Therapeutic anticoagulation in patients with acute pancreatitis and splanchnic vein thrombosis: a best evidence topic.

A best evidence topic in general surgery was written according to a structured protocol. The clinical question addressed was: in adult patients with splanchnic vein thrombosis in acute pancreatitis, would administration of therapeutic anticoagulation be advisable considering the rates of vessel recanalization and bleeding complications? Four hundred twenty-four papers were found on Ovid Embase and Medline whilst 222 were found on PubMed using the reported literature search. From these, five articles represented the best evidence to the clinical question. The authors, publication dates, countries, patient groups, study outcomes, and results of these papers were tabulated. There were three systematic reviews with meta-analyses, one systematic review without meta-analysis and one randomized, retrospective study. The authors conclude that among patients with splanchnic vein thrombosis in the context of acute pancreatitis, therapeutic anticoagulation improved the rates of recanalization without increasing the risk of bleeding complications. However, there remains a need for randomized studies to address this clinical dilemma to further increase the quality of available evidence.

Postoperative packing of perianal abscesses following incision and drainage.

A best evidence topic in general surgery was written according to a structured protocol, to address the question: in adult patients with perianal abscesses, should postoperative wound packing be undertaken considering the rates of pain experienced, wound healing and abscess recurrence? The literature search identified 159 papers on Ovid, Embase and Medline and 48 on PubMed. These were independently screened, and three articles were included in this review as these offered the best information to answer the question. One was a systematic review without meta-analysis, one was a randomised controlled trial and one was a multicentre observational study. Review of these articles led the authors to conclude that routine postoperative packing of perianal abscesses following incision and drainage is costly, associated with increased pain and confers no protection against recurrence of abscesses or formation of fistulae.

Management of Small Bowel Neuroendocrine Tumours: 10 Years' Experience at a Tertiary Referral Centre.

BACKGROUND: Neuroendocrine tumours (NET) arising from the small bowel are clinically challenging and are often diagnosed at advanced stages. Disease control with surgery alone can be demanding. Multimodal treatment concepts integrating surgery and non-surgical modalities could be of benefit. METHOD: Retrospective review of consecutive adult patients with SB NET treated at Imperial College Healthcare NHS Trust between 1 January 2010 and 31 December 2019. Data regarding clinicopathological characteristics, treatments, and disease trajectory were extracted and summarised. Overall and progression/recurrence-free survival were estimated at 5 and 10 years. RESULTS: 154 patients were identified, with a median age of 64 years (range 33-87); 135/154 (87.7%) had stage III/IV disease at diagnosis. Surgery was used in 125 individuals (81.2%), typically with either segmental small bowel resection (60.8%) or right hemicolectomy (33.6%) and mesenteric lymphadenectomy for the primary tumour. Systemic and/or liver-directed therapies were used in 126 (81.8%); 60 (47.6%) had more than one line of non-surgical treatment. Median follow-up was 67.2 months (range 3.1-310.4); overall survival at 5 and 10 years was 91.0% (95% CI: 84.9-94.7%) and 82.5% (95% CI: 72.9-88.9%), respectively. Imaging-based median progression-free survival was 42.7 months (95% CI: 24.7 to 72.4); 5-year progression-free survival was 63.4% (95% CI: 55.0-70.6%); 10-year progression-free survival was 18.7% (95% CI: 12.4-26.1). Nineteen patients (12.3%) reached 10 years follow-up without disease recurrence and therefore were considered cured. CONCLUSIONS: Most patients with SB NET present in a metastasised stage. Multimodal treatment concepts may be associated with excellent clinical outcomes. Future work should explore optimal approaches to treatment sequencing and patient selection.

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.

Radioembolisation with 90Y microspheres for neuroendocrine liver metastases: an institutional case series, systematic review and meta-analysis.

