Surgical Pancreatectomy Research Articles

Incidence of Diabetes Mellitus and Its Impact on Outcomes in Patients Undergoing Surgical Pancreatectomy for Non-Malignant and Malignant Pancreatobiliary Diseases-A Retrospective Analysis.

Diabetes mellitus (DM) is a prominent risk factor for malignant and non-malignant pancreatic diseases. Furthermore, the presence of DM predicts an unfavourable outcome in people with pancreatic cancer. This retrospective observational study investigated 370 patients who underwent pancreatic resection surgery for various indications (84.3% in malignant indication) in a single surgery centre in Graz, Austria. The preoperative and postoperative diabetes statuses were evaluated according to surgery method and disease entity and predictors for diabetes development after surgery, as well as outcomes (survival and cancer recurrence) according to diabetes status, were analysed. In the entire cohort, the postoperative diabetes (postopDM) incidence was 29%. PostopDM occurred significantly more frequently in malignoma patients than in those with benign diseases (31.3% vs. 16.7%; p = 0.040, OR = 2.28). In the malignoma population, BMI, longer surgery duration, and prolonged ICU and hospital stay were significant predictors of diabetes development. The 1- and 2-year follow-ups showed a significantly increased mortality of people with postopDM in comparison to people without diabetes (HR 1-year = 2.02, p = 0.014 and HR 2-years = 1.56, p = 0.034). Local cancer recurrence was not influenced by the diabetes status. Postoperative new-onset diabetes seems to be associated with higher mortality of patients with pancreatic malignoma undergoing pancreatobiliary surgery.

Laparoscopic partial pancreatectomy of the left limb using a harmonic scalpel in nine cats.

To describe a laparoscopic technique and outcome for partial pancreatectomy in cats. Prospective cohort study. Nine cats. Laparoscopic pancreatectomy was performed using a single incision laparoscopic surgery port and an additional 5.5 mm port. The left pancreatic limb was dissected, sealed and divided at the level of the splenic vein insertion to the portal vein using a harmonic device. Surgical time and complications were recorded. The weight and length of the resected pancreatic limb was recorded. Pre- and postoperative trypsin-like immunoreactivity (TLI), pancreatic lipase immunoreactivity (PLI), and hemoglobin A1C were documented. Laparoscopic partial pancreatectomy was performed successfully in all cats. One grade 1 intraoperative complication occurred (1/9; 11%) resulting in minor hemorrhage from a caudal splenic vein branch. A grade 2 postoperative complication occurred within 3 days after surgery in one cat (1/9; 11%), involving localized, sterile peritonitis in the region of the pancreatic angle. Signs resolved with conservative management. No cats exhibited signs of pancreatitis postoperatively. Long-term, mean TLI decreased by 37% ± 38% (p = .03) following partial pancreatectomy, while PLI and A1C were unchanged. All cats were alive and clinically well at last follow-up 250 to 446 days following surgery. Laparoscopic partial pancreatectomy using a harmonic device is effective in cats, and offers a minimally-invasive alternative to open surgical pancreatectomy techniques. Laparoscopic pancreatectomy of the left limb results in adequate exocrine and endocrine function in the long-term.

Abstract PR007: Three-dimensional genomic analysis of human pancreatic intraepithelial neoplasia (PanIN) reveals striking multifocality and genetic heterogeneity

