Addressing long-term mortality risk in patients undergoing total pancreatectomy with islet autotransplant (TPIAT): causes of death and risk factors.

BACKGROUND: Total pancreatectomy with islet autotransplant (TPIAT) can improve quality of life for individuals with pancreatitis but creates health risks including diabetes, exocrine insufficiency, altered intestinal anatomy and function, and asplenia. METHODS: We studied survival and causes of death for 693 patients who underwent TPIAT between 2001 and 2020, using the National Death Index with medical records to ascertain survival after TPIAT, causes of mortality, and risk factors for death. We used Kaplan Meier curves to examine overall survival, and Cox regression and competing-risks methods to determine pre-TPIAT factors associated with all-cause and cause-specific post-TPIAT mortality. RESULTS: Mean age at TPIAT was 33.6 years (SD = 15.1). Overall survival was 93.1% (95% CI 91.2, 95.1%) 5 years after surgery, 85.2% (95% CI 82.0, 88.6%) at 10 years, and 76.2% (95% CI 70.8, 82.3%) at 15 years. Fifty-three of 89 deaths were possibly related to TPIAT; causes included chronic gastrointestinal complications, malnutrition, diabetes, liver failure, and infection/sepsis. In multivariable models, younger age, longer disease duration, and more recent TPIAT were associated with lower mortality. CONCLUSIONS: For patients undergoing TPIAT to treat painful pancreatitis, careful long-term management of comorbidities introduced by TPIAT may reduce risk for common causes of mortality.

Nutritional Risks in Patients Undergoing Total Pancreatectomy Islet AutoTransplantation in the POST Consortium.

BACKGROUND AND AIMS: Total pancreatectomy with islet autotransplantation (TPIAT) can relieve pain for individuals with acute recurrent or chronic pancreatitis. However, TPIAT may increase the risk of poor nutritional status with complete exocrine pancreatic insufficiency, partial duodenectomy, and intestinal reconstruction. Our study's objective was to evaluate nutritional status, anthropometrics, and vitamin levels before and after TPIAT. METHODS: The multicenter Prospective Observational Study of TPIAT (POST) collects measures including vitamins A, D, and E levels, pancreatic enzyme dose, and multivitamin (MVI) administration before and 1-year after TPIAT. Using these data, we studied nutritional and vitamin status before and after TPIAT. RESULTS: 348 TPIAT recipients were included (68% adult, 37% male, 93% Caucasian). In paired analyses at 1-year follow-up, vitamin A was low in 23% (vs 9% pre-TPIAT, p < 0.001); vitamin E was low in 11% (vs 5% pre-TPIAT, p = 0.066), and 19% had vitamin D deficiency (vs 12% pre-TPIAT, p = 0.035). Taking a fat-soluble multivitamin (pancreatic MVI) was associated with lower risk for vitamin D deficiency (p = 0.002). Adults were less likely to be on a pancreatic MVI at follow-up (34% vs 66% respectively, p < 0.001). Enzyme dosing was adequate. More adults versus children were overweight or underweight pre- and post-TPIAT. Underweight status was associated with vitamin A (p = 0.014) and E (p = 0.02) deficiency at follow-up. CONCLUSIONS: Prevalence of fat-soluble vitamin deficiencies increased after TPIAT, especially if underweight. We strongly advocate that all TPIAT recipients have close post-operative nutritional monitoring, including vitamin levels. Pancreatic MVIs should be given to minimize risk of developing deficiencies.

Disconnected pancreatic duct syndrome in patients with necrotizing pancreatitis.

In a subset of patients with acute necrotizing pancreatitis, segmental necrosis affecting the main pancreatic duct may result in a discontinuity between the left-sided pancreas and the duodenum. Such an interruption in the setting of a viable upstream portion of the gland can give rise to the disconnected pancreatic duct syndrome (DPDS). By maintaining its secretory function, the disconnected segment may lead to persistent external pancreatic fistulae, recurrent pancreatic fluid collections, and/or obstructive recurrent acute or chronic pancreatitis of the isolated parenchyma. There are currently no universally accepted guidelines for the diagnosis or treatment of DPDS, and because the condition is underrecognized, the diagnosis is often delayed. DPDS is associated with a prolonged disease course and poses a burden on patients' quality of life as well as high health care resource utilization. The aim of our review is to summarize current knowledge, discuss diagnostic approaches, outline management options, and raise awareness of this challenging complication of necrotizing pancreatitis.

Intraportal Islet Autotransplantation Independently Improves Quality of Life After Total Pancreatectomy in Patients With Chronic Refractory Pancreatitis.

