Transgastric pancreatic necrosectomy: Tricks of the trade.

Necrotizing pancreatitis (NP) affects 20 % of the 300,000 patients diagnosed with acute pancreatitis every year. Mechanical intervention to debride necrotic and/or infected pancreatic and peripancreatic tissue is frequently required. Minimally invasive approaches to treat pancreatic necrosis have gained popularity over the last two decades, including transgastric pancreatic necrosectomy. The purpose of this report is to review the indications, surgical technique, advantages, and limitations of surgical transgastric necrosectomy.

Neoadjuvant therapy at local versus outside institutions does not adversely impact surgical timing or long-term outcomes in patients with pancreatic adenocarcinoma.

BACKGROUND: Although high-volume centers are known to have better surgical outcomes, patients with pancreatic adenocarcinoma often receive chemotherapy at treatment centers closer to home. This study aimed to determine whether treatment site of neoadjuvant therapy relative to surgery location impacts surgical timing and long-term outcomes. METHODS: All patients with pancreatic adenocarcinoma who underwent oncologic resection at a single, high-volume institution between January 2016 and February 2020 and had neoadjuvant chemotherapy before surgery were queried from a prospectively maintained database. Patients were sorted based on location of neoadjuvant chemotherapy. RESULTS: A total of 179 patients were included in the study. Seventy-four (41.3%) patients received neoadjuvant chemotherapy at the same institution as their surgery (group A), 20 (11.2%) received chemotherapy outside of their surgical institution but within the same hospital/healthcare system (group B), and 85 (47.5%) received chemotherapy at an outside location (group C). The time from completion of neoadjuvant therapy to surgery was not significantly different between groups (A vs B vs C median [interquartile range]: 34.5 [14] vs 41.5 [24] vs 36 [22] days, P = .08). Thirty-day readmission rate was lower in group A (n (%): 1 (1.4%) vs 2 (10.0%) vs 11 (12.9%), P = .02). However, the 90-day mortality and overall survival did not differ significantly between groups. CONCLUSION: Patients may receive neoadjuvant therapy at local centers without impacting surgical scheduling. Although these patients may experience higher postoperative readmission rates, perioperative mortality and long-term survival are not adversely affected by location of chemotherapy. Multidisciplinary care can be effectively practiced in different locations without affecting overall outcomes in patients with pancreatic adenocarcinoma.

Readmission in acute pancreatitis: Etiology, risk factors, and opportunities for improvement.

Acute pancreatitis is associated with a readmission rate ranging from 7 to 34%. Readmission rates are highest among biliary (4-37%) and alcohol-induced (2-60%) acute pancreatitis. Severe acute pancreatitis and necrotizing pancreatitis have readmission rates ranging from 20 to 75%. The most common causes of readmission include recurrent acute pancreatitis (17-45% of readmissions) and smoldering symptoms/local complications (17-38%). A number of risk scores reliably estimate risk of readmission in acute pancreatitis. Decreased rates of readmission were reported in patients that underwent same-admission cholecystectomy in biliary pancreatitis and alcohol cessation interventions in alcohol-induced pancreatitis. This review article discusses readmission in acute pancreatitis, including etiology, risk factors, and opportunities for improved patient care.

Obesity Worsens Local and Systemic Complications of Necrotizing Pancreatitis and Prolongs Disease Course.

