Acinar content at pancreatic resection margin is significantly associated with clinically relevant pancreatic fistula after partial pancreatoduodenectomy.

BACKGROUND: This study aimed to evaluate the clinical significance of acinar content at the pancreatic resection margin after partial pancreatoduodenectomy (PD). METHODS: A total of 228 consecutive patients undergoing PD were included for analysis. Resection margins were assessed for acinar, fibrosis, and fat contents by 2 pathologists blinded to the patients' clinical data. Univariate and multivariable analyses of possible predictors for clinically relevant postoperative pancreatic fistula (cr-POPF) were performed. RESULTS: The median acinar, fibrosis, and fat contents were 70% (IQR, 25%-82%), 13% (IQR, 5%-40%), and 15% (IQR, 9.25%-25%), respectively. The rates of cr-POPF were significantly higher in patients with an acinar content of >70% than in patients with an acinar content of ≤70% (26.4% vs 5.5%, respectively; P < .001). In addition, the rates of postoperative hyperamylasemia (POH) were significantly higher in patients with an acinar content of ≥70% than in patients with an acinar content of ≤70% (55.2% vs 13.8%, respectively; P < .001). The median fat content did not differ between patients with and without cr-POPF (13.0% [IQR, 7.5%-20.0%] vs 15.0% [IQR, 10.0%-30.0%], respectively; P = .06). An acinar content of >70% at the pancreatic resection margin (odds ratio [OR], 4.85; 95% CI, 1.61-14.58; P = .005) and a soft pancreatic texture (OR, 2.82; 95% CI, 1.02-7.76; P = .046) were independent predictive factors of cr-POPF in the multivariable analysis. CONCLUSION: An acinar content of ≥70% at the pancreatic resection margin was a significant predictive factor for cr-POPF after PD and was also significantly associated with POH, a precursor of cr-POPF after PD in many cases. Fatty infiltration of the pancreatic resection margin was not associated with cr-POPF.

[Individualized approach for MEN1-associated duodenopancreatic neuroendocrine neoplasms]. / Individualisiertes Vorgehen bei MEN1-assoziierten duodenopankreatischen neuroendokrinen Neoplasien.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1)-associated duodenopancreatic neuroendocrine neoplasms (dpNEN) represent the most frequent syndrome-associated cause of death, but the adequate treatment is sometimes considered controversial. OBJECTIVE: Presentation of possible diagnostic and therapeutic options for MEN1-associated dpNENs. MATERIAL AND METHODS: In this review article retrospective case studies, expert recommendations, national and international guidelines as well as personal experiences were analyzed and evaluated. RESULTS: Due to early detection programs and the use of the most modern imaging techniques, dpNEN are nowadays diagnosed much earlier. Nonfunctional pNENs currently represent the most frequent dpNENs with about 70%, followed by gastrinomas and insulinomas. Regardless of their functional activity, dpNENs with a size of > 2 cm are generally an indication for surgery. The choice of the optimal treatment strategy, however, in most cases remains the subject of controversial discussions, although nowadays surgery should always be performed in an organ-preserving and minimally invasive way when feasible. Recurrences or new dpNENs are expected in more than 60% of cases, necessitating a reoperation in up to 40% of these cases. Duodenopancreatic resections and reoperations can be carried out safely by experienced practitioners and with an acceptable level of risk. CONCLUSION: The planning of treatment requires careful consideration of the suitable timing, the extent of the operation, the risk of recurrence and potential morbidities. Furthermore, preserving pancreatic function and the quality of life is of utmost importance. In view of the complexity of the disease, MEN1 patients should be treated in specialized centers.

Serum amylase on postoperative day 1 is superior to serum lipase in predicting clinically relevant pancreatic fistula after partial pancreaticoduodenectomy.