OBJECTIVE: To determine if islet autotransplantation (IAT) independently improves the quality of life (QoL) in patients after total pancreatectomy and islet autotransplantation (TP-IAT). BACKGROUND: TP-IAT is increasingly being used for intractable chronic pancreatitis. However, the impact of IAT on long-term islet function and QoL is unclear. METHODS: TP-IAT patients at our center >1 year after TP-IAT with ≥1 Short Form-36 QoL measure were included. Patients were classified as insulin-independent or insulin-dependent, and as having islet graft function or failure by C-peptide. The associations of insulin use and islet graft function with QoL measures were analyzed by using a linear mixed model, accounting for time since transplant and within-person correlation. RESULTS: Among 817 islet autograft recipients, 564 patients [median (interquartile range) age: 34 (20, 45) years, 71% female] and 2161 total QoL surveys were included. QoL data were available for >5 years after TP-IAT for 42.7% and for >10 years for 17.3%. Insulin-independent patients exhibited higher QoL in 7 of 8 subscale domains and for Physical Component Summary and Mental Component Summary scores ( P <0.05 for all). Physical Component Summary was 2.91 (SE=0.57) higher in insulin-independent patients ( P <0.001). No differences in QoL were observed between those with and without graft function, but islet graft failure was rare (15% of patients). However, glycosylated hemoglobin was much higher with islet graft failure. CONCLUSIONS: QoL is significantly improved when insulin independence is present, and glycosylated hemoglobin is lower with a functioning islet graft. These data support offering IAT, rather than just performing total pancreatectomy and treating with exogenous insulin.

Quadruple, 4-segment, triple sector "Y-shaped stents" in complex hilar cholangiocarcinoma after cholangitis from plastic stents.

Video 1Video showing successful placement of 4 uncovered self-expanding metal stents in a stent-in-stent, Y-shaped configuration for cholangitis from plastic stents in a patient with unresectable cholangiocarcinoma.

Surgical approach and short-term outcomes in adults and children undergoing total pancreatectomy with islet autotransplantation: A report from the Prospective Observational Study of TPIAT.

BACKGROUND: Total pancreatectomy with islet autotransplantation (TPIAT) is a viable option for treating debilitating recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) in adults and children. No data is currently available regarding variation in approach to operation. METHODS: We evaluated surgical techniques, islet isolation and infusion approaches, and outcomes and complications, comparing children (n = 84) with adults (n = 195) enrolled between January 2017 and April 2020 by 11 centers in the United States in the Prospective Observational Study of TPIAT (POST), which was launched in 2017 to collect standard history and outcomes data from patients undergoing TPIAT for RAP or CP. RESULTS: Children more commonly underwent splenectomy (100% versus 91%, p = 0.002), pylorus preservation (93% versus 67%; p < 0.0001), Roux-en-Y duodenojejunostomy reconstruction (92% versus 35%; p < 0.0001), and enteral feeding tube placement (93% versus 63%; p < 0.0001). Median islet equivalents/kg transplanted was higher in children (4577; IQR 2816-6517) than adults (2909; IQR 1555-4479; p < 0.0001), with COBE purification less common in children (4% versus 15%; p = 0.0068). Median length of hospital stay was higher in children (15 days; IQR 14-22 versus 11 days; IQR 8-14; p < 0.0001), but 30-day readmissions were lower in children (13% versus 26%, p = 0.018). Rate of portal vein thrombosis was significantly lower in children than in adults (2% versus 10%, p = 0.028). There were no mortalities in the first 90 days post-TPIAT. CONCLUSIONS: Pancreatectomy techniques differ between children and adults, with islet yields higher in children. The rates of portal vein thrombosis and early readmission are lower in children.

Visceral artery pseudoaneurysms in necrotizing pancreatitis: risk of early bleeding with lumen-apposing metal stents.

