Pancreaticoduodenectomy Research Articles

Duodenal Adenocarcinoma Arising from Brunner’s Glands, A Rare Case Report

Abstract Introduction/Objective Malignancies arising from the Brunner’s glands in duodenum are exceedingly rare with very few cases reported in the literature. Here, we reported a case of duodenal adenocarcinoma of Brunner’s gland origin that obstructed duodenum and extended to involve the pancreatic head. Methods/Case Report A 48-year-old woman came to the Emergency Department of our hospital with epigastric and right upper quadrant abdominal pain. CT imaging demonstrated a heterogeneously enhancing 8.4 x 5.4 x 6 cm mass involving the duodenal lumen, wall, and pancreatic head. An endoscopic ultrasound showed a large fungating, infiltrative, and ulcerative mass in the second portion of the duodenum distal to the ampulla but not involving it. The pancreatic and common bile ducts were uninvolved. Her endoscopic ultrasound biopsy was positive for adenocarcinoma. CA19-9 levels were normal. The patient received chemotherapy with subsequent Whipple procedure. Gross examination revealed an exophytic, tan-white mass with the epicenter in the duodenal wall obstructing the duodenal lumen and extending to involve the pancreatic head inferiorly. The mass was predominantly solid with a few small mucus cysts. Light microscopy demonstrated moderately differentiated adenocarcinoma with prominent necrosis and inflammation. There are intestinal-type, gastric-type and indeterminate types of epithelia in the carcinoma. There are areas in the duodenal wall where a continuous transition from benign Brunner’s glands to dysplastic glands and then to adenocarcinoma is present. Neither adenoma in the overlying duodenal mucosa nor abnormalities in the pancreatic parenchyma is observed. Immunohistochemical stains showed that the neoplastic cells are positive for CAM 5.2, AE1/AE3, and CK7, while only patchy positivity with CK20 and CDX2. Taken together, a diagnosis of duodenal adenocarcinoma arising from Brunner’s glands was rendered. Results (if a Case Study enter NA) N/A Conclusion More cases are needed in order to establish standard treatment guidelines and determine prognostic factors.

Retroperitoneal Myoepithelial Carcinoma with Heterologous Bone Formation and EWSR1::ZNF444

Abstract Introduction/Objective Soft tissue myoepithelial tumors are rare tumors that affect a wide age range and diverse tissue sites. Fewer than five cases have been reported in the retroperitoneum. Most tumors are benign with the only histologic criterion for malignancy being cytologic atypia. The morphology is broad ranging from spindled to epithelioid cells of varying cellularity in sclerotic to myxoid stroma. Heterologous differentiation may be present. These tumors usually express cytokeratin, EMA, S100, and GFAP and show EWSR1 and FUS rearrangements. Here we present an unusual case of retroperitoneal myoepithelial carcinoma. Methods/Case Report A 29-year-old female presented with rash and painless jaundice. CT and MRCP revealed a relatively circumscribed 3.7 cm mass in the porta hepatis. On fine needle aspiration, a possible gastrointestinal stromal tumor was considered due to DOG1 expression. The patient underwent a Whipple procedure with negative margins showing tumor in soft tissue adjacent to the common bile duct. The tumor was multinodular and consisted predominantly of mild to moderately pleomorphic epithelioid cells in fibromyxoid stroma with interspersed woven bone. Mitoses were not appreciated, and necrosis not seen. The tumor was focally positive for CK AE1/AE3, GFAP, and DOG1 and negative for S100, SOX10, p63, and CD117. INI1 was retained. NGS identified EWSR1::ZNF44 and a diagnosis of myoepithelial carcinoma was rendered. The patient received no adjuvant therapy and has not shown any evidence of metastasis or recurrence for 17 months. Results (if a Case Study enter NA) NA Conclusion Soft tissue myoepithelial carcinomas are aggressive tumors with approximately 40% recurrence and over 50% metastasis. Standard treatment is complete surgical resection. The efficacy of radiation and chemotherapy is not clear. EWSR1 fusions with various partners including POU5F1, PBX1/3, and ZNF44 have been identified. Due to their rarity and varying histology and immunohistochemical expression, identification of gene fusions can be invaluable in diagnosing soft tissue myoepithelial tumors, especially in unusual locations.