PURPOSE: To compare the predictive value of serum amylase and lipase regarding the occurrence of clinically relevant postoperative pancreatic fistula (cr-POPF) after partial pancreaticoduodenectomy (PD). METHODS: Data from 228 consecutive patients undergoing PD were obtained from a prospective database. Serum amylase and lipase were measured on postoperative days (PODs) 0-2. Receiver-operating characteristics analysis was performed and cutoff values were tested using logistic regression. RESULTS: Serum amylase had a larger area under the curve (AUC) on POD1 (AUC 0.89, p <0.001) than serum lipase. For serum amylase POD 1, a cutoff value of 70 U/l showed sensitivity and specificity of 100% and 70% for the diagnosis of cr-POPF. Serum amylase POD 1 > 70 U/l (OR 9.815, 95% CI 3.683-26.152, p < 0.001), drain amylase POD 1 > 300 U/l (OR 2.777, 95% CI 1.071-7.197, p= 0.036), and a small (≤ 3mm) pancreatic duct diameter (OR 3.705, 95% CI 1.426-9.627, p= 0.007) were significant predictors of cr-POPF in the multivariable analysis. Patients were divided into three risk groups based on serum amylase POD 1 and pancreatic duct diameter. This model had a good performance in discriminating cr-POPF (AUC 0.846, 95% CI 0.793-0.898). The sensitivity, specificity, and negative predictive value for the combination of serum amylase POD 1 <70 U/l and pancreatic duct diameter >3 mm were 100%, 70%, and 100%. CONCLUSION: Serum amylase POD 1 was superior to serum lipase in predicting cr-POPF after PD. The proposed risk prediction model had a sensitivity and negative predictive value of 100%, allowing for early identification of cr-POPF.

[Indication and Surgical Procedures for MEN1-associated Duodenopancreatic Neuroendocrine Neoplasms]. / Indikation und operative Verfahren bei MEN1-assoziierten duodenopankreatischen neuroendokrinen Neoplasien.

The optimal therapy of duodenopancreatic neuroendocrine neoplasia (dpNEN), which occurs in the context of multiple endocrine neoplasia type 1, is still a major challenge and is controversial. Due to the rarity of the disease, there is a lack of prospective randomised studies, so that most recommendations regarding the surgical indication and procedure are based on retrospective case series. In summary, surgical therapy is indicated for non-functional dpNEN > 2 cm, suspected malignancy and functionally active dpNEN. Enucleation or formal pancreatic resections with or without lymphadenectomy may be considered. The aim of therapy should be to eliminate hormone-associated symptoms and prevent an aggressive metastatic disease. At the same time, pancreatic function and quality of life should be preserved in the mostly young patients by resections that save as much parenchyma as possible.

Synergic Induction of Autophagic Cell Death in Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC) has poor prognosis, high mortality rate and lack of effective therapy. A synergic combination of PD-L1 antibody together with cell death promoting substances like deacetylase inhibitors (DACi) and multi-kinase inhibitors (MKI) could sensitize ATC cells and promote decay by autophagic cell death. The PD-L1-inhibitor atezolizumab synergized with panobinostat (DACi) and sorafenib (MKI) leading to significant reduction of the viability, measured by real time luminescence, of three different patient-derived primary ATC cells, of C643 cells and follicular epithelial thyroid cells too. Solo administration of these compounds caused a significant over-expression of autophagy transcripts; meanwhile autophagy proteins were almost not detectable after the single administration of panobinostat, thus supporting a massive autophagy degradation process. Instead, the administration of atezolizumab caused an accumulation of autophagy proteins and the cleavage of the active caspases 8 and 3. Interestingly, only panobinostat and atezolizumab were able to exacerbate the autophagy process by increasing the synthesis, the maturation and final fusion with the lysosomes of the autophagosome vesicles. Despite ATC cells could be sensitized by atezolizumab via the cleavage of the caspases, no reduction of cell proliferation or promotion of cell death was observed. The apoptosis assay evidenced the ability of panobinostat alone and in combination with atezolizumab to induce the phosphatidil serine exposure (early apoptosis) and further the secondary necrosis. Instead, sorafenib was only able to cause necrosis. The increase of caspases activity induced by atezolizumab, the apoptosis and autophagy processes promoted by panobinostat synergize thus promoting cell death in well-established and primary anaplastic thyroid cancer cells. The combined therapy could represent a future clinical application for the treatment of such lethal and untreatable solid cancer.

Pancreaticoduodenectomy Is the Best Surgical Procedure for Zollinger-Ellison Syndrome Associated with Multiple Endocrine Neoplasia Type 1.

