Lhs1 dependent ERAD is determined by transmembrane domain context.

Transmembrane proteins have unique requirements to fold and integrate into the endoplasmic reticulum (ER) membrane. Most notably, transmembrane proteins must fold in three separate environments: extracellular domains fold in the oxidizing environment of the ER lumen, transmembrane domains (TMDs) fold within the lipid bilayer, and cytosolic domains fold in the reducing environment of the cytosol. Moreover, each region is acted upon by a unique set of chaperones and monitored by components of the ER associated quality control machinery that identify misfolded domains in each compartment. One factor is the ER lumenal Hsp70-like chaperone, Lhs1. Our previous work established that Lhs1 is required for the degradation of the unassembled α-subunit of the epithelial sodium channel (αENaC), but not the homologous ß- and γENaC subunits. However, assembly of the ENaC heterotrimer blocked the Lhs1-dependent ER associated degradation (ERAD) of the α-subunit, yet the characteristics that dictate the specificity of Lhs1-dependent ERAD substrates remained unclear. We now report that Lhs1-dependent substrates share a unique set of features. First, all Lhs1 substrates appear to be unglycosylated, and second they contain two TMDs. Each substrate also contains orphaned or unassembled TMDs. Additionally, interfering with inter-subunit assembly of the ENaC trimer results in Lhs1-dependent degradation of the entire complex. Finally, our work suggests that Lhs1 is required for a subset of ERAD substrates that also require the Hrd1 ubiquitin ligase. Together, these data provide hints as to the identities of as-yet unconfirmed substrates of Lhs1 and potentially of the Lhs1 homolog in mammals, GRP170.

Adipose Stem Cell Therapy Mitigates Chronic Pancreatitis via Differentiation into Acinar-like Cells in Mice.

The objective of this study was to assess the capacity of adipose-derived mesenchymal stem cells (ASCs) to mitigate disease progression in an experimental chronic pancreatitis mouse model. Chronic pancreatitis (CP) was induced in C57BL/6 mice by repeated ethanol and cerulein injection, and mice were then infused with 4 × 105 or 1 × 106 GFP+ ASCs. Pancreas morphology, fibrosis, inflammation, and presence of GFP+ ASCs in pancreases were assessed 2 weeks after treatment. We found that ASC infusion attenuated pancreatic damage, preserved pancreas morphology, and reduced pancreatic fibrosis and cell death. GFP+ ASCs migrated to pancreas and differentiated into amylase+ cells. In further confirmation of the plasticity of ASCs, ASCs co-cultured with acinar cells in a Transwell system differentiated into amylase+ cells with increased expression of acinar cell-specific genes including amylase and chymoB1. Furthermore, culture of acinar or pancreatic stellate cell lines in ASC-conditioned medium attenuated ethanol and cerulein-induced pro-inflammatory cytokine production in vitro. Our data show that a single intravenous injection of ASCs ameliorated CP progression, likely by directly differentiating into acinar-like cells and by suppressing inflammation, fibrosis, and pancreatic tissue damage. These results suggest that ASC cell therapy has the potential to be a valuable treatment for patients with pancreatitis.

A Prospective Randomized Multicenter Trial of Distal Pancreatectomy With and Without Routine Intraperitoneal Drainage.

