Glucagon receptor gene mutations with hyperglucagonemia but without the glucagonoma syndrome

Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity within the panel of non-syndromic disorders associated with hyperglucagonemia. This case report describes a 36-year-old female with a 10 years history of non-specific abdominal pain. No underlying cause was evident despite extensive diagnostic work-up. More recently she was diagnosed with gall bladder stones. Abdominal ultrasound, computerised tomography and magnetic resonance imaging revealed no pathologic findings apart from cholelithiasis. Endoscopic ultrasound revealed a 5.5 mm pancreatic lesion. Fine needle aspiration showed cells focally expressing chromogranin, suggestive but not diagnostic of a low grade neuroendocrine tumor. OctreoScan(®) was negative. Serum glucagon was elevated to 66 pmol/L (normal: 0-50 pmol/L). Other gut hormones, chromogranin A and chromogranin B were normal. Cholecystectomy and enucleation of the pancreatic lesion were undertaken. Postoperatively, abdominal symptoms resolved and serum glucagon dropped to 7 pmol/L. Although H and E staining confirmed normal pancreatic tissue, immunohistochemistry was initially thought to be suggestive of alpha cell hyperplasia. A count of glucagon positive cells from 5 islets, compared to 5 islets from 5 normal pancreata indicated that islet size and glucagon cell ratios were increased, however still within the wide range of normal physiological findings. Glucagon receptor gene (GCGR) sequencing revealed a heterozygous deletion, K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition

Endoscopic ultrasound guided radiofrequency ablation, for pancreatic cystic neoplasms and neuroendocrine tumors

AIM: To outline the feasibility, safety, adverse events and early results of endoscopic ultrasound (EUS)-radiofrequency ablation (RFA) in pancreatic neoplasms using a novel probe. METHODS: This is a multi-center, pilot safety feasibility study. The intervention described was radiofrequency ablation (RF) which was applied with an innovative monopolar RF probe (1.2 mm Habib EUS-RFA catheter) placed through a 19 or 22 gauge fine needle aspiration (FNA) needle once FNA was performed in patients with a tumor in the head of the pancreas. The Habib™ EUS-RFA is a 1 Fr wire (0.33 mm, 0.013") with a working length of 190 cm, which can be inserted through the biopsy channel of an echoendoscope. RF power is applied to the electrode at the end of the wire to coagulate tissue in the liver and pancreas. RESULTS: Eight patients [median age of 65 (range 27-82) years; 7 female and 1 male] were recruited in a prospective multicenter trial. Six had a pancreatic cystic neoplasm (four a mucinous cyst, one had intraductal papillary mucinous neoplasm and one a microcystic adenoma) and two had a neuroendocrine tumors (NET) in the head of pancreas. The mean size of the cystic neoplasm and NET were 36.5 mm (SD ± 17.9 mm) and 27.5 mm (SD ± 17.7 mm) respectively. The EUS-RFA was successfully completed in all cases. Among the 6 patients with a cystic neoplasm, post procedure imaging in 3-6 mo showed complete resolution of the cysts in 2 cases, whilst in three more there was a 48.4% reduction [mean pre RF 38.8 mm (SD ± 21.7 mm) vs mean post RF 20 mm (SD ± 17.1 mm)] in size. In regards to the NET patients, there was a change in vascularity and central necrosis after EUS-RFA. No major complications were observed within 48 h of the procedure. Two patients had mild abdominal pain that resolved within 3 d. CONCLUSION: EUS-RFA of pancreatic neoplasms with a novel monopolar RF probe was well tolerated in all cases. Our preliminary data suggest that the procedure is straightforward and safe. The response ranged from complete resolution to a 50% reduction in size

Minimally invasive versus open distal pancreatectomy for pancreatic neuroendocrine tumors: An analysis from the U.S. neuroendocrine tumor study group

BackgroundTo determine shortâ and longâ term oncologic outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for the treatment of pancreatic neuroendocrine tumor (pNET).MethodsThe data of the patients who underwent curative MIDP or ODP for pNET between 2000 and 2016 were collected from a multiâ institutional database. Propensity score matching (PSM) was used to generate 1:1 matched patients with MIDP and ODP.ResultsA total of 576 patients undergoing curative DP for pNET were included. Two hundred and fourteen (37.2%) patients underwent MIDP, whereas 362 (62.8%) underwent ODP. MIDP was increasingly performed over time (2000â 2004: 9.3% vs 2013â 2016: 54.8%; Pâ <â 0.01). In the matched cohort (nâ =â 141 in each group), patients who underwent MIDP had less blood loss (median, 100 vs 200â mL, Pâ <â 0.001), lower incidence of Clavienâ Dindoâ â ¥â III complications (12.1% vs 24.8%, Pâ =â 0.026), and a shorter hospital stay versus ODP (median, 4 versus 7 days, Pâ =â 0.026). Patients who underwent MIDP had a lower incidence of recurrence (5â year cumulative recurrence, 10.1% vs 31.1%, Pâ <â 0.001), yet equivalent overall survival (OS) rate (5â year OS, 92.1% vs 90.9%, Pâ =â 0.550) compared with patients who underwent OPD.ConclusionPatients undergoing MIDP over ODP in the treatment of pNET had comparable oncologic surgical metrics, as well as similar longâ term OS.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150595/1/jso25481_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150595/2/jso25481.pd