AIM: The aim of this research was to evaluate the long-term outcome of pancreaticoduodenectomy (PD) versus other duodenopancreatic resections (non-PD) for the surgical treatment of the Zollinger-Ellison syndrome (ZES) in patients with multiple endocrine neoplasia type 1 (MEN1). METHODS: Prospectively recorded patients with biochemically confirmed MEN1-ZES who underwent duodenopancreatic surgery were retrospectively analyzed in terms of clinical characteristics, complications, cure rate, and long-term morbidity, including quality of life assessment (EORTC QLQ-C30). RESULTS: 35 patients (16 female, 19 male) with MEN1-ZES due to duodenopancreatic gastrinomas with a median age of 42 (range 30-74) years were included. At the time of diagnosis, 28 (80%) gastrinomas were malignant, but distant metastases were only present in one (3%) patient. Eleven patients (31.4%) underwent pancreatoduodenectomy (PD) as the initial procedure, whereas 24 patients underwent non-PD resections involving duodenotomy with gastrinoma excision, enucleation of the pNEN from the head of the pancreas, and peripancreatic lymphadenectomy, either with or without distal pancreatectomy (i.e., either Thompson procedure, n = 12, or DUODX, n = 12). There was no significant difference in perioperative morbidity and mortality between the two groups (p ≥ 0.05). One (9%) patient of the PD group required reoperation for recurrent or metastatic ZES compared to eight (22.8%) patients of the non-PD resection groups. After a median follow-up time of 134 months (range 6-480) nine of 11 (82%) patients in the PD group, two of 12 (16%) patients in the Thompson procedure group, and three of 12 (25%) patients in the DUODX group had normal serum gastrin levels. In addition, the global health QoLScore was better in the PD group (76.9) compared to the Thompson procedure (57.4) and DUODX (59.5) groups. CONCLUSIONS: Initial PD seems to be the superior surgical procedure for MEN1-ZES, resulting in a long-term cure rate of about 80%, fewer duodenopancreatic reoperations, and an acceptable quality of life.

Regional Growth Velocity and Incidence of Pancreatic Neuroendocrine Neoplasias in Multiple Endocrine Neoplasia Type 1.

OBJECTIVES: Pancreatic neuroendocrine neoplasias (pNENs) in multiple endocrine neoplasia type 1 are predominantly found in the dorsal anlage. Whether their growth velocity and incidence might be related to their location in the pancreas has not been investigated yet. METHODS: We studied 117 patients using endoscopic ultrasound. RESULTS: Growth velocity could be calculated for 389 pNENs. Increase of largest tumor diameter (% per month) was 0.67 (standard deviation [SD], 2.04) in the pancreatic tail (n = 138), 1.12 (SD, 3.00) in the pancreatic body (n = 100), 0.58 (SD, 1.19) in the pancreatic head/uncinate process-dorsal anlage (n = 130), and 0.68 (SD, 0.77) in the pancreatic head/uncinate process-ventral anlage (n = 12). Comparing growth velocity of all pNENs in the dorsal (n = 368, 0.76 [SD, 2.13]) versus ventral anlage, no significant difference was detected. Annual tumor incidence rate was 0.21 in the pancreatic tail, 0.13 in the pancreatic body, 0.17 in the pancreatic head/uncinate process-dorsal anlage, 0.51 dorsal anlage together, and 0.02 in the pancreatic head/uncinate process-ventral anlage. CONCLUSIONS: Multiple endocrine neoplasia type 1 pNENs are unequally distributed between ventral (low prevalence and incidence) and dorsal anlage. However, there are no regional differences in growth behavior.

Clinical Implications of Postoperative Hyperamylasemia after Partial Pancreaticoduodenectomy.

Introduction: The present study aimed to examine the clinical implications of postoperative hyperamylasemia (POH) after partial pancreaticoduodenectomy (PD). Methods: Data from all consecutive patients undergoing PD were obtained from a prospectively maintained database and reviewed. POH was defined as an elevation of serum pancreatic amylase above the upper limit of normal (53 U/L) on postoperative days 0-2. Clinically relevant POH (cr-POH) was defined as POH in patients with clinically relevant (Clavien-Dindo ≥ III) postoperative complications. Results: POH occurred in 61 of 170 (35.9%) and cr-POH in 24 of 170 (14.1%) patients. Patients with POH had higher rates of clinically relevant postoperative pancreatic fistula (cr-POPF) (44.3 vs. 3.7%, p < 0.001) and clinically relevant postoperative complications than those without POH (39.3 vs. 21.1%, p = 0.001). Patients with cr-POH had higher C-reactive protein (CRP, milligrams per liter) levels on third (257.7 vs. 187.85 mg/L, p = 0.016) and fourth (222.5 vs. 151, p = 0.002) postoperative day (POD) than those with POH alone. Serum procalcitonin (PCT, micrograms per liter) levels on POD 2 (1.2 vs. 0.4 µg/L, p = 0.028) and POD 3 (0.85 vs. 0.4 µg/L, p = 0.001) were also higher in patients with cr-POH. Rates of cr-POPF in patients with cr-POH were higher than in those with POH alone (70.8 vs. 27%, p = 0.001). POH (OR 0.011, 95% CI: 0.001-0.097, p < 0.001) was an independent predictor of cr-POPF in the multivariable analysis. A high-risk pathology, defined as nonadenocarcinoma/nonchronic pancreatitis pathology (OR 0.277, 95% CI: 0.106-0.727, p = 0.009), and a small duct diameter (OR 0.333, 95% CI: 0.139-0.796, p = 0.013) were independent predictors of POH in the multivariable analysis. Conclusion: POH is a frequent, but not always clinically relevant, finding after partial PD. Serum CRP and PCT levels in the early postoperative period can be used to identify patients with cr-POH. POH is an independent risk factor for increased postoperative morbidity, including cr-POPF, after partial PD.