OBJECTIVE: The objective of this study was to test the hypothesis that distal pancreatectomy (DP) without intraperitoneal drainage does not affect the frequency of grade 2 or higher grade complications. BACKGROUND: The use of routine intraperitoneal drains during DP is controversial. Prior to this study, no prospective trial focusing on DP without intraperitoneal drainage has been reported. METHODS: Patients undergoing DP for all causes at 14 high-volume pancreas centers were preoperatively randomized to placement of a drain or no drain. Complications and their severity were tracked for 60 days and mortality for 90 days. The study was powered to detect a 15% positive or negative difference in the rate of grade 2 or higher grade complications. All data were collected prospectively and source documents were reviewed at the coordinating center to confirm completeness and accuracy. RESULTS: A total of 344 patients underwent DP with (N = 174) and without (N = 170) the use of intraperitoneal drainage. There were no differences between cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, or operative technique. There was no difference in the rate of grade 2 or higher grade complications (44% vs. 42%, P = 0.80). There was no difference in clinically relevant postoperative pancreatic fistula (18% vs 12%, P = 0.11) or mortality (0% vs 1%, P = 0.24). DP without routine intraperitoneal drainage was associated with a higher incidence of intra-abdominal fluid collection (9% vs 22%, P = 0.0004). There was no difference in the frequency of postoperative imaging, percutaneous drain placement, reoperation, readmission, or quality of life scores. CONCLUSIONS: This prospective randomized multicenter trial provides evidence that clinical outcomes are comparable in DP with or without intraperitoneal drainage.

The Impact of Cholecystectomy After Endoscopic Sphincterotomy for Complicated Gallstone Disease.

OBJECTIVES: Cholecystectomy after endoscopic sphincterotomy (ES) is associated with improved outcomes compared to ES alone, however randomized trials have included mainly fit surgical candidates. Our objective was to assess the impact of cholecystectomy after ES among elderly patients, in whom the perceived risks of surgery may be increased and the prevailing bias may be to defer cholecystectomy. METHODS: We performed adjusted analyses comparing clinical outcomes in patients ≥65 years of age who did and did not undergo follow-up cholecystectomy after endoscopic sphincterotomy for choledocholithiasis, ascending cholangitis, or gallstone pancreatitis. We also compared adverse events between the two groups. RESULTS: In the ES alone group, 39.3% of patients experienced a recurrent complication compared with 18.0% in the ES and cholecystectomy group. After adjusting for comorbidities using multivariable regression, cholecystectomy in addition to ES was associated with a reduced risk of recurrent choledocholithiasis (OR 0.38, 95%CI 0.34-0.42, P<0.001), ascending cholangitis (OR 0.28, 95%CI 0.23-0.34, P<0.001), and gallstone pancreatitis (OR 0.35, 95%CI 0.24-0.49, P<0.001) compared to ES alone. This benefit was preserved after propensity score adjustment, in patients ≥75 years of age, and in those with major comorbidities including cancer, heart failure, and liver disease. Serious post-operative complications such as myocardial infarction, pulmonary embolism, and pneumonia were not more common in the cholecystectomy group. CONCLUSIONS: Among older patients, including those with serious comorbidities, cholecystectomy after endoscopic sphincterotomy was associated with a significant and clinically important reduction in recurrent complications compared to sphincterotomy alone. This benefit did not appear to be outweighed by surgical complications, highlighting the importance of cholecystectomy, even in elderly patients whose lifespans may be limited by unrelated conditions.

Autotransplantation of culture-positive islet product: is dirty always bad?

BACKGROUND: In selected patients, total pancreatectomy with islet autotransplantation (TPIAT) effectively relieves pain caused by chronic pancreatitis and ameliorates the brittle diabetes of the apancreatic state. Patients often undergo multiple endoscopic and surgical interventions prior to TPIAT, increasing the risk for pancreas colonization with enteric microorganisms. Little is known of the safety of transplanting islet cells with microbial contamination. METHODS: A prospectively collected database of 80 patients submitted to TPIAT at the Medical University of South Carolina from March 2009 to February 2012 was retrospectively reviewed. Patient charts were reviewed for postoperative infectious complications and organisms identified were compared with those identified in pre-transplant islet cultures. RESULTS: A total of 35 patients (43.8%) had a positive pre-transplant islet cell Gram stain or islet cell culture from the final islet preparation solution. Of these 35 patients, 33 (94.3%) were given antibiotics prophylactically post-transplant for a positive islet Gram stain or culture. Twenty patients (57.1%) receiving Gram stain- or culture-positive islets developed postoperative infectious complications, but only four patients (11.4%) developed infections that concorded with their pre-transplant islet product. CONCLUSIONS: Islet transplant solutions are frequently culture-positive, presumably as a result of prior pancreas intervention. Microbial contamination of islet preparations should not preclude autotransplantation.