Evaluation of tissue perfusion of the gastric tube after esophagectomy with the use of microdialysis

OBJECTIVE: One of the most catastrophic events following major surgery is anastomotic leak. Leak leads to sepsis and if not treated promptly, to septic shock, multiple organ failure and death. When major surgical procedures are performed, various intraoperative hemodynamic alternations may occur. These are treated by the anesthesiology team with fluid loads and/or administration of inotropes and pressors. The study presented here investigates the effect of these drugs on tissue perfusion and hypoxia. We will evaluate the potency of such drugs to deteriorate perfusion, thus reducing the chance of the anastomosis to heal. METHODS: This was an experimental, prospective, observational study. Eight sus scrofa landrace swine were used. Transhiatal esophagectomy was performed, followed by administration of pressors and inotropes in a predetermined sequence. Originally the animals were stabilized and then, dopamine and nitroglycerine were administered, each for a time period of one hour. After that, we provoked hemorrhagic shock and we resuscitated the animals with noradrenaline. Microdilaysis (CMA microdialysis, Sweden) was used to evaluate the impact of these drugs on tissue perfusion. Microdialysis is a technique that allows monitoring of cell biochemistry. With the use of a catheter that mimics capillary microcirculation, anaerobic glucolysis can be determined. Simultaneously we were monitoring arterial blood pressure and heart rate of the animals. RESULTS: Esophagectomy was feasible in all cases. We had no intraoperative complications and all animals survived the procedure. The operation provoked minor anaerobic metabolism as underlined by a minor increase in lactate to pyruvate ratio which is a marker of hypoxia. The clinical reaction to the procedure was tachycardia and hypotension. The administration of dopamine and nitroglycerine did not affect either the metabolic state or the clinical condition of the animals. However, the hemorrhagic shock and, more importantly, the administration of noradrenaline compromised perfusion to the anastomosis as recorded by an elevation on lactate to pyruvate ratio. At the same time, clinical indices such as blood pressure and heart rate were rather unaffected. CONCLUSIONS: Apart from a bedside curiosity, microdialysis is a powerful tool for oxygen metabolism monitoring. Anastomotic integrity is influenced by a variety of parameters (adequate blood supply, meticulous technique). Some are known and are being taken care of intraoperatively. Specific drugs, especially pressors, should be avoided in the management of intraoperative hypotension since they may compromise the blood supply of the anastomotic line. This is particularly the case with esophagectomy, where the blood supply of the graft is dependent on a single artery, the right gastroepiploic artery.