How I do it. Pancreatojejunostomy: surgical tips to mitigate the severity of postoperative pancreatic fistulas after open or minimally invasive pancreatoduodenectomy.

Pancreatoduodenectomy is the most appropriate technique for the treatment of periampullary tumors. In the past, this procedure was associated with high mortality and morbidity, but with improvements in patient selection, anesthesia, and surgical technique, mortality has decreased to less than 5%. However, morbidity remains increased due to various complications such as delayed gastric emptying, bleeding, abdominal collections, and abscesses, most of which are related to the pancreatojejunostomy leak. Clinically relevant postoperative pancreatic fistula is the most dangerous and is related to other complications including mortality. The incidence of postoperative pancreatic fistula ranges from 5-30%. Various techniques have been developed to reduce the severity of pancreatic fistulas, from the use of an isolated jejunal loop for pancreatojejunostomy to binding and invagination anastomoses. Even total pancreatectomy has been considered to avoid pancreatic fistula, but the late effects of this procedure are unacceptable, especially in relatively young patients. Recent studies on the main techniques of pancreatojejunostomy concluded that duct-to-mucosa anastomosis is advisable, but no technique eliminates the risk of pancreatic fistula. The purpose of this study is to highlight technical details and tips that may reduce the severity of pancreatic fistula after pancreatojejunostomy during open or minimally invasive pancreatoduodenectomy.

Minimally Invasive Resection of the Uncinate Process of the Pancreas: Anatomical Considerations and Surgical Technique.

BACKGROUND: Low-grade lesions may benefit from pancreatic-sparing techniques. Resection of the uncinate process is rarely performed and reported due to its complexity that requires careful patient selection and accurate knowledge of the pancreatic anatomy. This study describes relevant anatomical elements to safely perform this complex operation in the minimally invasive setting. METHODS: In this study, consecutive patients undergoing resection of the uncinate process of the pancreas were studied. Patients undergoing open approach were used for comparison. Preoperative and intraoperative variables were recorded, and the diagnosis and tumor size were determined from the pathology reports. Immediate postoperative results and hospital stay were analyzed. Follow-up was used to assess long-term complications and endocrine and exocrine functions. RESULTS: Twenty-nine patients underwent resection of the uncinate process. The median age was 57 years. There were 21 males and eight females. Twenty patients underwent minimally invasive resection (14 laparoscopic and six by robotic approach) and nine were operated by open approach. A clinically relevant postoperative pancreatic fistula was observed in one patient (3.4%). Biochemical leakage was present in 44.8% of our patients. Mean follow-up was 62 months (3-147). Two patients needed reoperation during follow-up. No patient presented exocrine or endocrine insufficiency during late follow-up. CONCLUSION: Minimally invasive resection of the uncinate process of the pancreas is a complex but a feasible procedure that preserves the pancreatic endocrine and exocrine functions. This pancreas-sparing procedure is an interesting alternative to pancreaticoduodenectomy in selected patients.

Sodium Taurocholate Induced Severe Acute Pancreatitis in C57BL/6 Mice.

Biliary acute pancreatitis induction by sodium taurocholate infusion has been widely used by the scientific community due to the representation of the human clinical condition and reproduction of inflammatory events corresponding to the onset of clinical biliary pancreatitis. The severity of pancreatic damage can be assessed by measuring the concentration, speed, and volume of the infused bile acid. This study provides an updated checklist of the materials and methods used in the protocol reproduction and shows the main results from this acute pancreatitis (AP) model. Most of the previous publications have limited themselves to reproducing this model in rats. We have applied this method in mice, which provides additional advantages (i.e., the availability of an arsenal of reagents and antibodies for these animals along with the possibility of working with genetically modified strains of mice) that may be relevant to the study. For acute pancreatitis induction in mice, we present a systematic protocol, with a defined dose of 2.5% sodium taurocholate at an infusion speed 10 µL/min for 3 min in C57BL/6 mice that reaches its maximal level of severity within 12 h of induction and highlight results with outcomes that validate the method. With practice and technique, the total estimated time, from the induction of anesthesia to the completion of the infusion, is 25 min per animal.

Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy.

Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.

Drainage after distal pancreatectomy: Still an unsolved problem.

BACKGROUND: The use of intraperitoneal drainage after distal pancreatectomy is still controversial. Its use increases fistula risk, but its absence increases the severity of the fistula. Therefore, since 2014, we have systematically used two drains. METHODS: This study examined consecutive patients undergoing distal pancreatectomy with splenectomy. Two drains were routinely used. One closed-suction-type drain is placed in the left subphrenic space with the aim to avoid the accumulation of any fluid coming from the pancreatic stump. The second is a tubulo-laminar drain placed near the pancreatic stump. These patients were compared with a cohort of patients (n = 94) before the adoption of this strategy (control group). RESULTS: 127 patients underwent distal pancreatectomy. 48 patients presented no POPF, 60 patients presented biochemical leak and in 19 patients (14.9%), drain amylase level was high and the drain was removed at 4 weeks, classified as grade-B according to the Revised 2016 ISGPS or B1 according to grade-B subclass. No grade-C was observed. The comparison with the 94 patients in the control group with single drainage, the occurrence of POPF was not different. However, in the control group, POPF severity was statistically higher (grade-B 14.9% vs 33%; grade-C 0% vs 3,2%; P = 0.00026). CONCLUSIONS: Since changing the drainage strategy, we have observed a dramatic decrease in pancreatic abscess formation and fluid collections needing percutaneous drainage. The results of this study show that the strategy of double drainage after distal pancreatectomy may reduce the severity of POPF, thus avoiding reoperation or further interventions.

Associating Liver Partition and Portal vein ligation for Staged hepatectomy procedure using ischemic bipartition: Two case reports.

RATIONALE: The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure is a recently introduced treatment strategy for patients with advanced primary or metastatic liver tumors and small future liver remnants. ALPPS procedure using ischemic bipartition of the liver is a modified technique that may reduce complications compared to classical ALPPS. PATIENT CONCERNS: Two patients with multiple colorectal liver metastasis with extensive involvement of the liver were considered unresectable before treatment because of small future liver remnant (FLR). DIAGNOSES: Two patients were diagnosed by imaging examination with volumetry of the liver. INTERVENTIONS: In the first stage, ischemic bipartition of the liver is achieved using radiofrequency ablation. The Glissonian pedicles from Segment 4 are identified and ablated, the FLR is cleared, and the right portal vein is ligated. In the second stage, the typical procedure is performed, and an extended liver resection is performed. OUTCOMES: The procedure was feasible with acceptable hypertrophy of FLRs. Blood transfusions were unnecessary, and severe postoperative complications were avoided. LESSONS: The ALPPS procedure with ischemic bipartition is safe and feasible and can produce results that are the same as those of the classical ALPPS procedure while reducing invasiveness during the first stage.

Pancreas-preserving duodenectomy after living donor liver transplantation for invasive cytomegalovirus disease.

CMV infection plays an important role in the postoperative course following solid organ transplantation. We present the case of an 11-year-old male patient who underwent LDLT due to severe hepatopulmonary syndrome and biliary cirrhosis. Four weeks after LDLT, he developed persistent GI bleeding and was subjected to repeated endoscopic treatment and radiological arterial embolization to stop the bleeding from duodenal ulcers. Diagnostic workup was negative for CMV disease. Because the bleeding persisted, surgical treatment was indicated, and a pancreas-preserving duodenectomy was performed. Immunohistochemical staining of the surgical specimen demonstrated diffuse endothelial infiltration by CMV. Despite ganciclovir treatment, the patient developed new erosions in the jejunal mucosa and melena; ganciclovir was discontinued, and foscarnet was started, resulting in clinical improvement and the cessation of bleeding. This case highlights the technical aspects of performing a complex upper GI resection in a patient recently subjected to LDLT, taking care to avoid injury to the previous liver graft anastomosis and restore GI continuity. Moreover, CMV tissue-invasive disease compartmentalized in the GI tract may be difficult to diagnose, as indicated by the negative results of antigenemia and PCR assays and endoscopic superficial mucosal biopsies.