BACKGROUND: Obesity is epidemic in the USA. Limited data exist examining obesity's influence on necrotizing pancreatitis (NP) disease course. METHODS: Retrospective review of prospectively maintained database of 571 adult necrotizing pancreatitis patients treated between 2007 and 2018. Patients were grouped according to body mass index (BMI) at disease onset. Patient characteristics, necrotizing pancreatitis course, and outcomes were compared between non-obese (BMI < 30) and obese (BMI > 30) patients. RESULTS: Among 536 patients with BMI data available, 304 (57%) were obese (BMI > 30), and 232 (43%) were non-obese (BMI < 30). NP etiology in the obese group was more commonly biliary (55% versus 46%, p = 0.04) or secondary to hypertriglyceridemia (10% versus 2%, p < 0.001) and less commonly alcohol (17% versus 26%, p = 0.01). Obese patients had a higher incidence of baseline comorbid disease. The CT severity index was similar between groups though obese patients had a higher rate of > 50% pancreatic gland necrosis (27% versus 19%, p = 0.02). The rates of infected necrosis and organ failure were higher among obese patients. Percutaneous drainage was more common in obese patients. Time to first necrosis intervention was earlier with increasing BMI. NP disease duration was longer in obese patients. The overall mortality rate of non-obese and obese patients did not differ. However, mortality rate increased with increasing BMI. CONCLUSION: Necrotizing pancreatitis in obese patients is characterized by a prolonged disease course, a higher risk of organ failure, infected necrosis, and the need for early necrosis-related intervention. Mortality increases with increasing BMI.

Pancreatitis associated anxiety, depression, and stress: Hypothesis, definition, and intervention.

Necrotizing pancreatitis is characterized by a prolonged disease course requiring frequent hospitalization and intervention. Necrotizing pancreatitis patients have high rates of intensive care unit admission and organ failure. Critical illness is an identified risk factor for the development of anxiety, depression, and posttraumatic stress disorder. Limited literature examines quality of life in necrotizing pancreatitis patients, and studies examining psychiatric sequalae of necrotizing pancreatitis including depression, anxiety, and posttraumatic stress disorder are virtually nonexistent. Here, we review critical literature examining risk factors for poor mental health outcomes during and after necrotizing pancreatitis, identify several screening instruments to quantify mental health outcomes, and propose an intervention to improve mental health outcomes in patients with necrotizing pancreatitis. We conclude that establishing the incidence of mental health disorders and implementing strategies to improve mental health outcomes are critical to holistic care of necrotizing pancreatitis patients.

Contemporary Intervention in Necrotizing Pancreatitis: Improved Understanding Changing Practice.

BACKGROUND: Treatment of necrotizing pancreatitis (NP) has shifted in favor of a minimally invasive step-up approach rather than early open pancreatic debridement. We hypothesized that this paradigm shift would be reflected in the intervention, morbidity, and mortality profile of NP patients. STUDY DESIGN: Single-institution retrospective review of 767 NP patients treated between 2005 and 2019. Two eras of NP intervention were identified relative to the introduction of a minimally invasive approach to NP. Patients treated between 2005 and 2010 were classified as the "early" group and compared with patients treated between 2011 and 2019, classified as the "late" group. RESULTS: In total, 299 NP patients comprised the early group and 468 patients comprised the late group. No differences were seen in patient demographics, comorbidity profile, or NP etiology between groups. Necrosis volume, necrosis location, CT severity index (CTSI), and rates of infected necrosis were similar between groups. No difference was seen in mortality. Mechanical intervention for NP was more common in the early than the late group (86% vs. 73%, p < 0.001). Time to first intervention was similar between groups (79 ± 7d vs. 75 ± 6d). The early group had higher rates of open pancreatic debridement (72% vs. 55%, p < 0.001). Endoscopic intervention was less common in the early than the late group (7% vs. 16%, p < 0.001). NP disease duration was longer in the early than the late group (223 ± 12d vs. 179 ± 7d, p = 0.001). CONCLUSION: Contemporary management of necrotizing pancreatitis is marked by less frequent operative debridement and shorter disease duration.

Early postoperative serum hyperamylasemia: Harbinger of morbidity hiding in plain sight?