ΕΙΣΑΓΩΓΗ: Μια από τις καταστροφικότερες επιπλοκές της χειρουργικής είναι η διαφυγή από την αναστόμωση μεταξύ δυο οργάνων. Η διαφυγή οδηγεί με μαθηματική ακρίβεια σε σήψη που εάν δεν αντιμετωπιστεί έγκαιρα οδηγεί σε σηπτική καταπληξία, πολυοργανική ανεπάρκεια και θάνατο. Κατά τις μείζονες χειρουργικές επεμβάσεις συχνά εκτελούνται διάφορες αναστομώσεις μεταξύ οργάνων. Επιπρόσθετα, κατά τη διάρκεια αυτών των επεμβάσεων είναι συχνά τα αιμοδυναμικά συμβάματα τα οποία αντιμετωπίζονται από την αναισθησιολογική ομάδα με τη χορήγηση υγρών και ινότροπων φαρμάκων. Η έρευνα αυτή μελετά την επίδραση των αγγειοδραστικών φαρμάκων στην ιστική οξυγόνωση της οισοφαγογαστρικής αναστόμωσης μετά από οισοφαγεκτομή και ελέγχει το εάν η χορήγηση αυτών των φαρμάκων μπορεί να θέσει σε κίνδυνο τη βιωσιμότητα της αναστόμωσης. ΜΕΘΟΔΟΛΟΓΙΑ: Η μελέτη είναι πειραματική, προοπτική μελέτη παρατήρησης. Χρησιμοποιήθηκαν συνολικά οκτώ χοίροι στους οποίους έγινε οισοφαγεκτομή δια του διαφράγματος. Στη συνέχεια τα πειραματόζωα υποβλήθηκαν με τη σειρά σε τέσσερις χειρισμούς: χορήγηση ντοπαμίνης, χορήγηση νιτρογλυκερίνης, αιμορραγική καταπληξία και ανάνηψη με νοραδρεναλίνη. Για τη μελέτη της επίδρασης των χειρισμών αυτών στην ιστική οξυγόνωση της αναστόμωσης χρησιμοποιήθηκε η τεχνική της μικροδιάλυσης. Η μικροδιάλυση είναι μια τεχνική παρακολούθησης της κυτταρικής βιοχημείας. Με τη βοήθεια ενός ειδικά διαμορφωμένου καθετήρα ο οποίος μιμείται την λειτουργία των αγγειακών τριχοειδών, η μέθοδος έχει τη δυνατότητα να μετράει τον αναερόβιο μεταβολισμό της γλυκόζης και να δίνει στοιχεία σχετικά με την παρουσία ή την απουσία οξυγόνου στους ιστούς. Παράλληλα με τις μετρήσεις της μικροδιάλυσης έγιναν και μετρήσεις κλινικών παραμέτρων, όπως οι σφύξεις και η πίεση. ΑΠΟΤΕΛΕΣΜΑΤΑ: Η οισοφαγεκτομή δια του διαφράγματος ήταν εφικτή σε όλα τα πειραματόζωα. Δεν υπήρχαν μείζονα διεγχειρητικά συμβάματα εκτός πρωτοκόλλου και όλοι οι χοίροι επέζησαν της οισοφαγεκτομής. Η κλινική και μεταβολική ανταπόκριση στην επέμβαση και τους χειρισμούς ήταν η ίδια για όλα τα πειραματόζωα. Η επέμβαση καθεαυτή, συνοδεύτηκε από μέτρια επιδείνωση της ιστικής οξυγόνωσης, ταχυκαρδία και υπόταση. Στη συνέχεια, η χορήγηση ντοπαμίνης και νιτρογλυκερίνης δεν επηρέασε τα πειραματόζωα ούτε κλινικά ούτε μεταβολικά. Η αιμορραγική καταπληξία προκάλεσε ταχυκαρδία, υπόταση και επιδείνωση της ιστικής οξυγόνωσης, όμως σε μη στατιστικά σημαντικά επίπεδα. Η χορήγηση της νοραδρεναλίνης, προκάλεσε σημαντική επιδείνωση της ιστικής οξυγόνωσης, σε επίπεδα στατιστικά σημαντικά. ΣΥΜΠΕΡΑΣΜΑΤΑ: Πέραν της επαρκούς αιμάτωσης και της σωστής τεχνικής, η βιωσιμότητα μιας αναστόμωσης μπορεί να επηρεαστεί και από τη χορήγηση αγγειοδραστικών φαρμάκων, ιδίως νοραδρεναλίνης. Η σημαντική αγγειοσύσπαση που προκαλεί η συγκεκριμένη ουσία μπορεί να επηρεάσει την ιστική οξυγόνωση ιδιαίτερα σε περιοχές όπως η οισοφαγογαστρική αναστόμωση που η αιμάτωση όλου του μοσχεύματος εξαρτάται από ένα και μόνο αγγείο. Η χορήγηση αυτών των φαρμάκων για την ανάταξη της διεγχειρητικής υπότασης θα πρέπει να αποφεύγεται