The Role of a Community Surgeon in the Care of Hepatopancreatobiliary Patients: Short-Term Outcomes and Learning Curve.

Background Owing to the well-established volume-outcome relationship, hepatopancreatobiliary (HPB) surgery is commonly regionalized to academic, teaching hospitals. However, regionalization is associated with decreased access for some populations in need, as well as geographic and financial barriers for patients. If high surgeon and institutional volumes can be achieved, the community, non-teaching HPB surgical practice could help alleviate some issues associated with regionalization. The HPB experience of a community surgeon immediately after surgical oncology training was reviewed, hypothesizing that high volumes with acceptable short-term outcomes could be achieved, although a learning curve may be observed. Materials and methods Electronic medical records from 2013 to 2023 were reviewed. Data included patient demographics, perioperative details, pathology, complications, and deaths over 90 postoperative days. Perioperative quality metrics were assessed for trends over time in pancreaticoduodenectomy (PD) and liver resection subgroups. Results A total of 295 patients underwent 176 (59.7%) pancreatic and 119 (40.3%) hepatobiliary operations. The most common operations were PD (n=87; 49.4%) and partial hepatic lobectomy (n=56; 41.1%). In the pancreas group, morbidity was 25% (n=44), and mortality was 4.5% (n=8). In the hepatobiliary group, morbidity and mortality were 19.3% (n=23) and 5.0% (n=6), respectively. Within the PD and liver resection subgroups, operative time, estimated blood loss, and hospital length of stay (LOS) trended downward over time, with LOS decreasing significantly. Conclusion High HPB volumes with acceptable short-term outcomes can be achieved by a solo practitioner in the community, non-teaching setting. For PDs and liver resections, perioperative metrics trended downward over time, illustrating the learning curve encountered after training.

Results of surgical treatment of chronic pancreatitis with a high risk of developing pancreatic cancer

Objective. To analyze the results of surgical treatment of patients with pancreatic insufficiency and a high risk of developing pancreatic cancer. Materials and methods. The study included 39 patients treated in 2019–2023. In 20 (51%) patients, it was difficult to clearly differentiate between chronic pancreatitis and pancreatic cancer. In 19 (49%) patients, the diagnosis of chronic pancreatitis was not in doubt. All patients with complicated forms of chronic pancreatitis and suspected pancreatic tumor underwent a set of laboratory tests, and routine screening methods of instrumental diagnostics were used. In addition to standard methods of examination, the levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases in the blood plasma were studied. Results. The method of intraoperative multiple biopsy, improved by us, was an obligatory component of surgical care for a clear differential diagnosis of chronic pancreatitis and pancreatic cancer. In the presence of complicated chronic pancreatitis, during surgery, the biopsy was taken using a special punch instrument that resembles a pen, along the entire length of the main pancreatic duct along the upper and lower edges of the dissection in a checkerboard pattern. There were no complications of punch biopsy. Of the 20 patients in whom it was not possible to clearly differentiate between chronic pancreatitis and pancreatic cancer, 12 (60%) were diagnosed with diabetes mellitus. The characteristic changes in the pancreatic tissue gave grounds for performing extended resection interventions in these patients. In the remaining 8 (40%) patients without morphological changes inherent in malignancy, Whipple operation (2), longitudinal pancreaticoduodenectomy (2), Frey operation (2), and our proposed central pancreatic resection with preservation of the left anatomical segment (2) were performed. Drainage and resectional surgical interventions were performed in 19 (49%) patients with complicated forms of chronic pancreatitis. After radical surgical interventions for pancreatic cancer, 1 patient developed gastrostasis, and on the 11th day he underwent a relaparotomy with reconstruction of the gastroenteroanastomosis, and on the 30th day a subhepatic abscess was diagnosed in 1 patient, who underwent drainage with a subcostal mini–access with a positive effect. In 2 patients, after left–sided pancreatic resection, subdiaphragmatic abscesses were diagnosed on the left, they were treated minimally invasively with punctures and drainage under ultrasound control. Multiple organ failure occurred in 1 patient after surgery for internal pancreatic fistula, infected ascites as a complication of neglected chronic pancreatitis. The patient died. Infection of the median laparotomy wound occurred in 4 patients, and healing was achieved by controlled primary tension. Class B pancreatic fistulas occurred in 3 patients: 2 – after left–sided pancreatic resection, 1 – after longitudinal pancreaticoduodenostomy. In 1 patient, a class C permanent pancreatic fistula was formed after a combined (resection and drainage) intervention. Relaparotomy, subtotal resection with Roux–en–Y loop closure was performed. Conclusions. Morphological changes in the pancreatic tissue in chronic pancreatitis in combination with diabetes mellitus, corresponding to the development of PanIN, are direct predictors of adenocarcinoma. Multiple intraoperative pancreatic biopsies are effective in verifying pancreatic malignancy. Pre– and intraoperative diagnostics make it possible to optimize the surgical treatment of complicated forms of chronic pancreatitis and prevent the development of postoperative pancreatic fistula.