A comparative evaluation of transesophageal and transthoracic echocardiography for measurement of left ventricular systolic strain using speckle tracking.

OBJECTIVE: The authors hypothesized that the measurement of strain by speckle tracking with transesophageal echocardiography (TEE) is feasible and comparable to transthoracic echocardiography (TTE). DESIGN: A prospective observational comparative study. SETTING: A university hospital. PARTICIPANTS: Adult patients undergoing elective cardiac surgery. INTERVENTIONS: Structured intraoperative TTE and TEE examination. MEASUREMENTS AND MAIN RESULTS: Images were obtained after the induction of anesthesia from 25 patients to enable speckle tracking of the left ventricle in comparable short- and long-axis (SAX and LAX) views using TTE and TEE. Left ventricular strain was measured offline using both modalities and correlation assessed using the Pearson test with assessment of bias using the Bland-Altman method. Significantly more segments were tracked by TEE than TTE in LAX views but not SAX views. Correlation was moderate between TTE and TEE (r = 0.5-0.6) for longitudinal strain in the LAX views, whereas it was poor for regional radial strain (r = 0.07). Correlation for global circumferential strain was higher for the apical SAX views (r = 0.7) than the basal or mid- SAX views. Speckle tracking by TEE showed excellent reproducibility with small bias. CONCLUSIONS: Strain measured by speckle tracking in TEE correlated moderately with TTE for global strain and poorly for regional strain. This may be explained by differences in scanning frequency and other imaging factors. Nevertheless, because of the high degree of reproducibility, it may be a useful tool to quantify intraoperative changes in ventricular function with TEE. However, equivalence between TTE and TEE cannot be assumed, and limits of comparability should be recognized.

Percutaneous transhepatic islet cell autotransplantation after pancreatectomy for chronic pancreatitis: a novel approach.

BACKGROUND: In selected patients with chronic pancreatitis, extensive pancreatectomy can be effective for the treatment of intractable pain. The resultant morbid diabetes can be ameliorated with islet autotransplantation (IAT). Conventionally, islet infusion occurs intraoperatively after islet processing. A percutaneous transhepatic route in the immediate postoperative period is an alternative approach. METHODS: A prospectively collected database of patients undergoing pancreatectomy with percutaneous IAT (P-IAT) was reviewed. Hospital billing data were obtained and median charges determined and compared with estimated charges for an intraoperative infusion method of IAT (I-IAT). RESULTS: Thirty-six patients (28 women; median age 48 years) underwent pancreatectomy with P-IAT. Median operative time was 232 min (range: 98-395 min) and median estimated blood loss was 500 cc (range: 75-3000 cc). Median time from pancreatic resection to islet transplantation was 269 min (range: 145-361 min). A median of 208 248 IEq (2298 IEq/kg) were harvested. Median peak portal venous pressure during islet infusion was 13 mmHg (range: 5-37 mmHg). Postoperative complications occurred in 15 patients (42%) and included hepatic artery pseudoaneurysm and portal vein thrombosis; the latter occurred in two patients with portal pressures during infusion > 30 mmHg. At a median follow-up of 10.7 months, eight patients (22%) were insulin-free. Median pertinent charges for P-IAT were US$36,318 and estimated median charges for I-IAT were US$56,440. Surgeon time freed by P-IAT facilitated an additional 66 procedures, charges for which amounted to US$463,375. CONCLUSIONS: Percutaneous transhepatic IAT is feasible and safe. Islet infusion in the immediate postoperative period is cost-effective. Further follow-up is needed to assess longterm results.

US Medical Licensing Exam Performance and American Board of Surgery Qualifying and Certifying Examinations.