Effects of diazoxide in experimental acute necrotizing pancreatitis.

OBJECTIVE:: We aimed to assess the effects of diazoxide on the mortality, pancreatic injury, and inflammatory response in an experimental model of acute pancreatitis. METHODS:: Male Wistar rats (200-400 g) were divided randomly into two groups. Fifteen minutes before surgery, animals received physiological (0.9%) saline (3 mL/kg) (control group) or 45 mg/kg diazoxide (treatment group) via the intravenous route. Acute pancreatitis was induced by injection of 2.5% sodium taurocholate via the biliopancreatic duct. Mortality (n=38) was observed for 72 h and analyzed by the Mantel-Cox Log-rank test. To study pancreatic lesions and systemic inflammation, rats (10 from each group) were killed 3 h after acute pancreatitis induction; ascites volume was measured and blood as well as pancreases were collected. Pancreatic injury was assessed according to Schmidt's scale. Cytokine expression in plasma was evaluated by the multiplex method. RESULTS:: Mortality at 72 h was 33% in the control group and 60% in the treatment group (p=0.07). Ascites volumes and plasma levels of cytokines between groups were similar. No difference was observed in edema or infiltration of inflammatory cells in pancreatic tissues from either group. However, necrosis of acinar cells was lower in the treatment group compared to the control group (3.5 vs. 3.75, p=0.015). CONCLUSIONS:: Treatment with diazoxide can reduce necrosis of acinar cells in an experimental model of acute pancreatitis, but does not affect the inflammatory response or mortality after 72 h.

Effects of diazoxide in experimental acute necrotizing pancreatitis

OBJECTIVE: We aimed to assess the effects of diazoxide on the mortality, pancreatic injury, and inflammatory response in an experimental model of acute pancreatitis. METHODS: Male Wistar rats (200-400 g) were divided randomly into two groups. Fifteen minutes before surgery, animals received physiological (0.9%) saline (3 mL/kg) (control group) or 45 mg/kg diazoxide (treatment group) via the intravenous route. Acute pancreatitis was induced by injection of 2.5% sodium taurocholate via the biliopancreatic duct. Mortality (n=38) was observed for 72 h and analyzed by the Mantel-Cox Log-rank test. To study pancreatic lesions and systemic inflammation, rats (10 from each group) were killed 3 h after acute pancreatitis induction; ascites volume was measured and blood as well as pancreases were collected. Pancreatic injury was assessed according to Schmidt's scale. Cytokine expression in plasma was evaluated by the multiplex method. RESULTS: Mortality at 72 h was 33% in the control group and 60% in the treatment group (p=0.07). Ascites volumes and plasma levels of cytokines between groups were similar. No difference was observed in edema or infiltration of inflammatory cells in pancreatic tissues from either group. However, necrosis of acinar cells was lower in the treatment group compared to the control group (3.5 vs. 3.75, p=0.015). CONCLUSIONS: Treatment with diazoxide can reduce necrosis of acinar cells in an experimental model of acute pancreatitis, but does not affect the inflammatory response or mortality after 72 h.

Effect of parenteral infusion of fish oil-based lipid emulsion on systemic inflammatory cytokines and lung eicosanoid levels in experimental acute pancreatitis.