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5 year survival rate of 11%. PDAC arises from precursor lesions, the most common of which is pancreatic intraepithelial neoplasia (PanIN). Molecular analysis of human PanINs is critical to understand early pancreatic tumorigenesis, which could inform risk stratification, early detection, and cancer prevention approaches. Because PanINs are microscopic, it is challenging to determine their full extent and anatomic relationships using two dimensional histological sections. To determine the density and connectivity of PanINs, we utilized a novel machine learning algorithm (CODA) for three-dimensional (3D) reconstruction and cellular quantification. Large blocks of grossly normal pancreas were harvested from 39 surgical pancreatectomy specimens, followed by formalin fixation, paraffin-embedding, and complete serial sectioning. 3D reconstruction using CODA revealed striking multifocality of PanINs within the pancreata of most analyzed patients, with more than 600 spatially PanINs being modeled. Next, to determine whether these multifocal PanINs arose as independent neoplasms or via intraductal spread of a single PanIN, we assessed their clonal relationships using somatic multi-region DNA next generation sequencing (NGS). To do so, 8 additional blocks of grossly normal pancreatic tissue were harvested and 3D modeled, yielding 37 anatomically distinct PanINs for genomic analysis. Each spatially unconnected PanIN was separately microdissected in five different regions to assess both intra-PanIN and inter-PanIN genetic heterogeneity. 99 samples from the 37 PanIN lesions underwent targeted NGS using a panel covering major drivers of pancreatic ductal neoplasia. For PanINs with sufficient DNA, whole exome sequencing and deep sequencing of KRAS was also performed. Across the 8 blocks, 10 PanINs shared no mutations with other PanINs in the same block, indicating independent clonal origin. In addition, 8 PanINs shared only KRAS hotspot mutations with numerous other unshared mutations, likely indicating independent PanINs that shared hotspot mutations by chance. Six spatially separate low grade PanINs shared both driver and passenger mutations with at least one other spatially unconnected PanIN, demonstrating the ability of PanIN cells to dissociate from one lesion and establish unconnected, genetically related PanINs nearby. Furthermore, 5 PanINs harbored multiple KRAS mutations within a single PanIN, suggesting a polyclonal origin. One PanIN lacked any driver gene mutations. The genetic origins of the remaining 7 spatially separate PanINs could not be resolved due to a lack of discrete mutations found by targeted sequencing. Our 3D genomic analysis of anatomically distinct PanINs demonstrates that the unexpectedly large number of PanINs in normal pancreas most often arise independently, providing new foundations for our understanding of early pancreatic tumorigenesis. Determining the mechanisms for this multifocal neoplasia is an important direction for future research. Citation Format: Alicia M. Braxton, Ashley Kiemen, Rachel Karchin, Yuchen Jiao, Pei-Hsun Wu, Ralph H Hruban, Denis Wirtz, Laura D. Wood. Three-dimensional genomic analysis of human pancreatic intraepithelial neoplasia (PanIN) reveals striking multifocality and genetic heterogeneity [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR007.

Morphometric Analysis of Human Fetus and Fetal Pancreas in Different Gestational Age Groups

Introduction: Fetal biometric parameters are very often utilized for calculating gestational age. The pancreas is a gland with dual functions in our body – exocrine and endocrine, with the latter component being very often discussed in the context of diabetes mellitus. Through evaluation of variations in morphometry in relation to different gestational ages, the research intends to draw attention to various associated developmental correlations that were not mentioned in previous studies. Materials and Methods: The current research was carried out on 30 fetuses after obtaining due approval from Institute's Ethical Committee. Fetuses were divided into different gestational age groups and morphometric parameters such as crown-rump length, crown heel length, head circumference, abdomen circumference, chest circumference, hand length, and Foot Length (FL) were noted by measuring with nylon thread in centimetres. Fetal pancreases were removed after stepwise dissection and pancreatic weight along with length and thickness was measured by Vernier calipers. All the parameters were then compared within different gestational age groups. Results: All the parameters and the age group of fetuses were positively correlated and showed statistical significance. Conclusion: The study would add substantial knowledge in the areas of pancreatic regeneration, surgical pancreatectomy, and treatment protocols for diabetes mellitus and pancreatic cancer. Through evaluation of variations in morphometry in relation to different gestational ages, the research intends to draw attention to various associated developmental correlations.

Feasibility of modeling human intraductal papillary mucinous neoplasms of the pancreas using an organoid approach