BACKGROUND: The clinical significance of postoperative serum pancreatic enzyme elevation after pancreatoduodenectomy is understudied. We hypothesized that elevation in serum enzymes predicts morbidity and mortality after pancreatoduodenectomy. METHODS: Retrospective review of 677 patients who underwent pancreatoduodenectomy at a single institution from 2013 to 2019. Patients were categorized based on serum enzyme concentrations. Patient characteristics, drain amylase, and outcomes among groups were compared. RESULTS: In total, 415 of 677 patients had postoperative serum amylase concentrations measured. Of these, 243 (59%) were normal, 96 (23%) were classified as postoperative serum hyperamylasemia, and 76 (18%) were classified as postoperative acute pancreatitis. Major morbidity was lower among patients with normal enzyme concentration (10%) and higher in patients with postoperative serum hyperamylasemia (23%) and postoperative acute pancreatitis (18%) (P = .008). Patients with normal enzymes were less likely to develop postoperative pancreatic fistula (5%) compared with patients with postoperative serum hyperamylasemia (26%) and postoperative acute pancreatitis (21%) (P < .001) and less likely to develop delayed gastric emptying (9% vs 23% and 20%, respectively); P = .002. No difference in mortality was seen among groups. CONCLUSION: Elevated serum pancreatic enzyme concentration occurs frequently after pancreatoduodenectomy and is associated with increased postoperative morbidity. Serum enzyme concentration should be considered in management after pancreatoduodenectomy.

Outcomes in Endoscopic and Operative Transgastric Pancreatic Debridement.

OBJECTIVES: Select patients with anatomically favorable walled off pancreatic necrosis may be treated by endoscopic (Endo-TGD) or operative (OR-TGD) transgastric debridement (TGD). We compared our experience with these 2 approaches. SUMMARY BACKGROUND DATA: Select necrotizing pancreatitis (NP) patients are suitable for TGD which may be accomplished endoscopically or surgically. Limited experience exists contrasting these techniques exists. METHODS: Patients undergoing Endo-TGD and OR-TGD at a single, high-volume pancreatic center between 2008 and 2019 were identified from a prospective database. Patient characteristics, procedural details, and outcomes of these 2 groups were compared. RESULTS: Among 498 NP patients undergoing necrosis intervention, 160 (32%) had TGD: 59 Endo-TGD and 101 OR-TGD. The groups were statistically similar in age, comorbidity, pancreatitis etiology, necrosis anatomy, pancreatitis severity, and timing of TGD from pancreatitis insult. OR-TGD required 1.1 ±â€Š0.5 and Endo-TGD 3.0 ±â€Š2.0 debridements/patient. Fewer hospital readmissions and repeat necrosis interventions, and shorter total inpatient length of stay were observed in OR-TGD patients. New-onset organ failure [Endo-TGD (13%); OR-TGD (13%); P = 1.0] was similar between groups. Hospital length of stay after TGD was significantly longer in patients undergoing Endo-TGD (13.8 ±â€Š20.8 days) compared to OR-TGD (9.4 ±â€Š6.1 days; P = 0.047). Mortality was 7% in Endo-TGD and 1% in OR-TGD (P = 0.04). CONCLUSIONS: Operative and endoscopic transgastric debridement achieve necrosis resolution with different temporal and procedural profiles. Clear multidisciplinary communication is essential to determine appropriate approach to individual necrotizing pancreatitis patients.

Prospective Analysis of the Mechanisms Underlying Ineffective Deep Vein Thrombosis Prophylaxis in Necrotizing Pancreatitis.