BACKGROUND: Neuroendocrine liver metastases are clinically challenging due to their frequent disseminated distribution. This study aims to present a British experience with an emerging modality, radioembolisation with yttrium-90 labelled microspheres, and embed this within a meta-analysis of response and survival outcomes. METHODS: A retrospective case series of patients treated with SIR-Spheres (radiolabelled resin microspheres) was performed. Results were included in a systematic review and meta-analysis of published results with glass or resin microspheres. Objective response rate (ORR) was defined as complete or partial response. Disease control rate (DCR) was defined as complete/partial response or stable disease. RESULTS: Twenty-four patients were identified. ORR and DCR in the institutional series was 14/24 and 21/24 at 3 months. Overall survival and progression-free survival at 3-years was 77.6% and 50.4%, respectively. There were no grade 3/4 toxicities post-procedure. A fixed-effects pooled estimate of ORR of 51% (95% CI: 47%-54%) was identified from meta-analysis of 27 studies. The fixed-effects weighted average DCR was 88% (95% CI: 85%-90%, 27 studies). CONCLUSION: Current data demonstrate evidence of the clinical effectiveness and safety of radioembolisation for neuroendocrine liver metastases. Prospective randomised studies to compare radioembolisation with other liver directed treatment modalities are needed.

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.

Surgical Management of Patients with Neuroendocrine Neoplasms of the Appendix: Appendectomy or More.

BACKGROUND: Appendiceal neuroendocrine neoplasms (ANEN) are mostly indolent tumours treated effectively with simple appendectomy. However, controversy exists regarding the necessity of oncologic right hemicolectomy (RH) in patients with histologic features suggestive of more aggressive disease. We assess the effects of current guidelines in selecting the surgical strategy (appendectomy or RH) for the management of ANEN. Methods/Aims: This is a retrospective review of all ANEN cases treated over a 14-year period at 3 referral centres and their management according to consensus guidelines of the European and the North American Neuroendocrine Tumor Societies (ENETS and NANETS, respectively). The operation performed, the tumour stage and grade, the extent of residual disease, and the follow-up outcomes were evaluated. RESULTS: Of 14,850 patients who had appendectomies, 215 (1.45%) had histologically confirmed ANEN. Four patients had synchronous non-ANEN malignancies. One hundred and ninety-three patients had index appendectomy. Seventeen patients (7.9%) had lymph node metastases within the mesoappendix. Forty-nine patients underwent RH after appendectomy. The percentages of 30-day morbidity and mortality after RH were 2 and 0%, respectively. Twelve patients (24.5%) receiving completion RH were found to have lymph node metastases. Two patients had liver metastases, both of them synchronous. The median follow-up was 38.5 months (range 1-143). No patient developed disease recurrence. Five- and 10-year overall survival for all patients with ANEN as the only malignancy was both 99.05%. CONCLUSIONS: The current guidelines appear effective in identifying ANEN patients at risk of harbouring nodal disease, but they question the oncological relevance of ANEN lymph node metastases. RH might present an overtreatment for a number of patients with ANEN.

Tumour diameter is not reliable for management of non-secreting pancreatic neuroendocrine tumours.

Small non-functioning pancreatic NETs (pNETs) ≤2 cm can pose a management dilemma in terms of surveillance or resection. There is evidence to suggest that a surveillance approach can be considered since there are no significant radiological changes observed in lesions during long-term follow-up. However, other studies have suggested loco-regional spread can be present in ≤2 cm pNETs. The aim of this study was to characterise the prevalence of malignant features and identify any useful predictive variables in a surgically resected cohort of pNETs. 418 patients with pNETs were identified from 5 NET centres. Of these 227 were included for main analysis of tumour characteristics. Mean age of patients was 57 years, 47% were female. The median follow-up was 48.2 months. Malignant features were identified in 38% of ≤2 cm pNETs. ROC analysis showed that the current cut-off of 20 mm had a sensitivity of 84% for malignancy. The rate of malignant features is in keeping with other surgical series and challenges the belief that small pNETs have a low malignant potential. This study does not support a 20 mm size cut-off as being a solitary safe parameter to exclude malignancy in pNETs.