Presenter: Nicholas Peters MD | Yale University School of Medicine Background: Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing, premalignant cystic lesion arising from the pancreatic ducts that can result in invasive pancreatic adenocarcinoma. The molecular origin of IPMN and etiology of malignant degeneration remains poorly understood, in part due to the lack of an in vitro model for study. Organoid-based systems have emerged as a genetically-tractable approach for tumor study. We sought to assess the feasibility of creating an organoid-based model system for the study of human IPMN. Methods: Patients undergoing surgical resection for presumed IPMN of any histological subtype or category of dysplasia were eligible for study inclusion. Within 30 minutes of resection, fresh aliquots of IPMN and grossly normal pancreatic duct were obtained. Specimens were enzymatically digested to oligo-cell clusters, embedded in solubilized basement membrane (Matrigel), and grown in permissive media promoting enrichment of the ductal epithelial fraction. Creation of spherical organoids capable of sustained growth, defined as 3 sequential culture passages, was defined as a successfully propagated culture. Microscopy, immunohistochemistry (IHC), and genotypic analysis of known highly-penetrant IPMN mutations were then performed on mature organoid cultures when possible. Results: 29 unique cyst wall or adjacent, grossly normal pancreatic ductal tissue sections from 11 patients (range, 1-6 sections/patient) were freshly harvested from surgical pancreatectomy specimens. The source tissues were then subsequently confirmed as IPMN via histologic examination by an experienced pancreatic surgical pathologist. The harvested tissue subjected to enzymatic digestion and culture ranged from 18 – 164mg. Spheroid formation and successful, sustained growth for at least three passages was attained in 11 organoid cultures (38%) as demonstrated by phase-contrast microscopy (Figure 1A). Continuous cultures were sustained in successful isolates from 22 - 385 days (median, 92 days). Genomic DNA was successfully isolated from 10 organoid cultures. Targeted sequencing was completed in 4 samples and revealed KRAS G12x/Q61x or GNAS R201x mutations in 3/3 IPMN samples, and 0/1 adjacent normal samples. To date, IHC analysis of 1 organoid demonstrated recapitulation of pathognomonic IPMN-defining protein expression consistent with the clinical tissue of origin (CDX2, MUC2, MUC5AC shown in Figure 1 B, C, and D, respectively). Conclusion: Creation of sustained human-derived IPMN organoids is feasible and the current data shows recapitulation of key driver mutations and IPMN-specific protein expression in vitro. Future improvements in organoid generation efficiency, durability and characterization will enhance the applicability of this approach.

Treatment of Pancreatic Exocrine Insufficiency with Enteric Coated Pancreatin Formulations: An Overview

Pancreatin is a mixture of several digestive enzymes produced by the exocrine cells of the pancreas. It is composed of amylase, lipase and protease. It is used to treat conditions in which pancreatic secretions are deficient, such as surgical pancreatectomy, pancreatitis and cystic fibrosis. Pancreatin products contain the pancreatic enzymes trypsin, amylase and lipase. The patients with pancreatic diseases often suffer from pancreatic exocrine insufficiency. In such condition pancreas does not secrete required amount of digestive enzymes for proper digestion to occur. Severe pancreatic insufficiency occurs in cystic fibrosis, chronic pancreatitis, tumors or after surgical resection. Thus pancreatic exocrine insufficiency may result in clinical manifestation of malnutrition, weight loss and steatorrhea leading towards the increased risk of morbidity and mortality. For the improvement of clinical symptoms, restriction of fat intake and pancreatic enzyme replacement therapy are recommended. The enzyme substitution therapy is very much challenging because the optimal enzyme dose is highly variable to mimic the physiological pattern of pancreatic exocrine secretion. Regulatory authorities have approved several pancreatic enzyme formulations in the form of enteric coated minimicrosphere which are now available commercially. This review focuses on the physiological considerations of pancreatic exocrine insufficiency and its treatment with enteric coated pancreatin formulations.

Pseudomyxoma peritonei arising from intraductal papillary neoplasm after surgical pancreatectomy: report of 2 cases and review of the literature.

We report 2 cases of pseudomyxoma peritonei (PMP) combined with an intraductal papillary mucinous neoplasm (IPMN) and a review of the literature. In both cases, PMP emerged after surgical resection of the IPMN. In one case, neoplastic foci were present in the surgical margin and PMP was found 1year after the initial resection, while PMP emerged 5years after surgical resection in the other case. Including these 2 cases, 8 cases of PMP arising from IPMN have been reported. This condition occurs more frequently in males (7 males, 1 female), while the age at diagnosis ranges from 49 to 82years, with a mean of 63.3years. IPMNs occur more commonly in the tail of the pancreas (62.5%). Two different patterns regarding the mechanism of PMP arising from IPMN have been indicated; a rupture of the pancreatic duct, after which the neoplasm spreads through the fistula into the peritoneal cavity, and post-surgical development of PMP after insufficient surgical treatment for an IPMN. Our findings indicate that attention must be given to avoid mucous leakage and obtain a negative surgical margin during surgical treatment of an IPMN.

Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations

Congenital hyperinsulinism is a condition of dysregulated insulin secretion often caused by inactivating mutations of the ATP-sensitive K+ (KATP) channel in the pancreatic beta cell. Though most disease-causing mutations of the 2 genes encoding KATP subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating KATP mutations, we have identified and characterized 16 families with 14 different dominantly inherited KATP mutations, including a total of 33 affected individuals. The 16 probands presented with hypoglycemia at ages from birth to 3.3 years, and 15 of 16 were well controlled on diazoxide, a KATP channel agonist. Of 29 adults with mutations, 14 were asymptomatic. In contrast to a previous report of increased diabetes risk in dominant KATP hyperinsulinism, only 4 of 29 adults had diabetes. Unlike recessive mutations, dominantly inherited KATP mutant subunits trafficked normally to the plasma membrane when expressed in COSm6 cells. Dominant mutations also resulted in different channel-gating defects, as dominant ABCC8 mutations diminished channel responses to magnesium adenosine diphosphate or diazoxide, while dominant KCNJ11 mutations impaired channel opening, even in the absence of nucleotides. These data highlight distinctive features of dominant KATP hyperinsulinism relative to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy, without the need for surgical pancreatectomy.

Use of the Continuous Glucose Monitoring System in Goettingen Minipigs, With a Special Focus on the Evaluation of Insulin-Dependent Diabetes

Objectives Adult pig islet isolation has greatly improved in the past few years. Islet grafts may now be tested in large animals. Continuous Glucose Monitoring System (CGMS) was applied to diabetic Goettingen Minipigs (GMP) to improve the management of hyperglycemia and hypoglycemia and their welfare before transplantation. Methods GMP (25–35 kg) received a minipig diet once daily. Diabetes was induced by streptozotocin (STZ; 150 mg/kg intravenous [IV]; n = 5) or by surgical pancreatectomy (PGMP; n = 3). Interstitial glucose concentration (IGC) was monitored continuously with an implanted sensor; CGMS was calibrated using conventional blood glucose tests 3–4 times per day; CGMS data were fed into the monitor memory and analyzed using CGMS software. Results Glucose sensors were handled accurately. Diabetes occurred 2–3 days after STZ or immediately after pancreatectomy with basal C-peptide secretion of <0.4 ng/mL (measured using intravenous glucose tolerance test) and prompt loss of body weight. Insulin substitution was necessary to keep the GMP in good condition for up to 5–6 months, with stable body weight and normal behavior. Some GMP became hypoglycemic, which was only documented by CGMS, but not by conventional glucose assays. Tight glucose control and substitution of exocrine enzymes (Creon 25,000 E/d) reduced morbidity of the PGMP, which was then comparable with that of STZ-GMP. Conclusions The CGMS, developed for humans, is equally suitable for the 2 GMP diabetes models. Close-meshed glucose monitoring and insulin treatment improved the general condition of the diabetic GMP, ie, the islet graft recipients, and will thus greatly add to posttransplantation success.

Studies of the isolation, viability, and preservation of purified islets after surgical pancreatectomy in large pigs

Abstract: Previous studies have shown separation of mass quantities of islets from slaughterhouse pig pancreases. In these studies, we examined the isolation, viability, and preservation of pig islets obtained by surgical pancreatectomy. Pigs aged 6 to 30 months weighing 100 to 200 kg were subjected to laparotomy under general anesthesia. The splenic lobe of pancreas was mobilized without warm ischemia. Islets were immediately isolated by collagenase perfusion through the duct, automated dissociation, and Ficoll purification. Yields of islets (150 μm size) were 8500 to 9300/g for two different collagenases before purification. Purification yielded 90% pure islets, but yields decreased to 400 to 600/g. Perifusate insulin release was biphasic after glucose/theophylline with 3 to 5‐fold stimulation. Following culture/cryopreservation marked islet losses occurred but viability was preserved. Quantities of 1,500 islet equivalents resulted in euglycemia in nude mice. These data show that mass quantities of viable islets can be isolated after pancreatectomy, but there is marked islet loss during purification and subsequent preservation due to inherent islet fragility.

Cerebral blood flow and metabolism in dogs with chronic diabetes.

Previously, the authors found that anesthetized diabetic dogs had increased cerebral blood flow (CBF) and oxygen consumption (CMRO2). These results may have been influenced by anesthesia or surgery. The aim of this study was to determine whether CBF and CMRO2 are increased in the awake or anesthetized state in the absence of acute surgical stress in diabetic dogs. A second aim was to determine whether increased CBF and CMRO2 in diabetic dogs are mediated through beta-adrenergic mechanisms. Diabetic dogs (n = 8) underwent total surgical pancreatectomy followed by 4 months of insulin management (16 +/- 0.4 units/day, mean +/- SE) to maintain fasting and 3 PM blood glucose 10-17 mM. Control dogs (n = 8) underwent sham operation followed by a 4-month convalescence. Using previously inserted catheters, CBF (radiolabelled microspheres) and CMRO2 (sagittal sinus sampling) were measured before and after propranolol (2 mg/kg) in both the awake and anesthetized states. During the 4 months before CBF studies, the fasting blood glucose was greater in diabetic group than in the control group (11.0 +/- 0.3 vs. 4.0 +/- 0.1 mM, respectively). No difference occurred between groups in CBF or CMRO2. In the awake state, propranolol administration caused no CBF or CMRO2 changes. However, during anesthesia with 50 micrograms/kg fentanyl plus 10 mg/kg pentobarbital, propranolol administration decreased CBF in control, but not in diabetic, dogs. The authors' previous results showing increased CBF and CMRO2 with diabetes may be secondary to a differential response to acute surgical stress, a factor that was eliminated in this study. These results indicate that diabetes is associated with changes in the beta-adrenergic system that become evident under fentanyl/pentobarbital anesthesia.