Delayed gastric emptying risk stratification in patients with pancreatic ductal adenocarcinoma after pancreatoduodenectomy: An international validation cohort study.

Currently, there is still a lack of an accurate predictive model for delayed gastric emptying (DGE) following pancreaticoduodenectomy (PD) in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to develop a concise model that could effectively predict the risk of DGE. This retrospective cohort study included a training cohort of 1251 consecutive PDAC patients who underwent PD from the US multicenter ACS-NSQIP database. Additionally, a validation cohort of 934 consecutive PDAC patients who underwent PD was included from the National Cancer Center in China. A total of 46 perioperative indicators were incorporated in the analysis. The DGE risk stratification (DGERS) model was then developed and validated using Lasso-logistic regression. After screening using Lasso-logistic regression, we identified four independent predictors that were significantly correlated with DGE: days to pancreatic drain removal (HR, 1.05; 95% CI, 1.02-1.08; p<0.001), pancreatic fistula (HR, 2.61; 95% CI, 1.65-4.12; p<0.001), sepsis/septic shock (HR, 2.46; 95% CI, 1.52-3.91; p<0.001), and reoperation (HR, 4.16; 95% CI, 2.27-7.57; p<0.001). Based on these factors, we developed a nomogram to predict postoperative DGE. The model demonstrated excellent calibration and optimal performance in the validation cohorts (AUC, 0.73; 95% CI, 0.67-0.73). In the validation cohort, the DGERS exhibited significant risk stratification ability, with AUC values of 0.7, 0.61, and 0.74 for the low-, moderate-, and high-risk groups, respectively. This study identified four factors that independently increased the occurrence of DGE in patients with PDAC after PD, including days to pancreatic drain removal, pancreatic fistula, sepsis/septic shock, and reoperation. Based on these findings, we developed a personalized and straightforward DGERS that enables dynamic and precise prediction of DGE risk, allowing for effective stratification of individuals based on their risk profiles.

Application of 3D Printing to Design and Manufacture Pancreatic Duct Stent and Animal Experiments.