BACKGROUND AND AIMS: Visceral artery pseudoaneurysm (PSA) in necrotizing pancreatitis (NP) is associated with significant morbidity and mortality. This study aimed to evaluate the incidence, clinical presentation, management, and outcomes of PSA in NP. METHODS: All NP patients managed at our institution between 2010 and 2020 were retrospectively reviewed from a prospectively maintained database for PSA. Demographics, clinical presentation, method of diagnosis, management, and outcomes were collected. RESULTS: Thirty-nine of 607 patients (6.4%) with NP had a confirmed diagnosis of PSA. Demographics, presence of infected necrosis, development of organ failure(s), and severity of disease were similar between PSA and no PSA. Endoscopic and percutaneous drainages for walled-off necrosis (WON) were more common in the PSA group. Seven patients developed PSA without requiring any intervention for WON, and 17 patients (43.6%) had lumen-apposing metal stents (LAMSs) placed before PSA diagnosis. The time from NP diagnosis to PSA diagnosis was shorter in these patients (n = 17) compared with the remaining patients (n=22; 47 days [interquartile range {IQR}: 17-85] vs 109 days [IQR: 61-180.5, P=0.009]). In addition, 7 of 11 patients (63.6%) with early PSA (defined by <3 weeks from index cystgastrostomy/cystduodenostomy) had an indwelling LAMS at the time of the PSA diagnosis. Seventy-seven percent of patients presented with anemia, 74.3% with GI bleeding, and 30% with hemorrhagic shock. CT was diagnostic for PSA in 83.9% with a false-negative rate of 16.1%. Splenic (50%) and gastroduodenal (28%) arteries were the most common arteries involved by PSA. Angiography and embolization for PSA were successful in 33 of 35 patients. In-hospital mortality was observed in 9 patients (23.1%). CONCLUSIONS: Although visceral artery PSA affects a small percentage of NP patients, it is associated with significant morbidity and mortality. In addition, bleeding from PSA induced by erosion of LAMSs may occur in the first 2 weeks, prompting individualization of removal intervals.

Reduced bone mineral density in the first year after total pancreatectomy with islet autotransplantation (TPIAT).

BACKGROUND/OBJECTIVES: The effect of total pancreatectomy with islet autotransplantation (TPIAT) on bone mineral density (BMD) in patients with CP is unknown. We aimed to assess bone health in patients with CP after TPIAT. METHODS: We measured BMD, BMD Z-score, and bone mineral content (BMC) for total body, lumbar spine, right and left hip in 78 patients before and after TPIAT using dual-energy X-ray absorptiometry (DXA, n = 78 pre-TPIAT, n = 65 paired pre- and 12 months post-TPIAT, n = 33 paired 12 and 18 months post-TPIAT), and tested for association with clinical history including age, smoking status, and medications using paired and two-sample t-tests, linear regression, and Fisher's exact test. Laboratory measures related to bone health were also assessed. RESULTS: In the patients with pre-TPIAT DXA, 12% had low BMD (Z-score ≤ -2). BMD, BMD Z-score, and BMC all decreased from pre-to 12 months post-TPIAT. BMD declined by 1.7%-4.1% with the greatest change at the hips. Adjusted for change in lean and fat body mass, DXA changes remained significant for total body and hip. Serum carboxy-terminal collagen crosslinks telopeptide and alkaline phosphatase increased at 12 months post-TPIAT, suggesting possible increased bone remodeling. BMD, BMD Z-score, and BMC did not change between 12 months and 18 months in any of the four regions (p > 0.6). CONCLUSIONS: TPIAT is associated with decreases in BMD in the body, lumbar, and hip regions of patients with CP in the first year after TPIAT but these appear to stabilize between 12 and 18 months after TPIAT.

The Association of Smoking and Alcohol Abuse on Anxiety and Depression in Patients With Recurrent Acute or Chronic Pancreatitis Undergoing Total Pancreatectomy and Islet Autotransplantation: A Report From the Prospective Observational Study of TPIAT Cohort.

OBJECTIVES: Smoking and alcohol use are risk factors for acute and chronic pancreatitis, and their role on anxiety, depression, and opioid use in patients who undergo total pancreatectomy and islet autotransplantation (TPIAT) is unknown. METHODS: We included adults enrolled in the Prospective Observational Study of TPIAT (POST). Measured variables included smoking (never, former, current) and alcohol abuse or dependency history (yes vs no). Using univariable and multivariable analyses, we investigated the association of smoking and alcohol dependency history with anxiety and depression, opioid use, and postsurgical outcomes. RESULTS: Of 195 adults studied, 25 were current smokers and 77 former smokers, whereas 18 had a history of alcohol dependency (of whom 10 were current smokers). A diagnosis of anxiety was associated with current smoking (P = 0.005), and depression was associated with history of alcohol abuse/dependency (P = 0.0001). However, active symptoms of anxiety and depression at the time of TPIAT were not associated with smoking or alcohol status. Opioid use in the past 14 days was associated with being a former smoker (P = 0.005). CONCLUSIONS: Active smoking and alcohol abuse history were associated with a diagnosis of anxiety and depression, respectively; however, at the time of TPIAT, symptom scores suggested that they were being addressed.