BACKGROUND: Patients with necrotizing pancreatitis (NP) have the highest rate of venous thromboembolism (VTE) of any hospitalized patient (57%). We hypothesized that VTE prophylaxis might be inadequate in the setting of this profound inflammatory disease and that early detection of deep vein thrombosis would limit pulmonary embolism. STUDY DESIGN: All patients with NP treated at a single center between August 2018 and December 2019 were enrolled in prospective, weekly VTE screening, including 4-extremity duplex ultrasound. Routine chemoprophylaxis included low-molecular-weight or unfractionated heparin. Peak serum anti-factor Xa concentration was measured during weekly screening (goal prophylaxis 0.2 to 0.4 IU/mL). RESULTS: Eighty-five patients with NP underwent a total of 201 screening events (mean 2.4 per patient). VTE developed in 55 patients (65%), including splanchnic vein thrombosis in 41 patients (48%) and extremity deep vein thrombosis (eDVT) in 32 patients (38%). Extremity DVT was diagnosed a mean ± SD of 44 ± 30 days after NP onset. Symptomatic pulmonary embolism was prevented in all patients diagnosed with eDVT and no contraindication to anticoagulation (0 of 29). Prophylactic anti-factor Xa concentration was only achieved in 21% (12 of 57 screening events); no eDVTs developed in patients achieving prophylactic anti-factor Xa concentration. CONCLUSIONS: In patients with NP, identification of eDVT by screening ultrasound permits early treatment and prevents symptomatic pulmonary embolism. Fixed dosing of chemical prophylaxis is inadequate in most patients with NP and likely contributes to the mechanism of increased VTE in NP.

Duodenal complications in necrotizing pancreatitis: Challenges of an overlooked complication.

BACKGROUND: Duodenal complications of necrotizing pancreatitis (NP) are challenging and understudied. We sought to characterize the demographics and clinical course of NP patients with duodenal complications. METHODS: Single institution retrospective review of 687 NP patients treated from 2005 to 2018. RESULTS: Duodenal complications developed in 40 (6%) patients including fistula in 11 (2%) and stricture in 29 (4%) patients. Patients with duodenal complications had increased computed tomography severity index (CTSI), degree of glandular necrosis, organ failure, infected necrosis, and disease duration. Mortality from NP was increased in patients with duodenal fistula (36%) compared to patients with duodenal stricture (7%) and patients without duodenal complications (9%). Surgical management of duodenal complications was required in 9/11 (82%) patients with fistula and 17/29 (59%) patients with stricture. CONCLUSIONS: Duodenal complications occurred in 6% of necrotizing pancreatitis patients. Sixty five percent of patients with duodenal complications required surgical correction. Duodenal fistula was associated with increased mortality.

Routine Venous Thromboembolism Prophylaxis May Be Inadequate in the Hypercoagulable State of Severe Coronavirus Disease 2019.

OBJECTIVES: The aim of this study was to determine the frequency of venous thromboembolism in critically ill coronavirus disease 2019 patients and associate a degree of inflammatory marker elevation to venous thromboembolism development. DESIGN: An observational study that identified patients with severe coronavirus disease 2019 between March 12, 2020, and March 31, 2020. Data reported are those available through May 6, 2020. SETTING: A multicenter study including three Indianapolis area academic hospitals. PATIENTS: Two-hundred forty consecutive patients with confirmed severe acute respiratory syndrome coronavirus 2 infection were admitted to one of three hospitals. One-hundred nine critically ill coronavirus disease 2019 patients admitted to the ICU were included in the analysis. INTERVENTIONS: All patients received routine subcutaneous chemical venous thromboembolism prophylaxis. MEASUREMENTS AND MAIN RESULTS: The primary outcome of this study was to determine the frequency of venous thromboembolism and the degree of inflammatory and coagulation marker elevation associated with venous thromboembolism development. Descriptive statistics outlined the frequency of venous thromboembolism at any time during severe coronavirus disease 2019. Clinical course and laboratory metrics were compared between patients that developed venous thromboembolism and patients that did not develop venous thromboembolism. Hypercoagulable thromboelastography was defined as two or more hypercoagulable parameters. MAIN RESULTS: One-hundred nine patients developed severe coronavirus disease 2019 requiring ICU care. The mean (± SD) age was 61 ± 16 years and 57% were male. Seventy-five patients (69%) were discharged home, 7 patients (6%) remain in the hospital, and 27 patients (25%) died. Venous thromboembolism was diagnosed in 31 patients (28%) 8 ± 7 days after hospital admission, including two patients diagnosed with venous thromboembolism at presentation to the hospital. Elevated admission D-dimer and peak D-dimer were associated with venous thromboembolism development (p < 0.05). D-dimer greater than 2,600 ng/mL predicted venous thromboembolism with an area under the receiver operating characteristic curve of 0.760 (95% CI, 0.661-0.858; p < 0.0001), sensitivity of 89.7%, and specificity of 59.5%. Twelve patients (11%) had thromboelastography performed and 58% of these patients had a hypercoagulable study. The calculated coagulation index was hypercoagulable in 50% of patients with thromboelastography. CONCLUSIONS: These data show that coronavirus disease 2019 results in a hypercoagulable state. Routine chemical venous thromboembolism prophylaxis may be inadequate in preventing venous thromboembolism in severe coronavirus disease 2019.

Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma.

Conjunctival melanoma (CM) is a rare ocular malignancy with a high tendency to reoccur locally and with a high risk of metastatic disease. Metastases are often unresponsive to conventional treatment. Recently, an animal model was set up using human CM cells. Orthotopic xenografts from human CM were created by subconjunctival injection of three different CM cell lines into NOD.Cg-Prkdcscid IL2rgtm1Wjl /SzJ (NSG) mice. Subconjunctival injection of cultured CM cells led to excellent subconjunctival growth, but no metastases were found. When single-cell suspensions were obtained from the subconjunctival xenografts and passaged in vivo, all mice developed metastases. As recent findings indicate that cancer stem cells are linked to tumor recurrences, we used this new murine model to determine the expression of the stem cell marker ABCB5 during tumor progression. Expression of the ABCB5 protein was determined in three cell lines and during different stages of tumor development as observed in our model. All three cell lines contained a subpopulation of cells positive for ABCB5. During tumor development, expression of ABCB5 increased during phases of tumor expansion. Furthermore, expression of ABCB5 was increased in metastases. Using this model for CM, we were able to initiate metastatic spread and determine the expression of the stem cell marker ABCB5 during different stages of tumor development, identifying ABCB5 as a potential novel therapeutic target. This study illustrates the potential of our newly established murine model.

A Murine Model for Metastatic Conjunctival Melanoma.

PURPOSE: Conjunctival melanoma (CM) is an ocular malignancy with a high rate of local recurrences after treatment, and can give rise to deadly metastases. The establishment of a murine model will further our understanding of this disease and allow in vivo testing of new therapies. We therefore analyzed the ability of three CM cell lines to grow orthotopically and spread to distant sites. Furthermore, we determined the characteristics of the xenografts and their metastases. METHODS: Orthotopic xenografts of human CM were established by subconjunctival injection of three different CM cell lines into NOD/SCID IL2 rγnull mice. Single-cell suspensions were generated from the primary tumors and placed subconjunctivally in another set of mice, which were then screened for metastases. The presence of melanoma markers was determined on the cell lines and during tumor development. RESULTS: Subconjunctival injection of cultured CM cells into immunodeficient mice led to excellent subconjunctival tumor growth in all inoculated mice (n = 101) within 2 weeks; however, no metastases were found at the time of autopsy. Serial in vivo passage of primary tumor cells resulted in metastatic tumors in the draining lymph nodes (n = 21). The CM cell lines, as well as the tumor xenografts and their metastases, were positive for the melanoma markers HMB-45, S100B, and MART-1. Two cell lines and their corresponding xenografts carried a BRAF mutation, the third showed an NRAS mutation. CONCLUSIONS: We established a murine model for CM that shows excellent formation of metastases in a pattern that accurately resembles metastatic human CM following in vivo passaging.

ABCB5 is a limbal stem cell gene required for corneal development and repair.

Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs), and LSC deficiency is a major cause of blindness worldwide. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts, a gene allowing for prospective LSC enrichment has not been identified so far. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5) marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs in mice and p63α-positive LSCs in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.