Objective: Postoperative pancreatic fistula (POPF) is a common and challenging complication following pancreaticoduodenectomy (PD), occurring in 2% to 46% of cases. Despite various pancreaticojejunostomy techniques, an effective method to prevent POPF has not been established. This study aimed to develop and evaluate a novel 3D-printed biodegradable pancreatic duct stent to simplify the surgical process of pancreaticojejunostomy, reduce anastomotic complexity, and minimize postoperative complications. Methods: Data from 32 patients undergoing total laparoscopic pancreaticoduodenectomy were utilized. Preoperative CT scans were transformed into 3D reconstructions to guide the design and printing of customized stents using polylactic acid (PLA). The stents were assessed for mechanical integrity, surface texture, and thermal stability. Animal experiments were conducted on 16 mini pigs, with the experimental group receiving the novel stent and the control group receiving traditional silicone stents. Results: The 3D-printed stents demonstrated accurate dimensional replication and mechanical reliability. In the animal experiments, the experimental group showed no significant difference in postoperative complications compared to the control group. At 4 weeks post-surgery, CT scans revealed well-healed anastomoses in both groups, with no significant inflammation or other complications. Histological examination and 3D reconstruction models confirmed good healing and device positioning in the experimental group. Conclusion: The 3D-printed biodegradable pancreatic duct stent offers a promising solution for pancreaticojejunostomy, with comparable safety and efficacy to traditional methods. Further research is needed to validate its clinical application.

THE ROLE OF CA 19.9 IN PREDICTING THE OPERABILITY OF CARCINOMA PANCREAS

Objectives: Adenocarcinoma of the pancreas remains a relatively incurable disease despite advances in surgical care. Approximately 25% of patients will be found to have unresectable tumors during surgery even though computed tomography (CT) has demonstrated that they are resectable. There is a controversy regarding the use of cancer antigen 19-9 (CA 19-9) to decide the resectability of pancreatic adenocarcinoma [1]. Our aim is to study the use of CA 19-9 in determining the operability of carcinoma pancreas [2]. Methods: This was a prospective study which included 69 patients and the study period was from December 2021 to December 2022. Data were collected from all patients with carcinoma of the pancreas who underwent surgical management. CA 19-9 levels were measured and recorded [3]. During surgery, the operative findings on resectability were documented and tabulated against corresponding CA 19-9 levels and contrast-enhanced CT (CECT) findings. Results: Of the 69 patients who were operated on, 38 patients had resectable tumors and underwent the Whipples procedure and 31 of them had non-resectable tumors and had to undergo palliative bypass procedures. Among the 31 patients whose tumors were non-resectable, only four were diagnosed non-resectable preoperatively with CECT, and the other 27 were found to be non-resectable only during surgery. That shows the relevance of this study. Of the 31 non-resectable cases, 14 (45.2%) patients had elevated CA 19-9 values of more than 501, and the rest 17 (54.8%) patients had low CA 19-9 values. Among the 38 resectable cases, 12 patients (31.6%) had elevated CA 19-9 more than 501, and 26 patients (68.4%) had low values. In conclusion, among non-resectable cases, 45.2% had raised CA 19-9, and among operable cases, 31.6% showed raised CA 19-9. Hence, CA 19-9 seems to be an insignificant predictor of tumor resectability [4]. Conclusion: It was found that the need for a pre-operative predictor for resectability of carcinoma pancreas is relevant while considering mortality and morbidity in operating carcinoma pancreas cases. On evaluating CA 19-9 as a pre-operative predictor, we found that CA 19-9 has no significant role as an indicator of local advancement or metastasis. Hence, we cannot consider CA 19-9 as a predictor of resectability of carcinoma pancreas preoperatively [5].

Resección pancreática por cáncer de células renales metastásico: experiencia de un hospital mexicano de alto volumen