BACKGROUND: Program directors use US Medical Licensing Exam (USMLE) scores as criteria for ranking applicants. First-time pass rates of the American Board of Surgery (ABS) Qualifying (QE) and Certifying (CE) Examinations have become important measures of residency program quality. USMLE Step 1 will become pass/fail in 2022. STUDY DESIGN: American Board of Surgery QE and CE success rates were assessed considering multiple characteristics of highly ranked (top 20) applicants to 22 general surgery programs in 2011. Chi-square, t-test, Wilcoxon Rank sum, linear and logistic regression were used, as appropriate. RESULTS: The QE and CE first attempt pass rates were 96% (235/244) and 86% (190/221), respectively. QE/CE success was not significantly associated with sex, race, research experience, or publications. Alpha Omega Alpha (AΩA) status was associated with success on the index CE (98% vs 83%; p = 0.008). Step 1 and Step 2 Clinical Knowledge (CK) scores of surgeons who passed QE on their first attempt were higher than scores of those who failed (Step 1: 233 vs 218; p = 0.016); (Step 2CK: 244 vs 228, p = 0.009). For every 10-point increase in Step 1 and 2CK scores, the odds of passing CE on the first attempt increased 1.5 times (95% CI 1.12, 2.0; p = 0.006) and 1.5 times (95% CI 1.11, 2.02, p = 0.008), respectively. For every 10-point increase in Steps 1 and 2CK scores, the odds of passing the QE on the first attempt increased 1.85 times (95% CI 1.11, 3.09; p = 0.018) and 1.86 times (95% CI 1.14, 3.06, p = 0.013), respectively. CONCLUSIONS: USMLE Step 1 and Step 2 CK examination scores correlate with American Board of Surgery QE and CE performance and success. The USMLE decision to transition Step 1 to a pass/fail examination will require program directors to identify other factors that predict ABS performance for ranking applicants.

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.

Mucinous cystic neoplasms of the pancreas: how much preoperative evaluation is needed?

Cystic lesions of the pancreas are identified with increasing frequency by modern imaging. The mucinous cystic neoplasm (MCN) is treated with resection for its malignant potential. How much preoperative evaluation is needed before undertaking operation is frequently a diagnostic dilemma. A retrospective review of 32 patients who underwent resection of a MCN between 1994 and 2007 was performed to define the preoperative evaluation and operative treatment of MCN patients. Thirty-two patients (30 women; mean age 49) had histology-proven MCN. Twenty-seven patients had symptomatic cysts (84%). Five had a history of gallstones and/or acute pancreatitis. All patients were worked up with CT and/or MRI. Endoscopic ultrasound was performed in 14 (44%) and endoscopic retrograde cholangiopancreatography in six (18%). Cytology was obtained in 13 (40%). Pathology revealed 22 benign MCNs (68%), five malignant MCNs (16%), and five MCNs with borderline pathology. Preoperative workup including CT or MRI imaging and cytology suggested MCN as the lesion in 15 patients (46%). CT features by itself predicted MCN in three patients (9%). Cytology revealed another six patients (19%) with possible MCN. In this series, preoperative workup did not identify three of five patients with MCN malignancy. A preoperative diagnosis cannot be made in most patients with MCN. Operative treatment can be based on clinical presentation and CT imaging because endoscopic ultrasound and fine needle aspiration for evaluation may be misleading. Middle-aged women with cystic lesions in the tail of the pancreas without prior gallstone or pancreatitis history most typically fit the profile of the MCN patient.

Pancreatic cyst: pseudocyst or neoplasm? Pitfalls in endoscopic retrograde cholangiopancreatography diagnosis.