Neuroendocrine neoplasms: Identification of novel metabolic circuits of potential diagnostic utility

The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (1H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36–85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker 1H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine-N-oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort

Goblet cell carcinomas of the appendix: rare but aggressive neoplasms with challenging management.

Goblet cell carcinomas (GCC) are a rare, aggressive sub-type of appendiceal tumours with neuroendocrine features, and controversy exists with regards to therapeutic strategy. We undertook a retrospective review of GCC patients surgically treated at two tertiary referral centres. Clinical and histopathological data were extracted from a prospectively maintained database. Survival analyses utilised Kaplan-Meier methodology. Twenty-one patients were identified (9 females). Median age at diagnosis was 55years (range 32-77). There were 3, 6 and 9 grade 1, 2 and 3 tumours, respectively. One, 10, 5 and 5 patients had stage I, II, III and IV disease at diagnosis, respectively. There were 8, 10 and 3 Tang class A, B and C tumours, respectively. Index operation was appendectomy (n=12), right hemicolectomy (n=6) or resections including appendix/right colon, omentum and the gynaecological system (n=3). Eight patients underwent completion right hemicolectomy. Surgery for recurrence included small bowel resection (n=2), debulking with peritonectomy and heated intraperitoneal chemotherapy, and hysterectomy and bilateral salpingo-oophorectomy (all n=1). Median follow-up was 30months (range 2.5-123). One-, 3- and 5-year OS was 79.4%, 60% and 60%, respectively. Mean OS (1-, 3-, and 5-year OS) for Tang class A, B and C tumours were 73.1months (85.7%, 85.7%, 51.4%), 83.7months (all 66.7%) and 28.5months (66.7%, 66.7%, not reached), respectively. Chromogranin A/B and 68Ga-DOTATATE PET/CT were not useful in follow-up, but CEA, CA 19-9, CA 125 and 18F-FDG PET/CT identified tumour recurrence. GCC must be clearly discriminated from relatively indolent appendiceal neuroendocrine neoplasms. 18F-FDG PET/CT and CEA/CA19-9/CA-125 are useful in detecting recurrence of GCC

Incidence of Second Primary Malignancies in Patients with Neuroendocrine Tumours

Background: An association between neuroendocrine tumours (NET) and increased risk of developing second primary malignancies (SPM) has been recognised. Methods: This was a retrospective review of our institutional prospectively maintained database of NET patients. We identified patients who had been diagnosed with both neuroendocrine and any additional malignancies via examination of patient notes. Results: Clinical data for 169 patients were analysed. After exclusion of patients known to have hereditary tumour predisposition syndromes, 29 SPM were identified in 26 patients (15.38%), the commonest being colorectal (n = 6), breast and renal carcinomas (both n = 5). SPM were classified as previous, synchronous or subsequent relative to NET diagnosis. Rates of SPM in pancreatic and small-bowel NET patients were comparable (15.7 vs. 19.6%, p = 0.78). A personyear methodology was used to compare observed numbers of SPM against expected values generated from age-and sex-specific incidence tables, with standardised incidence ratios (SIR) and 95% confidence intervals (CI) calculated. SPM incidence was significantly elevated in the synchronous subset (SIR 2.732, CI 1.177-5.382) whilst significantly fewer NET patients had a cancer history compared to the general population (SIR 0.4, CI 0.241-0.624). No overall differences were evident between observed and expected incidences of subsequent SPM (SIR 0.36, CI 0.044-1.051). The incidence of synchronous colorectal cancers was markedly elevated (SIR 13.079, CI 4.238-30.474). Conclusions: Our data support the use of colonoscopy in the diagnostic work-up of NET patients in anticipation of a colorectal SPM. The mechanistic underpinnings of this clinical phenomenon require further genetic investigation, and consideration of this knowledge in patient management pathways is warranted. (C) 2015 S. Karger AG, Base

Goblet cell carcinomas of the appendix: rare but aggressive neoplasms with challenging management

Goblet cell carcinomas (GCC) are a rare, aggressive sub-type of appendiceal tumours with neuroendocrine features, and controversy exists with regards to therapeutic strategy. We undertook a retrospective review of GCC patients surgically treated at two tertiary referral centres. Clinical and histopathological data were extracted from a prospectively maintained database. Survival analyses utilised Kaplan–Meier methodology. Twenty-one patients were identified (9 females). Median age at diagnosis was 55 years (range 32–77). There were 3, 6 and 9 grade 1, 2 and 3 tumours, respectively. One, 10, 5 and 5 patients had stage I, II, III and IV disease at diagnosis, respectively. There were 8, 10 and 3 Tang class A, B and C tumours, respectively. Index operation was appendectomy (n = 12), right hemicolectomy (n = 6) or resections including appendix/right colon, omentum and the gynaecological system (n = 3). Eight patients underwent completion right hemicolectomy. Surgery for recurrence included small bowel resection (n = 2), debulking with peritonectomy and heated intraperitoneal chemotherapy, and hysterectomy and bilateral salpingo-oophorectomy (all n = 1). Median follow-up was 30 months (range 2.5–123). One-, 3- and 5-year OS was 79.4, 60 and 60%, respectively. Mean OS (1-, 3-, and 5-year OS) for Tang class A, B and C tumours were 73.1 months (85.7, 85.7, 51.4%), 83.7 months (all 66.7%) and 28.5 months (66.7, 66.7%, not reached), respectively. Chromogranin A/B and 68Ga-DOTATATE PET/CT were not useful in follow-up, but CEA, CA 19-9, CA 125 and 18F-FDG PET/CT identified tumour recurrence. GCC must be clearly discriminated from relatively indolent appendiceal neuroendocrine neoplasms. 18F-FDG PET/CT and CEA/CA19-9/CA 125 are useful in detecting recurrence of GCC