Objective: The aim of our study was to report the oncological and surgical outcomes of the pancreatic resections due to solitary pancreatic metastasis of RCC in a tertiary care reference center for pancreatic masses in Mexico. Materials y methods: All pancreatic resections at our Institution from 2002 to 2022 were retrospectively analyzed. We only included patients treated with pancreatic resections due to metastatic RCC to the pancreas. We evaluated symptoms, time from nephrectomy to pancreatic resection, type of surgery, complications and oncological outcomes. Results: Eight pancreatic resections due to solitary metastases of RCC were performed. The median age of presentation was 69 years. The most prevalent symptom was abdominal pain (50 %). 6 pancreatoduodenectomies (Whipple procedure), 1 distal pancreatectomy and 1 total pancreatomy were done. The median time between radical nephrectomy and pancreatic resection was 122 months (8-247 months). Seven had negative surgical margins. The median follow-up time after pancreatic surgery was 42 months (1-109 months). The only case that died had pulmonary metastases and the resection was R1. Originality and value: Original study demonstrating the survival outcomes of pancreatic resection for metastatic renal cell carcinoma in a high-volume hospital in Mexico. Limitations: Retrospective study and the limited number of cases. Conclusions: Pancreatic resections due to solitary metastases from CCR could offer some advantages on survival, as long as they are done in high volume centers.

6799 RZ358 Therapy. A Novel Approach to Hyperinsulinemia in Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. W. Madeleine: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

9286 RZ358 Therapy. A Novel Approach To Hyperinsulinemia In Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. M. Welsh: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

6799 RZ358 Therapy. A Novel Approach To Hyperinsulinemia In Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. W. Madeleine: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

9286 RZ358 Therapy. A Novel Approach to Hyperinsulinemia in Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. M. Welsh: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

6419 Cushing’s Syndrome due to Metastatic Pancreatic Neuroendocrine Neoplasm With Incidental Pituitary Microadenoma

Abstract Disclosure: A. Ibrahim: None. L. Esper: None. R. Jain: None. N. El Asmar: None. Introduction: Pancreatic neuroendocrine neoplasms (PNENs) are rare with a reported incidence of 1-2/100,000. While the majority are non-functional, insulinomas and gastrinomas are the most common functional PNENs. Our case of ACTH-producing PNENs is extremely rare. Case presentation: A previously healthy 47-year-old female was hospitalized for worsening dyspnea. Her symptoms included rapid weight gain, skin hyperpigmentation, and lower extremity edema. Her exam was notable for elevated blood pressure of 181/120 mmHg, moon facies, purple abdominal striae, and proximal myopathy. Her lab analysis showed a cortisol level of 42 mcg/dL (6.2-19.4), ACTH of 254 pg/ml (7.2-63), DHEA sulfate of 171 mcg/dl (41-243), HbA1C 7%, K of 3 mmol/l and 24H urine cortisol &amp;gt;2100 mcg/24hrs. A post low-dose DST cortisol level was 42.7 mcg/dl. CT chest demonstrated an ill-defined hypodense lesion in the region of the pancreatic head. MRI abdomen revealed a 3 x 2.3 x 2.3 cm mass in the pancreatic head and many small enhancing lesions within the right lobe of the liver. Adrenal glands appeared normal. Subsequent PET CT scan with GA 68 DOTOTATE showed increased uptake in the pancreatic head mass and in the right hepatic lobe. Her pituitary MRI revealed a right pituitary gland 6 mm hypointense lesion, possibly a microadenoma. A high dose DST resulted in a cortisol level of 80 mcg/dl mostly consistent with ectopic ACTH secretion. EUS-guided biopsy of the pancreatic mass showed a well-differentiated neuroendocrine tumor that stained positive for ACTH, chromogranin, synaptophysin, and CD56. Treatment with Ketoconazole 600mg q6h and Octreotide 50mg q6h was started 3 days before surgery to control acute hypercortisolism as she developed acute psychosis. The patient subsequently underwent a Whipple procedure with successful resection of the pancreatic mass. Post-op, her ACTH levels dropped to 19 pg/ml with a cortisol level of 6 mcg/dl. Final pathology showed a well-differentiated grade 3 neuroendocrine tumor with a KI-67 labeling index greater than 20%. After surgery, the patient received a short course of stress dose hydrocortisone which was tapered off over the following 2 months. The patient is being followed for planning further intervention given the aggressive grade of the tumor and hepatic metastases. Conclusion: Ectopic ACTH-producing PNENs are rare. An accurate and timely diagnosis, while challenging, is key. Patients usually present with rapidly progressing symptoms that could cause life-threatening complications such as thrombosis and sepsis. We demonstrated the importance of utilizing a multidisciplinary team approach and starting cortisol-lowering medications early given the complexity of the disease, requiring rapid intervention and lifelong follow-up. Presentation: 6/3/2024