Pancreatic pseudocysts represent the majority of cystic lesions, and can usually be differentiated from cystic neoplasms, which have malignant potential. Endoscopic retrograde cholangiopancreatography (ERCP) can help in solving diagnostic dilemmas. When ERCP demonstrates cyst communication with the pancreatic duct, the diagnosis of pseudocyst is usually secure. There are exceptions, however, as reported in these two case reports. A retrospective chart review was conducted of two patients undergoing distal pancreatectomy in 2008 to 2009 for cystic lesions communicating with the main pancreatic duct on ERCP. Both patients were women (ages 37 and 42) with a history of chronic abdominal pain and pancreatitis. Radiologic imaging showed cystic lesions in the pancreatic tail. ERCP demonstrated main pancreatic duct communication. When endoscopic management failed, surgical therapy was undertaken. Both patients underwent distal pancreatectomy with splenectomy. Pathologic findings were mucinous cystadenoma. The conventional wisdom that a pancreatic cyst communicating with the main pancreatic duct is a benign pseudocyst is not always wise. As seen in this series, mucinous cystadenomas can erode into the main pancreatic duct. Women in the fourth and fifth decade with symptomatic cysts in the pancreatic tail with a history of pancreatitis should undergo distal pancreatectomy, regardless of ductal communication on ERCP.

Revision of anastomotic stenosis after pancreatic head resection for chronic pancreatitis: is it futile?

BACKGROUND: Because survival after pancreaticoduodenectomy for cancer is limited, it is difficult to assess longterm pancreaticojejunal anastomotic patency. However, in patients with benign disease, pancreaticojejunal anastomotic stenosis may become problematic. What happens when pancreaticojejunal anastomosis revision is undertaken? METHODS: Patients undergoing pancreatic anastomotic revision after pancreatic head resection for benign disease between 1997 and 2007 at the Medical University of South Carolina were identified. A retrospective chart review and analysis were undertaken with the approval of the Institutional Review Board for the Evaluation of Human Subjects. Longterm follow-up was obtained by patient survey at a clinic visit or by telephone. RESULTS: During the study period, 237 patients underwent pancreatic head resection. Of these, 27 patients (17 women; median age 42 years) underwent revision of pancreaticojejunal anastomosis. Six patients (22%) had a pancreatic leak or abscess at the time of the index pancreatic head resection. The indication for revision of anastomosis was intractable pain. All patients underwent preoperative magnetic resonance cholangiopancreatography (MRCP), which indicated anastomotic stricture in 18 patients (63%). Nine other patients underwent exploration based on clinical suspicion caused by recurrent pancreatitis and stenosis was confirmed at the time of surgery. Six patients (22%) had perioperative complications after revision. The median length of stay was 12 days. There were no perioperative deaths; however, late mortality occurred in four patients (15%). Six of 23 survivors (26%) at the time of follow-up (median 56 months) reported longterm pain relief. CONCLUSIONS: Stricture of the pancreaticojejunal anastomosis after pancreatic head resection presents with recurrent pancreatitis and pancreatic pain. MRCP has good specificity in the diagnosis of anastomotic obstruction, but lacks sensitivity. Pancreaticojejunal revision is safe, but rarely effective, as a means of pain relief in patients with the pain syndrome associated with chronic pancreatitis.

Artificial Intelligence and Echocardiography: A Primer for Cardiac Sonographers.

Artificial intelligence (AI) is emerging as a key component in diagnostic medical imaging, including echocardiography. AI with deep learning has already been used with automated view labeling, measurements, and interpretation. As the development and use of AI in echocardiography increase, potential concerns may be raised by cardiac sonographers and the profession. This report, from a sonographer's perspective, focuses on defining AI, the basics of the technology, identifying some current applications of AI, and how the use of AI may improve patient care in the future.

Management of common bile duct injury during partial gastrectomy.

Injury to the common bile duct (CBD) during upper gastrointestinal surgery for peptic ulcer disease is a serious complication with an underestimated prevalence in light of the few cases reported in the surgical literature. Three cases of CBD injury were referred to a multidisciplinary specialized gastrointestinal unit for management over a 4-year period. Anomalous anatomy, adhesions, and potential duodenal shortening secondary to contracture all predispose the biliary ducts to intraoperative injury. The axial nature of the blood supply to the extrahepatic ducts and the tendency of bile itself to cause rapid collagen turnover and fibrosis, combined with the inflammation and subsequent fibrosis to the surrounding tissues caused by bile leakage, give the bile ducts a high propensity for stricture formation. Frequently presenting symptoms of CBD injury immediately after surgery include jaundice, elevated bilirubin values, elevated t-tube drainage, and symptoms of sepsis. The most common complaints noted in patients who present in a delayed manner are symptoms of cholangitis. Even when injuries are rapidly identified and corrected, the potential for lasting negative impact on quality of life is great in many cases. When CBD injury occurs, the pancreatic duodenal union can be concomitantly disrupted.