Role of the pancreas in the control of interdigestive gastrointestinal motility

Our aim was to determine if the pancreas regulates the interdigestive motor patterns of the upper gut. Four dogs were prepared with gastric and intestinal manometry catheters and interdigestive (fasting) motility was measured before and after total surgical pancreatectomy. The characteristics of the gastric and intestinal migrating motor complex were very similar before and after pancreatectomy. The time intervals between successive migrating motor complexes in the antrum (145 ± 11 vs. 135 ± 15 min, mean ± SE) or small intestine (133 + 10 vs. 137 ± 16 min) were not significantly (p > 0.4) altered by pancreatectomy, but the antral motility index (the sum of the antral contractions in a 15-min period) was greater after pancreatectomy (53 ± 6 vs. 27 ± 4; p < 0.05). Pancreatectomy led to undetectable plasma concentrations of pancreatic polypeptide, but had no effect on absolute concentrations of plasma motilin or on the cycling of plasma motilin in association with the duodenal migrating motor complex. We conclude that the pancreas and pancreatic polypeptide play little, if any, role in controlling canine interdigestive motility of the upper gut.

Insulin dependence of the actions of growth hormone and somatostatin on splanchnic biogenic amines of the dog.

It is known from studies previously conducted in this laboratory that an iv injection of ovine growth hormone (GH, 100 micrograms/kg BW) or an equimolar amount of somatostatin (SRIF, 7.5 micrograms/kg BW), given to normal conscious dogs into a saphenous vein, leads to a significant increase in hepatic portal plasma serotonin and a simultaneous decrease in the concentrations of dopamine, norepinephrine and epinephrine. The changes take place within 12 minutes after the injection and are observed only in the portal circulation. The purpose of the present experiment was to investigate whether or not similar results could be obtained in diabetic animals. Mongrel dogs were rendered diabetic by surgical pancreatectomy and fitted with an indwelling hepatic portal catheter. Radioenzymatic methods were employed for quantitative measurements of plasma free serotonin and catecholamines. No response was noted when the same type of experiments as those conducted in normal dogs were now carried out in trained, fully conscious totally pancreatectomized dogs deprived of exogenous insulin supply. When the same animals were given an injection into a peripheral vein of 50 mU/kg BW regular crystalline insulin (a small dose that affected neither plasma glucose nor biogenic amine levels) 10 minutes prior to the administration of the other hormones, the usual response to both GH and SRIF was restored, i.e. the data were comparable to those of normal dogs. It is concluded that the GH/SRIF effect on gut biogenic amines is insulin dependent.

Effects of Partial Surgical Pancreatectomy in Rats

The capacity for pancreatic regeneration in male Wistar rats of average weight 176 g was determined after surgical resection of 50, 70, or 90% of the pancreas. In control animals of this weight pancreatic growth was still taking place but ceased after 2 months. Growth of the residual pancreas in resected animals over this period was greater than in controls and the final weight of the residual pancreas was 21, 32, and 78% greater than that of the corresponding segments in sham-operated animals after 50, 70, and 90% resection respectively. Proliferation of acinar cells was assayed by autoradiographic detection of tritiated thymidine incorporation in controls and after 90% resection. Proliferation of acinar cells in control animals during the first 2 weeks of the experiment was significantly higher than at later times when it fell to very low levels. Proliferation in 90% resected animals was markedly higher than in controls from 2 to 5 days after resection and, together with the limited hypertrophy occurring at this time, adequately accounted for the increase in weight of the residual pancreas during the first 2 weeks. We were unable to explain the increase in pancreatic weight in control or resected animals between 2 weeks and 2 months either in terms of hypertrophy or hyperplasia of acinar cells.