7940 Insulinoma as a Rare Manifestation of MEN4

Abstract Disclosure: H. Han: None. J. Moalem: None. A.R. Shih: None. B.J. Gigliotti: None. Background/Objective: Multiple endocrine neoplasia 4 (MEN4) is a rare syndrome that is caused by germline mutations in CKDN1B. Its phenotypic expression is similar to multiple endocrine neoplasia 1 (MEN1). Manifestations include primary hyperparathyroidism (PHPT), pituitary adenomas, and pancreatic neuroendocrine tumors (NET). Prevalence of MEN4 is less than one per million. Case Report: A 55-year-old female with history of hypercalcemia presented with symptomatic hypoglycemia. She had a fasting plasma glucose of 41mg/dL, proinsulin of 84.3 pmol/L, insulin level of 24 uIU/mL, c-peptide of 5.2 ng/mL, and beta hydroxybutyrate level of 0.34 mmol/L, consistent with endogenous hyperinsulinism. She was incidentally noted to have PHPT. CT abdomen showed a 1.5 x 1.1 x 1.0 cm pancreatic lesion consistent with an insulinoma. Pathology from subsequent Whipple surgery showed that it was a well-differentiated neuroendocrine tumor with no metastasis. She became normoglycemic after surgery. Germline testing revealed a variant of unknown significance in CDKN1B (p.R93W). Discussion: Increasing evidence suggests that MEN4 exhibits subtle differences in penetrance and natural history compared to MEN1. A recent systemic review of MEN4 cases showed that most gastrointestinal NETs in MEN4 are non-functional NETs and gastrinomas; to date, no insulinomas have been reported. PHPT in MEN4 may exhibit a lower risk of recurrence after parathyroidectomy. This case highlights the importance of germline genetic testing when a patient presents with clinical manifestations of MEN1. Conclusion: This is the first reported case of insulinoma in MEN4. Presentation: 6/3/2024

Development and validation of a nomogram for predicting clinically relevant delayed gastric emptying in patients undergoing total pancreatectomy

BackgroundCurrent research on delayed gastric emptying (DGE) after pancreatic surgery is predominantly focused on pancreaticoduodenectomy (PD), with little exploration into DGE following total pancreatectomy (TP). This study aims to investigate the risk factors for DGE after TP and develop a predictive model.MethodsThis retrospective cohort study included 106 consecutive cases of TP performed between January 2013 and December 2023 at Peking Union Medical College Hospital (PUMCH). After applying the inclusion criteria, 96 cases were selected for analysis. These patients were randomly divided into a training set (n = 67) and a validation set (n = 29) in a 7:3 ratio. LASSO regression and multivariate logistic regression analyses were used to identify factors associated with clinically relevant DGE (grades B/C) and to construct a predictive nomogram. The ROC curve, calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were employed to evaluate the model's prediction accuracy.ResultsThe predictive model identified end-to-side gastrointestinal anastomosis, intraoperative blood transfusion, and venous reconstruction as risk factors for clinically relevant DGE after TP. The ROC was 0.853 (95%CI 0.681–0.900) in the training set and 0.789 (95%CI 0.727–0.857) in the validation set. The calibration curve, DCA, and CIC confirmed the accuracy and practicality of the nomogram.ConclusionWe developed a novel predictive model that accurately identifies potential risk factors associated with clinically relevant DGE in patients undergoing TP.

Alterations in the Gut Microbiota in Patients with Long-Term Follow-Up after Pancreaticoduodenectomy and Their Association with Postoperative Fatty Liver: A Pilot Study.