Endoscopic retrograde cholangiopancreatography gut perforations: when to wait! When to operate!

Most perforations of the gastrointestinal tract during endoscopic retrograde cholangiopancreatography (ERCP) can be managed nonoperatively. Identifying patients who require operative management is problematic. A clinical endoscopy database was queried for patients who sustained ERCP perforation over a 13-year period. Records were reviewed and analyzed with approval of the Institutional Review Board. During the study period, 12,817 patients underwent ERCP; 24 (0.2%) had an endoscopic perforation. Twelve patients had a retroperitoneal perforation during sphincterotomy and all were successfully managed nonoperatively. Nine of these were undergoing treatment for sphincter of Oddi dysfunction. Twelve patients had perforation remote from the papilla. Of these, 10 required surgical intervention. Six patients had surgically altered anatomy (three postpancreaticoduodenectomy, three post-Billroth II gastrectomy) and one had situs inversus. Six of these seven required surgical intervention. Median length of stay of all patients was 7.5 days, morbidity was 25 per cent, and one patient died 16 days after surgery. Gut perforation after ERCP requires prompt surgical evaluation. Patients with sphincterotomy-related retroperitoneal perforation can be managed safely with nonoperative therapy in most instances. Patients with remote perforation usually need surgical intervention. Altered foregut anatomy leads to injuries that usually require operative management.

The Impact of Endoscopic Retrograde Cholangiopancreatography on Islet Cell Yield During Total Pancreatectomy With Islet Autotransplantation.

OBJECTIVES: Many patients with recurrent acute and chronic pancreatitis who are candidates for total pancreatectomy and islet cell autotransplantation (TPIAT) undergo endoscopic retrograde cholangiopancreatography (ERCP). However, little is known on the impact of ERCP on TPIAT outcomes. We aimed to explore the effect of antecedent ERCP on islet yield and postoperative insulin requirement after TPIAT. METHODS: Through a prospectively maintained database, we identified patients who underwent TPIAT at our institution between 2009 and 2016. After adjusting for confounders, islet cell yield and postoperative insulin requirement were compared between subjects who did and did not undergo ERCP within 2 years prior to TPIAT. RESULTS: Data were available on 167 TPIAT patients during the study period; 105 (62.9%) had undergone ERCP within 2 years prior. Prior ERCP was not associated with a reduction in islet equivalents per patient kilogram (odds ratio, 1.37; 95% confidence interval, 0.75-2.5; P = 0.31). Antecedent ERCP was not associated with increased postoperative insulin requirement among patients with no diabetes undergoing TPIAT (odds ratio, 0.85; 95% confidence interval, 0.39-1.83; P = 0.67). CONCLUSIONS: Antecedent ERCP does not appear to have a deleterious impact on islet cell yield during TPIAT. Additional multicenter data are needed to more clearly determine the impact of ERCP in this context.

Mesenchymal Stem Cells from Chronic Pancreatitis Patients Show Comparable Potency Compared to Cells from Healthy Donors.