Prostate-Specific Membrane Antigen in Anaplastic and Poorly Differentiated Thyroid Cancer-A New Diagnostic and Therapeutic Target?

Several studies have demonstrated an expression of the prostate-specific membrane antigen (PSMA) in the cancer-related neovasculature of thyroid malignancies. Due to the poor prognosis and limited therapeutic options for patients with anaplastic (ATC) and poorly differentiated (PDTC) thyroid carcinoma, the aim of our study was to investigate the theranostic approach of PSMA expression in these patients. The PSMA uptake on Gallium-68 (68Ga)-PSMA-positron emission tomography/computed tomography (PET/CT) and glucose uptake on F-18-Fluordeoxyglucose (18F-FDG)-PET/CTs were analysed in two ATC and six PDTC patients. The PSMA expression in corresponding patients' tissue samples was detected by immunohistochemistry. In addition, various tissue sections from 22 ATC and six PDTC patients were examined concerning PSMA expression. 68Ga-PSMA-PET/CT showed heterogeneous PSMA expression among patients and lesions. Six of the eight analyzed patients (two ATC, four PDTC) showed increased glucose metabolism without increased PSMA uptake after PET/CT. In one patient (PDTC), 18F-FDG-PET/CT tracer uptake was positive and 68Ga-PSMA-PET/CT showed heterogeneous results. Another patient (PDTC) evidenced only PSMA-positive lesions and received two cycles of Lutetium-177 (177Lu)-PSMA therapy, which kept his disease stable for seven months. There was a correlation between immunohistochemical PSMA expression and uptake on 68Ga-PMSA-PET/CT in three of the examined patients. Twenty-seven of the analyzed 39 ATC and 13 of the analyzed 22 PDTC tissue sections showed a strong PSMA expression. Considering the rarity of PDTC and ATC, which is the reason for the small patient population we studied, the findings of this study confirm the high diagnostic sensitivity and superiority of 18F-FDG-PET/CT in comparison to 68Ga-PSMA-PET/CT in the diagnosis of ATC and PDTC. However, it can be suggested that 68Ga-PMSA-PET/CT can be considered as a beneficial adjunct to the well-established 18F-FDG-PET/CT for a few individual selected patients with ATC and PDTC to detect lesions not discovered by 18F-FDG-PET/CT and to determine patients' eligibility for a radioligand therapy. Radiolabelled PSMA-ligands may, in the future, represent a theranostic approach with only minor side effects for a few individual selected patients with ATC and PDTC who need alternative treatment options in case of progression when established therapies are no longer effective. However, due to the small sample size of our collective, larger studies are needed to allow for a final evaluation on the significance of PSMA-targeted diagnostic and therapy for ATC and PDTC.

Pancreatic Neuroendocrine Neoplasias in Multiple Endocrine Neoplasia Type 1 Are Predominantly Located in the Dorsal Anlage: An Endoscopic Ultrasound Study.

OBJECTIVES: Pancreatic neuroendocrine neoplasias (pNENs) frequently occur in multiple endocrine neoplasia type 1 (MEN1). Their distribution referring to embryology, that is, the pancreatic anlagen, has not been investigated yet. METHODS: In the time between 1998 and 2019, we studied the distribution of pNENs in MEN1 concerning the embryologic origin of the pancreas, that is, the dorsal versus ventral anlage using endoscopic ultrasound in 117 MEN1 patients: 56 women, 61 men; aged 40 years (standard deviation, 14 years) at first endoscopic ultrasound. RESULTS: In 105 patients, a total of 628 pNENs were detected. They were located in the pancreatic tail: 231; pancreatic body: 177; pancreatic head/uncinate process: 220. Of the latter, 22 were located in the ventral anlage, 176 in the dorsal anlage, and 22 remained undefined. In summary, just 3.5% of all detected pNENs were located in the ventral anlage, 93.0% in the dorsal anlage, and 3.5% could not be assigned. CONCLUSIONS: Our study indicates that the vast majority of pNENs in MEN1 is located in the dorsal anlage, whereas the ventral anlage of the pancreas seems to be to a large extend spared from pNENs. Implications for new surgical strategies might be considered.