Background/Purpose: Gut microbiota status after pancreaticoduodenectomy (PD) is unclear, and postoperative fatty liver is an important complication after PD. This study evaluated the relationship between postoperative fatty liver and gut microbiota after PD. MethodsFecal samples were collected from patients who had undergone PD and remained stable after 6 months of follow-up. A comprehensive bacterial analysis using 16S rRNA gene amplicon sequencing was performed. The results were compared with those of 85 healthy volunteers. The association between perioperative factors, gut microbiota, and development of fatty liver was investigated. ResultsTwenty-four patients after PD, including 10 in the fatty liver (FL) group and 14 in the normal liver (NL) group were investigated. The β-diversity of the gut microbiota was significantly different between the healthy volunteers and patients after PD, with more Escherichia coli and Streptococcus gallolyticus and less Bifidobacterium catenulatum and Faecalibacterium prausnitzii in the patients with PD. Lactobacillus gasseri was significantly less abundant in the FL group than in the healthy volunteers, although this change was not observed in the NL group. ConclusionsThe gut microbiota of patients after PD was in dysbiosis at postoperative ≥6 months. Development of fatty liver might be associated with significant differences in gut microbiota.

Modified reconstruction approach after pancreaticoduodenectomy optimizes postoperative outcomes: Results from a multivariate cohort analysis.

Despite technical advances in recent decades and a decrease in hospital mortality (<5%), pancreaticoduodenectomy (PD) is still associated with major postoperative complications, even in high-volume centers. The present study aimed to assess the effect of a modified reconstruction technique on postoperative morbidity and mortality. A cohort study of all patients (n=218) undergoing PD between January 2010 and December 2019 was performed at Attikon University Hospital (Athens, Greece). Several variables were studied, including demographic data, past medical history, perioperative parameters, tumor markers and pathology, duration of hospitalization, postoperative complications, 30-day-survival, postoperative mortality and overall survival using multivariate logistic regression and survival analysis techniques. In this cohort, 123 patients [modified PD (mPD) group] underwent a modified reconstruction after a pylorus-preserving pancreaticoduodenectomy, which consisted of gastrojejunostomy and pancreaticojejunostomy on the same loop and an isolated hepaticojejunostomy on another loop. In the standard PD (StPD) group, 95 patients underwent standard reconstruction. The median age was 67 years, ranging from 25 to 89 years. Compared with in the StPD group, the mPD group had significantly lower rates of grade B and C pancreatic fistula (4.9% vs. 28.4%), delayed gastric emptying (7.3% vs. 42.1%), postoperative hemorrhage (3.3% vs. 20%), intensive care unit admission (8.1% vs. 18.9%), overall morbidity (Clavien-Dindo grade III-V: 14.7% vs. 42.0%), perioperative mortality (4.1% vs. 14.7%), and shorter hospitalization stay (11 days vs. 20 days). However, no difference was noted regarding median survival (35 months vs. 30 months). In this single-center series, a modified reconstruction after PD appears to be associated with improved postoperative outcomes. However, further evaluation in larger multi-center trials is required.

Prophylactic intra-abdominal drainage during pancreaticoduodenectomy: A systematic review and meta-analysis