Parenteral fish oil lipid emulsion (FOLE) might mitigate inflammation after injury. Acute pancreatitis (AP) can occur following major surgery and is characterized by tissue and systemic release of inflammatory mediators that contributes to the systemic inflammatory response syndrome and multiple organ failure. AIM: We evaluated the effect of short-term FOLE infusion before experimental induction of AP on systemic cytokine and lung eicosanoid profiles. METHODS: Lewis rats (n = 72) received parenteral infusion of FOLE (FO group) or saline (SS group), or remained without parenteral infusion (CG group) for 48 h. Thereafter, AP was induced by retrograde injection of sodium taurocholate into the pancreatic duct. Animals were sacrificed after 2, 12 and 24 h. Blood and lung samples were collected to assess serum inflammatory cytokines (Luminex) and tissue eicosanoids (ELISA), respectively. RESULTS: Serum TNF-α increased over time and serum IL-10 decreased from 12 to 24 h in CG group. In SS group serum TNF-α increased from 12 to 24 h (p = 0.039) and serum IL-10 decreased over time. Both CG and SS groups exhibited increased IL-6/IL-10 ratio (p = 0.040). From 12 to 24 h animals from FO group showed decreased serum IL-1 (p < 0.001), IL-4 (p < 0.002) and IL-6 (p = 0.050), and a trend towards increased IL-10 (p = 0.060). All experimental groups showed a trend towards increased PGE2 and decreased LTB4 in the lung at 24 compared with 12 h CONCLUSION: Parenteral infusion of FOLE for 48 h before the induction of experimental AP appears to favorably influence the cytokine response without affecting lung eicosanoids at the time points measured. The use of FOLE to prevent and treat AP following major surgery needs to be further explored.

Effect of Previous High Glutamine Infusion on Inflammatory Mediators and Mortality in an Acute Pancreatitis Model.

Parenteral glutamine supplementation in acute inflammatory conditions is controversial. We evaluated the inflammatory and survival responses after parenteral glutamine infusion in sodium taurocholate-induced acute pancreatitis (AP) model. Lewis rats received 1 g/kg parenteral glutamine (n = 42), saline (n = 44), or no treatment (n = 45) for 48 h before AP induction. Blood, lung, and liver samples were collected 2, 12, and 24 h after AP to measure serum cytokines levels and tissue heat shock protein (HSP) expression. From each group, 20 animals were not sacrificed after AP for a 7-day mortality study. Serum cytokine levels did not differ among groups at any time point, but the intragroup analysis over time showed higher interferon-γ only in the nontreatment and saline groups at 2 h (versus 12 and 24 h; both p ≤ 0.05). The glutamine group exhibited greater lung and liver HSP90 expression than did the nontreatment group at 2 and 12 h, respectively; greater liver HSP90 and HSP70 expression than did the saline group at 12 h; and smaller lung HSP70 and liver HSP90 expression than did the nontreatment group at 24 h (all p ≤ 0.019). The 7-day mortality rate did not differ among groups. In experimental AP, pretreatment with parenteral glutamine was safe and improved early inflammatory mediator profiles without affecting mortality.

Pentoxifylline enhances the protective effects of hypertonic saline solution on liver ischemia reperfusion injury through inhibition of oxidative stress.

BACKGROUND: Liver ischemia reperfusion (IR) injury triggers a systemic inflammatory response and is the main cause of organ dysfunction and adverse postoperative outcomes after liver surgery. Pentoxifylline (PTX) and hypertonic saline solution (HTS) have been identified to have beneficial effects against IR injury. This study aimed to investigate if the addition of PTX to HTS is superior to HTS alone for the prevention of liver IR injury. METHODS: Male Wistar rats were allocated into three groups. Control rats underwent 60 minutes of partial liver ischemia, HTS rats were treated with 0.4 mL/kg of intravenous 7.5% NaCl 15 minutes before reperfusion, and HPTX group were treated with 7.5% NaCl plus 25 mg/kg of PTX 15 minutes before reperfusion. Samples were collected after reperfusion for determination of ALT, AST, TNF-alpha, IL-6, IL-10, mitochondrial respiration, lipid peroxidation, pulmonary permeability and myeloperoxidase. RESULTS: HPTX significantly decreased TNF-alpha 30 minutes after reperfusion. HPTX and HTS significantly decreased ALT, AST, IL-6, mitochondrial dysfunction and pulmonary myeloperoxidase 4 hours after reperfusion. Compared with HTS only, HPTX significantly decreased hepatic oxidative stress 4 hours after reperfusion and pulmonary permeability 4 and 12 hours after reperfusion. CONCLUSION: This study showed that PTX added the beneficial effects of HTS on liver IR injury through decreases of hepatic oxidative stress and pulmonary permeability.