Circulating miRNA in Patients Undergoing Total Pancreatectomy and Islet Autotransplantation.

Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples (n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p (P = 0.03), hsa-miR-148a-3p (P = 0.04) and hsa-miR-221-3p (P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p (P = 0.04) and hsa-miR-7-5p (P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p (P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p (P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg (r = -0.20, P = 0.02). Also, hsa-miR-200c (r = 0.18, P = 0.03) and hsa-miR-221-3p (r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.

Metabolic measures before surgery and long-term diabetes outcomes in recipients of total pancreatectomy and islet autotransplantation.

In this single-center, retrospective cohort study, we aimed to elucidate simple metabolic markers or surrogate indices of ß-cell function that best predict long-term insulin independence and goal glycemic HbA1c control (HbA1c ≤ 6.5%) after total pancreatectomy with islet autotransplantation (TP-IAT). Patients who underwent TP-IAT (n = 371) were reviewed for metabolic measures before TP-IAT and for insulin independence and glycemic control at 1, 3, and 5 years after TP-IAT. Insulin independence and goal glycemic control were achieved in 33% and 68% at 1 year, respectively. Although the groups who were insulin independent and dependent overlap substantially on baseline measures, an individual who has abnormal glycemia (prediabetes HbA1c or fasting glucose) or estimated IEQs/kg < 2500 has a very high likelihood of remaining insulin dependent after surgery. In multivariate logistic regression modelling, metabolic measures correctly predicted insulin independence in about 70% of patients at 1, 3, and 5 years after TP-IAT. In conclusion, metabolic testing measures before surgery are highly associated with diabetes outcomes after TP-IAT at a population level and correctly predict outcomes in approximately two out of three patients. These findings may aid in prognostic counseling for chronic pancreatitis patients who are likely to eventually need TP-IAT.

Preoperative ERCP has no impact on islet yield following total pancreatectomy and islet autotransplantation (TPIAT): Results from the Prospective Observational Study of TPIAT (POST) cohort.

BACKGROUND AND AIMS: Many patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for severe, refractory chronic pancreatitis or recurrent acute pancreatitis have a history of endoscopic retrograde cholangiopancreatography (ERCP). Using data from the multicenter POST (Prospective Observational Study of TPIAT) cohort, we aimed to determine clinical characteristics associated with ERCP and the effect of ERCP on islet yield. METHODS: Using data from 230 participants (11 centers), demographics, pancreatitis history, and imaging features were tested for association with ERCP procedures. Logistic and linear regression were used to assess association of islet yield measures with having any pre-operative ERCPs and with the number of ERCPs, adjusting for confounders. RESULTS: 175 (76%) underwent ERCPs [median number of ERCPs (IQR) 2 (1-4). ERCP was more common in those with obstructed pancreatic duct (p = 0.0009), pancreas divisum (p = 0.0009), prior pancreatic surgery (p = 0.005), and longer disease duration (p = 0.004). A greater number of ERCPs was associated with disease duration (p < 0.0001), obstructed pancreatic duct (p = 0.006), and prior pancreatic surgery (p = 0.006) and increased risk for positive islet culture (p < 0.0001). Mean total IEQ/kg with vs. without prior ERCP were 4145 (95% CI 3621-4669) vs. 3476 (95% CI 2521-4431) respectively (p = 0.23). Adjusting for confounders, islet yield was not significantly associated with prior ERCP, number of ERCPs, biliary or pancreatic sphincterotomy or stent placement. CONCLUSIONS: ERCP did not appear to adversely impact islet yield. When indicated, ERCP need not be withheld to optimize islet yield but the risk-benefit ratio of ERCP should be considered given its potential harms, including risk for excessive delay in TPIAT.

Type 1 diabetes mellitus in patients with recurrent acute and chronic pancreatitis: A case series.

BACKGROUND/OBJECTIVES: Pancreatogenic diabetes mellitus has been assumed to result from non-immune beta cell destruction when the pancreas is replaced by fibrotic tissue secondary to acute and chronic pancreatitis. We hypothesize that recurrent episodes of pancreatic inflammation may increase the risk for developing ß-cell autoimmunity in susceptible individuals. METHODS: We describe 11 patients who had both recurrent acute and/or chronic pancreatitis and type 1 diabetes (T1D) requiring insulin therapy. RESULTS: All 11 patients had positive autoantibodies and 8 patients tested had minimal to undetectable (7/8) or moderate (1/8) stimulated C-peptide at 12 months after T1D onset. Three had biopsy confirmation of insulitis. CONCLUSIONS: These cases lend support to the theory that pancreatitis may increase risk for T1D. We postulate that the pro-inflammatory conditions of pancreatitis may increase posttranslational protein modifications of ß-cell antigens and neoepitope generation, which are potential initiating events for loss of ß-cell self-tolerance.