Background: Prophylactic abdominal drainage during pancreaticoduodenectomy (PD) is a common treatment strategy for pancreatic fistula. However, its benefits and safety have been the subject of debate. The objective of this meta-analysis and system review is to assess the effects of prophylactic drainage, various types of drainage (active and passive), and the timing of drainage removal (early and late) on the postoperative outcomes of PD. Methods: A systematic literature search was conducted in the PubMed, Web of Science, and Cochrane Library databases as of April 28, 2024. Randomized controlled trials (RCTs) comparing prophylactic abdominal drainage, different drainage patterns, and the timing of drainage removal after PD were included, and the postoperative outcomes were evaluated. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to aggregate dichotomous outcomes. Meta-analysis was performed using the Mantel-Haenszel fixed- and random-effects models. Results: Nine RCTs, including a total of 1638 patients, were incorporated in our study. The meta-analysis showed no statistically significant differences in postoperative outcomes between the closed-suction drain (CSD) group and the passive drain to gravity (PDG) group. Compared to the late drain removal (LDR) group, the early drain removal (EDR) group had a significant reduction in the incidence of Clinically relevant postoperative pancreatic fistula (CR-POPF) (OR=0.39, 95% CI=0.20 to 0.79; P=0.009), morbidity (OR=0.41, 95% CI=0.20 to 0.84; P=0.01) and intra-abdominal infection (OR=0.40, 95% CI=0.22 to 0.75; P=0.004). For the group of present of drainage and the group of absent of drainage, the patient inclusion criteria of the included studies were too heterogeneous, making meta-analysis inappropriate. Conclusion: The existing evidence is insufficient to negate the necessity of prophylactic drainage after PD. The meta-analysis did not show superiority of any specific approaches of drainage tube. But this review did indicate that patients benefit from EDR in terms of CR-POPF, morbidity and intra-abdominal infection. EDR was recommended for low/intermediate risk patients.

Anemia after pancreaticoduodenectomy in patients followed-up for 5 years.

Anemia is a common long-term metabolic sequela caused by anatomical changes after major gastrointestinal surgery, such as bariatric surgery and gastrectomy. Pancreaticoduodenectomy (PD) involves resection of the duodenum and enteral bypass, which may contribute to malabsorption and nutrient deficiency. Hence, PD may cause anemia. This study included 322 patients who presented with PD during the 5-year follow-up from 2006 to 2017. The Kaplan-Meier method and the Cox regression model were used to investigate the association between risk factors and anemia. Approximately 44.4% of patients developed post-PD anemia during the 5-year post-PD follow-up. Further, 30 (9.3%) patients were treated with oral iron supplementation for anemia with associated symptoms. In the Cox multivariate model, a higher Charlson Comorbidity Index (CCI) score and pancreatic ductal adenocarcinoma were significantly associated with the development of post-PD anemia. Post-PD anemia is a common sequela among long-term survivors. A higher CCI and pancreatic ductal adenocarcinoma diagnosis were considered as independent risk factors for post-PD anemia. Therefore, regular monitoring of hematological profiles and appropriate management of post-PD anemia are required during follow-up.

Preoperative risk-stratified analysis: External versus internal pancreatic stents in pancreatoduodenectomy

BackgroundSeveral risk-stratified studies have compared the outcomes of external and internal pancreatic stents in pancreatoduodenectomy (PD), but no resolute standard for a fistula-mitigation strategy exists. The study investigated the efficacy of these stents in a preoperative risk-stratified setting. MethodsData from 285 patients who underwent PD with pancreaticojejunostomy using an external or internal stent from 2015 to 2023 were analyzed. The preoperative pancreatic fistula score (preFRS) was used to classify patients into low-risk (preFRS: 0–5) and high-risk (preFRS: 6–8) groups. ResultsPreFRS accurately predicted the risk of clinically relevant postoperative pancreatic fistula (CR-POPF) as 0% and >40% in patients with preFRS ≤1 and ≥7, respectively. Although no significant difference was observed in postoperative outcomes in low-risk patients, the external stent significantly reduced CR-POPF (21% vs 44%, P = .024) and postpancreatectomy hemorrhage (PPH, 0% vs 19%, P = .02) in high-risk patients, leading to the superiority of the external stent in the entire cohort in terms of CR-POPF (12% vs 24%, P = .033) and PPH (1% vs 11%, P = .013). There were no significant differences in stent-related complications or pancreatic dysfunction. External stent malfunction occurred in 14% and significantly affected CR-POPF development in both low- (20% vs 0%, P < .01) and high-risk groups (60% vs 14%, P = .021). ConclusionThe external pancreatic stent showed a more beneficial effect on CR-POPF and PPH, especially in high-risk patients, without increasing other complications. Risk-stratified strategy and improving stent management might enhance postoperative outcomes.