Blood measurement of neuroendocrine gene transcripts defines the effectiveness of operative resection and ablation strategies.

BACKGROUND: Surgery is the only curative treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but the prediction of residual disease/recurrence is limited in the absence of optimal biomarkers. We examined whether a blood-based multianalyte neuroendocrine gene transcript assay (NETest) would define tumor cytoreduction and therapeutic efficacy. METHODS: The NETest is a polymerase chain reaction-based analysis of 51 genes. Disease activity is scaled 0-100%; minimal <14%, low 14-47%, and high >47%. A total of 35 GEP-NETs in 2 groups were evaluated. I: after surgery (R0, n = 15; residual, n = 12); II: nonsurgery (n = 8: embolization with gel-foam alone [bland: n = 3]), transarterial chemoembolization (n = 2), and radiofrequency embolization (n = 3). Measurement (quantitative real-time-polymerase chain reaction) and chromogranin A (CgA; enzyme-linked immunosorbent assay) were undertaken preoperatively and 1 month after treatment. RESULTS: NETest score was increased in 35 (100%) preoperatively; 14 (40%) had increased CgA (χ(2) = 30, P < 2 × 10(-8)). Resection reduced NETest from 80 ± 5% to 29% ± 5, (P < .0001). CgA decrease was insignificant (14.3 ± 1.6 U/L to 12.2 ± 1.7 U/L). NETest decreases correlated with diminished tumor volume (R(2) = 0.29, P = .03). Cytoreduction significantly reduced NETest from 82 ± 3% to 41% ± 6, P < .0001). CgA was not decreased (21.4 ± 5.5 U/L to 18.4 ± 10.1 U/L). Four (36%) of 11 R0s with increased NETest at 1 month developed positive imaging (sensitivity 100%, specificity 20%). One hundred percent (ablated group) were transcript- and image-positive. CONCLUSION: Blood NET transcripts delineate surgical resection/cytoreduction and facilitate identification of residual disease.

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.

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.

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 person-year 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.

Laparoscopic versus open pancreas resection for pancreatic neuroendocrine tumours: a systematic review and meta-analysis.

BACKGROUND: Over the last decade laparoscopic pancreatic surgery (LPS) has emerged as an alternative to open pancreatic surgery (OPS) in selected patients with neuroendocrine tumours (NET) of the pancreas (PNET). Evidence on the safety and efficacy of LPS is available from non-comparative studies. OBJECTIVES: This study was designed as a meta-analysis of studies which allow a comparison of LPS and OPS for resection of PNET. METHODS: Studies conducted from 1994 to 2012 and reporting on LPS and OPS were reviewed. Studies considered were required to report on outcomes in more than 10 patients on at least one of the following: operative time; hospital length of stay (LoS); intraoperative blood loss; postoperative morbidity; pancreatic fistula rates, and mortality. Outcomes were compared using weighted mean differences and odds ratios. RESULTS: Eleven studies were included. These referred to 906 patients with PNET, of whom 22% underwent LPS and 78% underwent OPS. Laparoscopic pancreatic surgery was associated with a lower overall complication rate (38% in LPS versus 46% in OPS; P < 0.001). Blood loss and LoS were lower in LPS by 67 ml (P < 0.001) and 5 days (P < 0.001), respectively. There were no differences in rates of pancreatic fistula, operative time or mortality. CONCLUSIONS: The nature of this meta-analysis is limited; nevertheless LPS for PNET appears to be safe and is associated with a reduced complication rate and shorter LoS than OPS.

Does tissue ischemia actually contribute to leak after sleeve gastrectomy? An experimental study.