The histopathology of SPINK1-associated chronic pancreatitis.

BACKGROUND: The identification of genetic risk factors for chronic pancreatitis, such as PRSS1, CFTR and SPINK1, provides the opportunity to define key pathologic hallmarks and etiologic-specific changes. For example, pancreata from PRSS1 and CFTR patients exhibit progressive lipomatous atrophy without significant fibrosis. Considering the pathology of SPINK1-associated pancreatitis is ill-defined, we examined the pancreata of SPINK1 patients with chronic pancreatitis. METHODS: Histologic sections after total pancreatectomy with islet autotransplantation and associated clinicopathologic data were collected from 28 patients with SPINK1 germline alterations. Clinical findings, germline data, anatomic anomalies and pathologic findings were descriptively evaluated. RESULTS: Patients ranged in age from 5 to 48 years (median, 21.6 years) with abdominal pain between 2 and 25 years (median, 5.8 years). Most patients were SPINK1 heterozygous and 14 (50%) had co-occurring CFTR (n = 12) and CTRC (n = 2) mutations. Other pancreatitis risk factors included anatomic anomalies (n = 9) and tobacco use (n = 1). Overall, 24 (86%) patients had additional pancreatitis-associated germline alterations, SPINK1 homozygosity, anatomic anomalies or environmental factors. Examination of pancreata revealed a sequential pattern of exocrine parenchymal loss and replacement by prominent fibrosis, dependent on the duration of abdominal pain. No malignancies were identified, but low-grade pancreatic intraepithelial neoplasia was present for 2 cases. CONCLUSIONS: Within this descriptive study, SPINK1-associated pancreatitis is characterized by parenchymal fibrosis and suggests divergent pathophysiologic mechanisms from PRSS1 and CFTR-associated pancreatitis. Moreover, SPINK1 patients frequently had additional etiologic factors that did not impact the development of pancreatic fibrosis and may implicate SPINK1 as a disease modifier gene.

Single-Session Endoscopic Ultrasound-Directed Transgastric ERCP ("EDGE") in a Bariatric Patient with Pancreatic Mass and Biliary Obstruction.

This video case report presents a patient with an invasive pancreatic mass and a history of Roux-en-Y gastric bypass surgery who underwent single-session endoscopic ultrasound-directed transgastric ERCP for tissue sampling and biliary stenting with subsequent maintenance of the newly established gastrogastrostomy. The demonstrated technique enables spectrum of endoscopic interventions in gastric bypass patients by facilitating a direct endoscopic passage through the reconnected stomach. Importantly, the method carries a risk of weight regain by essentially reversing the bypass. However, this can be an actual desire in selected cases, e.g., oncologic patients, making it a favorable choice over other alternatives.

Alterations in Enteroendocrine Hormones After Total Pancreatectomy With Islet Autotransplantation.

OBJECTIVE: When total pancreatectomy with islet autotransplantation (TPIAT) is performed for chronic pancreatitis, the pancreas and most of the duodenum are removed, with Roux-en-Y reconstruction of the gastrointestinal tract. Enteroendocrine cells in the intestines and pancreas secrete hormones coordinating digestion and motility, but anatomic reconstruction alters transit of nutrients to these cells. We hypothesized that TPIAT leads to changes in enteroendocrine hormones. METHODS: Glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and pancreatic polypeptide (PP) were measured from mixed-meal tolerance tests of 34 clinical trial participants before and 18 months after TPIAT. Area under the curve of GLP-1 and PYY-stimulated responses were calculated by trapezoidal method, and the PP response was measured as the stimulated max minus baseline (ΔPP). RESULTS: Area under the curve of GLP-1 and PYY increased significantly after TPIAT (GLP-1 average +553.1 pg/mL per minute, P = 0.004; PYY average +4647.9 pg/mL per minute, P = 0.02). ΔPP trended toward lower after TPIAT (average, -52.2 pg/mL, P = 0.06). CONCLUSIONS: In this novel study of enteroendocrine hormones in TPIAT patients, stimulated levels of GLP-1 and PYY were significantly higher after versus before TPIAT. ΔPP was lower after TPIAT, but not significantly. These hormone changes have potential clinical implications that warrant further research.