Severe acute pancreatitis: a possible role of intramyocardial cytokine production.

CONTEXT: Several mechanisms are involved in the development of the local and systemic response in acute pancreatitis. Cardiovascular system may be affected throughout the clinical course of acute pancreatitis. The aim was to evaluate local myocardial cytokine production, as well as, functional and histological myocardial alterations in severe acute pancreatitis. METHODS: The animals were divided into three groups: Group 1: control; Group 2: sham; Group 3: severe acute pancreatitis. Echocardiographic assessment of cardiac function, serum levels of amylase and cytokines (TNF-α, IL-6 and IL-10), and mRNA expression of TNF-α, IL-6 and TGF-ß were measured. Myocardial tissue alterations were analysed by histological examination. RESULTS: The serum TNF-α and IL-10 levels were significant higher in AP 2h group. The mRNA IL-6 levels from group AP 2h were statistically higher. The mRNA TNF-α level from sham group and AP 2h were statistically lower. Significant changes in the left ventricular diameter were found in AP 2h and AP 12h groups. There were statistical changes for vacuolar degeneration, picnosis and loss of nucleus, and lymphocytes. CONCLUSION: We found cardiac and histological changes compatible with the inflammatory process triggered by SAP with the promotion of local myocardial cytokine production.

PGC-1α expression is increased in leukocytes in experimental acute pancreatitis.

Severe acute pancreatitis (AP) induces a systemic inflammatory disease that is responsible for high mortality rates, particularly when it is complicated by infection. Therefore, differentiating sepsis from the systemic inflammation caused by AP is a serious clinical challenge. Considering the high metabolic rates of leukocytes in response to stress induced by infection, we hypothesized that the transcription coactivator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α), a master regulator of mitochondrial biogenesis and function, would be distinctly expressed during inflammation or infection and, therefore, could constitute a useful marker to differentiate between these two conditions. Rats were subjected to injection of taurocholate into the main pancreatic duct, which caused a severe AP with high amylase levels and white blood cell counts. In these animals, a marked increase in PGC-1α mRNA levels in circulating leukocytes was observed 48 h after the surgical procedure, a time when bacteremia is present. Antibiotic treatment abolished PGC-1α up-regulation. Moreover, PGC-1α expression was higher in peritoneal macrophages from animals subjected to a bacterial insult (cecal ligation and puncture) than in animals with AP. In isolated macrophages, we also observed that PGC-1α expression is more prominent in the presence of a phagocytic stimulus (zymosan) when compared to lipopolysaccharide-induced aseptic inflammation. Moreover, abolishing PGC-1α expression with antisense oligos impaired zymosan phagocytosis. Together, these findings suggest that PGC-1α is differentially expressed during aseptic inflammation and infection and that it is necessary for adequate phagocytosis. These results could be useful in developing new tests for differentiating infection from inflammation for clinical purposes in patients with AP.

Penetrance of functioning and nonfunctioning pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 in the second decade of life.