BACKGROUND: Staple line leak, although rare, is among the most common postoperative complications after sleeve gastrectomy (SG) and usually occurs in the gastroesophageal (GE) junction. Increased intragastric pressure, regional ischemia, and technical failure of stapling devices have been reported as the main risk factors of postoperative leak. The aim of this study was to evaluate the impact of ischemia and intraluminal pressure in leak appearance. METHODS: Landrace swine (n = 12) were subjected to SG and total gastrectomy subsequently. Lactic acid, glycerol, and pyruvate were measured by microdialysis in GE junction and pylorus before and nine times after operation, and lactate/pyruvate (L/P) ratio was calculated as well. Moreover, ex vivo air was insufflated inside the tubularized stomach till a rupture of the staple line occurs. Maximum air pressure reached and location of rupture were recorded. RESULTS: Increase of lactic acid and L/P ratio were demonstrated in GE junction measurements; however, when the measurements between GE junction and pylorus were compared, no statistically significant differences were found, with the exception of a slightly increased lactate concentration in pylorus in the midst of measurements. The maximum air pressure recorded varied from 3 to 75 mmHg (mean 24.5 mmHg) and the majority of ruptures (n = 8) occurred in GE junction. In one of them, clip displacement was noticed. CONCLUSIONS: No evidence of increased ischemia in GE junction compared to pylorus was recorded. Increased intraluminal pressure and stapling malfunction may play the most important role in leak appearance.

Is octreotide beneficial in patients undergoing pancreaticoduodenectomy? Best evidence topic (BET).

A best evidence topic was written according to a structured protocol. The question addressed was whether the prophylactic administration of somatostatin or somatostatin analogues in patients undergoing pancreaticoduodenectomy (Whipple's procedure) is beneficial in terms of improved surgical outcomes, reduced morbidity or reduced mortality. A total of 118 papers were found using the reported searches of which 5 represented the best evidence (1 meta-analysis, 1 systematic review and 3 randomized control trials). The authors, date, journal, study type, population, main outcome measures and results were tabulated. There is evidence that the perioperative administration of somatostatin or somatostatin analogues reduces biochemical incidence of pancreatic fistula but, it is still unclear if there is a beneficial effect in the incidence of clinically significant pancreatic fistula. Further adequately powered trials with low risk of bias are necessary. From the available data, somatostatin or somatostatin analogues have no effect on mortality post Whipple's. Interestingly, there are only limited data available on the cost-benefit and financial constraints imposed by this treatment, an issue that has only been addressed in a few studies.

Metabonomic profiling: a novel approach in neuroendocrine neoplasias.

BACKGROUND: A metabonomic phenotyping strategy was developed as part of a pilot study to define a diagnostic metabolic phenotype for neuroendocrine neoplasms (NEN). METHODS: Twenty-eight patients with NEN were prospectively recruited: small bowel NEN, n = 8; pancreatic NEN, n = 10; and others, n = 10 (mean age 49.4 years [26­81] male/female ratio 17:11). There were 17 healthy control patients. Urine samples were subjected to 1H nuclear magnetic resonance spectroscopic profiling via the use of a Bruker Avance 600-MHz spectrometer (Bruker, Rheinstetten, Germany). Acquired spectral data were imported into SIMCA and MATLAB for supervised and unsupervised multivariate analysis. RESULTS: Partial least squares-discriminant analysis differentiated between NEN and healthy samples with accuracy (R(2)Y = 0.79, Q2Y = 0.53, area under the curve [AUC] 0.90). Orthogonal partial least squares-discriminant analysis was able to distinguish between small bowel NEN and pancreatic NEN (R2Y = 0.91, Q2Y = 0.35). Subclass analysis also demonstrated class separation between functional and nonfunctional NEN (R2Y = 0.98, Q2Y = 0.77, AUC 0.6) and those with metastases (R2Y = 0.72 , Q2 Y = 0.41, AUC 0.86) due to variations in hippurate metabolism (P < .0001). CONCLUSION: Metabonomic analysis suggests that subgroups of NEN may possess a stratified metabolic phenotype. Metabolic profiling could provide novel biomarkers for NEN.