37; 95% CI, 1.10-1.70). The risk was increased among patients with Crohn's disease (7 studies: RR, 1.80; 95% CI, 1.17-2.75) and ulcerative colitis (7 studies: RR, 1.23; 95% CI, 1.01-1.50). The risk of melanoma was higher in studies performed before introduction of biologic therapies (before 1998) (8 studies: RR, 1.52; 95% CI, 1.02-2.25) but not in studies performed after 1998 (2 studies: RR, 1.08; 95% CI, 0.59-1.96). CONCLUSIONS: Based on a meta-analysis, IBD has been associated with an increased risk of melanoma, independent of the use of biologic therapy. Patients diagnosed with IBD should be counseled on their risk for melanoma.

Evaluation of the current management protocols for prophylaxis against Pneumocystis jiroveci pneumonia and other opportunistic infections in patients living with HIV/AIDS.

Opportunistic infections (OIs) are a leading cause of mortality and morbidity in patients living with HIV/AIDS. Data on the proper administration of prophylactic regimes for the prevention of OIs in such patients are scarce. A total of 205 confirmed HIV-infected patients were enrolled in the study from the inpatient wards and outpatient services. The treatment given to them for the prevention of Pneumocystis carinii (jiroveci) pneumonia was compared with the established guidelines and the proportions of those receiving proper treatment were calculated. Primary prophylaxis was seen to be satisfactory in the case of P. carinii (jiroveci) pneumonia. The prophylaxis was not given properly for tuberculosis and other common OIs. Secondary prophylaxis was up to the mark. Prophylaxis in AIDS patients seems to be a major problem area and a lot of efforts need to be directed toward it since patients suffering from AIDS are bound to have a downhill course despite provision of all available treatment options.

Comparative diagnostic accuracy of EUS needles in solid pancreatic masses: a network meta-analysis.

Background and study aims Endoscopic ultrasound (EUS)-guided tissue sampling is the standard of care for diagnosing solid pancreatic lesions. While many two-way comparisons between needle types have been made in randomized controlled trials (RCTs), it is unclear which size and type of needle offers the best probability of diagnosis. We therefore performed a network meta-analysis (NMA) to compare different sized and shaped needles to rank the diagnostic performance of each needle. Methods We searched MEDLINE, EMBASE and Cochrane Library databases through August, 2020 for RCTs that compared the diagnostic accuracy of EUS fine-needle aspiration (FNA) and biopsy (FNB) needles in solid pancreatic masses. Using a random-effects NMA under the frequentist framework, RCTs were analyzed to identify the best needle type and sampling technique. Performance scores (P-scores) were used to rank the different needles based on pooled diagnostic accuracy. The NMA model was used to calculate pairwise relative risk (RR) with 95 % confidence intervals. Results Review of 2577 studies yielded 29 RCTs for quantitative synthesis, comparing 13 different needle types. All 22G FNB needles had an RR > 1 compared to the reference 22G FNA (Cook) needle. The highest P-scores were seen with the 22G Medtronic FNB needle (0.9279), followed by the 22G Olympus FNB needle (0.8962) and the 22G Boston Scientific FNB needle (0.8739). Diagnostic accuracy was not significantly different between needles with or without suction. Conclusions In comparison to FNA needles, FNB needles offer the highest diagnostic performance in sampling pancreatic masses, particularly with 22G FNB needles.

Erratum: Comparative diagnostic accuracy of EUS needles in solid pancreatic masses: a network meta-analysis.

[This corrects the article DOI: 10.1055/a-1381-7301.].