Mesenchymal stem cells (MSCs) are proven to be beneficial in islet transplantation, suggesting a potential therapeutic role of them in total pancreatectomy with islet autotransplantation (TP-IAT) for chronic pancreatitis (CP) patients. We investigated whether MSCs derived from CP patients are suitable for use in autologous cell therapy. MSCs from healthy donors (H-MSCs) and CP patients (CP-MSCs) were studied for phenotype, colony formation potential, multilineage differentiation ability, proliferation, senescence, secretory characters, and immunosuppressive functions. The potential protective effect of CP-MSCs was evaluated on hypoxia-induced islet cell death. Cell surface markers were similar between H-MSCs and CP-MSCs, as well as the ability of colony formation, multilineage differentiation, secretion of vascular endothelial growth factor and transforming growth factor (TGF-ß), senescence, and inhibition of T cells proliferation in vitro. We found that growth differentiation factor 6 and hepatocyte growth factor (HGF) were significantly downregulated, whereas TGFß and matrix metalloproteinase-2 were significantly upregulated in CP-MSCs compared with H-MSCs, among 84 MSC-related genes investigated in this study. MSCs from CP patients secreted less HGF, compared with the H-MSCs. A higher interferon-γ-induced indoleamine 2,3-dioxygenase expression was observed in CP-MSCs compared to H-MSCs. Moreover, CP-MSCs prevented hypoxia-induced ß cell deaths to a similar extent as H-MSCs. Regardless of moderate difference in gene expression, CP-MSCs possess similar immunomodulatory and prosurvival functions to H-MSCs, and may be suitable for autologous cell therapy in CP patients undergoing TP-IAT. Stem Cells Translational Medicine 2019;8:418-429.

Islet Harvest in Carbon Monoxide-Saturated Medium for Chronic Pancreatitis Patients Undergoing Islet Autotransplantation.

Stresses encountered during human islet isolation lead to unavoidable ß-cell death after transplantation. This reduces the chance of insulin independence in chronic pancreatitis patients undergoing total pancreatectomy and islet autotransplantation. We tested whether harvesting islets in carbon monoxide-saturated solutions is safe and can enhance islet survival and insulin independence after total pancreatectomy and islet autotransplantation. Chronic pancreatitis patients who consented to the study were randomized into carbon monoxide (islets harvested in a carbon monoxide-saturated medium) or control (islets harvested in a normal medium) groups. Islet yield, viability, oxygen consumption rate, ß-cell death (measured by unmethylated insulin DNA), and serum cytokine levels were measured during the peri-transplantation period. Adverse events, metabolic phenotypes, and islet function were measured prior and at 6 months post-transplantation. No adverse events directly related to the infusion of carbon monoxide islets were observed. Carbon monoxide islets showed significantly higher viability before transplantation. Subjects receiving carbon monoxide islets had less ß-cell death, decreased CCL23, and increased CXCL12 levels at 1 or 3 days post transplantation compared with controls. Three in 10 (30%) of the carbon monoxide subjects and none of the control subjects were insulin independent. This pilot trial showed for the first time that harvesting human islets in carbon monoxide-saturated solutions is safe for total pancreatectomy and islet autotransplantation patients.

A Study on the Effect of Patient Characteristics, Geographical Utilization, and Patient Outcomes for Total Pancreatectomy Alone and Total Pancreatectomy With Islet Autotransplantation in Patients With Pancreatitis in the United States.

OBJECTIVES: A selective therapy for pancreatitis is total pancreatectomy and islet autotransplantation. Outcomes and geographical variability of patients who had total pancreatectomy (TP) alone or total pancreatectomy with islet autotransplantation (TPIAT) were assessed. METHODS: Data were obtained from the Healthcare Cost and Utilization Project National Inpatient Sample database. Weighed univariate and multivariate analyses were performed to determine the effect of measured variables on outcomes. RESULTS: Between 2002 and 2013, there were 1006 TP and 825 TPIAT in patients with a diagnosis of chronic pancreatitis, and 1705 TP and 830 TPIAT for any diagnosis of pancreatitis. The majority of the TP and TPIAT were performed in larger urban hospitals. Costs were similar for TP and TPIAT for chronic pancreatitis but were lower for TPIAT compared with TP for any type of pancreatitis. The trend for TP and TPIAT was significant in all geographical areas during the study period. CONCLUSIONS: There is an increasing trend of both TP and TPIAT. Certain groups are more likely to be offered TPIAT compared with TP alone. More data are needed to understand disparities and barriers to TPIAT, and long-term outcomes of TPIAT such as pain control and glucose intolerance need further study.