CONTEXT: Data are scarce on the penetrance of multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-PETs) and insulinomas in young MEN1 patients. A potential positive correlation between tumor size and malignancy (2-3 cm, 18%; >3 cm, 43%) has greatly influenced the management of MEN1 adults with NF-PETs. OBJECTIVE: The aim of the study was to estimate the penetrance of NF-PETs, insulinomas, and gastrinomas in young MEN1 carriers. DESIGN: The data were obtained from a screening program (1996-2012) involving 113 MEN1 patients in a tertiary academic reference center. PATIENTS: Nineteen MEN1 patients (aged 12-20 y; 16 patients aged 15-20 y and 3 patients aged 12-14 y) were screened for NF-PETs, insulinomas, and gastrinomas. METHODS: Magnetic resonance imaging/computed tomography and endoscopic ultrasound (EUS) were performed on 10 MEN1 carriers, magnetic resonance imaging/computed tomography was performed on five patients, and four other patients underwent an EUS. RESULTS: The overall penetrance of PETs during the second decade of life was 42% (8 of 19). All eight PET patients had NF-PETs, and half of those tumors were multicentric. One-fifth of the screened patients (21%; 4 of 19) harbored at least one large tumor (>2.0 cm). Insulinoma was detected in two NF-PET patients (11%) at the initial screening; gastrinoma was not present in any cases. Six of the 11 (54%) screened patients aged 15-20 years who underwent an EUS had NF-PETs. Potential false-positive EUS results were excluded based on EUS-guided biopsy results, the reproducibility of the NF-PET findings, or the observation of increased tumor size during follow-up. Distal pancreatectomy and the nodule enucleation of pancreatic head tumors were conducted on three patients with large tumors (>2.0 cm; T2N0M0) that were classified as grade 1 neuroendocrine tumors (Ki-67<2%). CONCLUSIONS: Our data demonstrated high penetrance of NF-PETs in 15- to 20-year-old MEN1 patients. The high percentage of the patients presenting consensus criteria for surgery for NF-PET alone or NF-PET/insulinoma suggests a potential benefit for the periodic surveillance of these tumors in this age group.

Laparoscopic pylorus-preserving pancreatoduodenectomy with double jejunal loop reconstruction: an old trick for a new dog.

BACKGROUND: Pancreatoduodenectomy is an established procedure for the treatment of benign and malignant diseases located at the pancreatic head and periampullary region. In order to decrease morbidity and mortality, we devised a unique technique using two different jejunal loops to avoid activation of pancreatic juice by biliary secretion and therefore reduce the severity of pancreatic fistula. This technique has been used for open pancreatoduodenectomy worldwide but to date has never been described for laparoscopic pancreatoduodenectomy. This article reports the technique of laparoscopic pylorus-preserving pancreatoduodenectomy with two jejunal loops for reconstruction of the alimentary tract. MATERIALS AND METHODS: After pancreatic head resection, retrocolic end-to-side pancreaticojejunostomy with duct-to-mucosa anastomosis is performed. The jejunal loop is divided with a stapler, and side-to-side jejunojejunostomy is performed with the stapler, leaving a 40-cm jejunal loop for retrocolic hepaticojejunostomy. Finally, end-to-side duodenojejunostomy is performed in an antecolic fashion. RESULTS: This technique has been successfully used in 3 consecutive patients with pancreatic head tumors: 2 patients underwent hand-assisted laparoscopic pylorus-preserving pancreatoduodenectomy, and 1 patient underwent totally laparoscopic pylorus-preserving pancreatoduodenectomy. One patient presented a Grade A pancreatic fistula that was managed conservatively. One patient received blood transfusion. Mean operative time was 9 hours. Mean hospital stay was 7 days. No postoperative mortality was observed. CONCLUSIONS: Laparoscopic pylorus-preserving pancreatoduodenectomy with double jejunal loop reconstruction is feasible and may be useful to decrease morbidity and mortality after pancreatoduodenectomy. This operation is challenging and may be reserved for highly skilled laparoscopic surgeons.

[Endogenous hyperinsulinism: review and follow-up of 24 cases]. / Hiperinsulinismo endógeno: revisão e seguimento de 24 casos.

Hypoglycemia due to endogenous hyperinsulinism (EH) is diagnosed in a symptomatic patient with low levels of plasma glucose concomitant with elevated plasma insulin and C-peptide. Causes of EH are pancreatic islet-cells disease, use of insulin secretagogues, and autoimmune hypoglycemia. In this review, the authors studied 24 patients with hypoglycemia due to endogenous hyperinsulinism in order to describe aspects of diagnosis and treatment. Our study demonstrated that after 12 hours of fasting (mini-fasting test; at least three samples), all patients presented the diagnostic criteria for EH. Additionally, we found that 11 of 12 patients (91.7%) who underwent glucagon test achieved glucose levels less than 50 mg/dL and below baseline after 120 minutes. Mini-fasting (3 samples) and glucagon test may be useful to prevent prolonged fasting test to clarify the diagnosis of endogenous hyperinsulinism.