Postoperative morbidity following pancreatic cancer surgery is significantly associated with worse overall patient survival; systematic review and meta-analysis.

BACKROUND: The influence of postoperative morbidity on survival after potentially curative resection for pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: Medline, Web of Science and Cochrane Library were searched for studies reporting survival in patients with and without complications, defined according to the Clavien-Dindo classification, after primary, potentially curative resection for pancreatic cancer followed by adjuvant treatment. Meta-analysis was performed using a random-effects model. RESULTS: Fourteen retrospective cohort studies comprising a total of 7.604 patients with an overall complication rate of 40.8% (n = 3.103 patients) were included. Median overall survival for the entire patient cohort ranged from 15.5 to 24 months. Overall survival in patients with severe postoperative complications ranged from 7.1 to 37.1 months and was significantly worse compared to the overall survival in patients without severe complications ranging from 16.5 to 38.2 months. Postoperative complication rates ranged from 24.3% to 64%, severe (Clavien-Dindo ≥ III) complication rates from 4.2% to 31%. Results sufficient for meta-analysis were reported by ten studies, representing 6.028 patients. Meta-analysis showed reduced overall survival following any complication (summary adjusted HR 1.47; 95% CI 1.23-1.76, p < 0.0001). Hazard of death was 1.5 times higher in patients experiencing severe postoperative complications than in patients without severe complications (summary adjusted HR 1.45; 95% CI 1.13-1.85, p = 0.003). CONCLUSIONS: Postoperative complications after potentially curative resection of PDAC are significantly associated with worse overall patient survival.

Gastric enterochromaffin-like cell changes in multiple endocrine neoplasia type 1.

BACKGROUND: Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES. METHODS: Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed. RESULTS: Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5 mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n = 22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206 pg/ml vs. 30.5 pg/ml, p < .001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p = .302, chromogranin A: p = .464). CONCLUSION: Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.

Gender Differences in Multiple Endocrine Neoplasia Type 1: Implications for Screening?

BACKGROUND: Some gender-related differences have been reported in multiple endocrine neoplasia type 1 (MEN1), although not all reports are conclusive. This systematic review with analysis of the own MEN1 cohort evaluates gender differences and potential consequences for screening. METHODS: A systematic review of the literature between 1990 and 2019 with the search terms "MEN1" or "multiple endocrine neoplasia type 1" and "gender" or "sex" was performed. In addition, the prospectively collected data of a genetically confirmed MEN1 cohort of the Philipps University Marburg were retrospectively analyzed. RESULTS: Review of the literature identified five retrospective case series with original data of 1,057 MEN1 patients. One series suggested a higher frequency of pancreatic neuroendocrine neoplasms (NEN), especially gastrinomas, in men (61 vs. 54%) and a higher frequency of pituitary tumors in women (47 vs. 30%), but others did not. Only thymic NEN occurred predominantly in men throughout all studies. Women with MEN1 were found to have an increased risk of breast cancer. In the own series consisting of 116 MEN1 patients (male = 58, female = 58), thymic lesions were also more frequently detected in male patients (male = 5, female = 1). No gender difference was found with regard to the other manifestations. CONCLUSION: Regarding the typical MEN1 tumor manifestations, gender-adapted diagnostic and therapeutic approaches cannot be recommended. Female MEN1 patients should be encouraged to participate in breast cancer screening programs.

Single gland excision for MEN1-associated primary hyperparathyroidism.

IMPORTANCE: Guidelines advocate subtotal parathyroidectomy (SPTX) or total parathyroidectomy with autotransplantation (TPTX) with bilateral cervical thymectomy for primary hyperparathyroidism (pHPT) associated with multiple endocrine neoplasia type 1 (MEN1). However, both procedures are associated with a significant risk of permanent hypoparathyroidism. OBJECTIVE: The aim of the current study was to compare long-term results of either single gland excision (SGE, 1-2 glands), SPTX and TPTX for the treatment of MEN1-associated pHPT. DESIGN AND SETTING: Data of genetically confirmed MEN1 patients who underwent surgery for pHPT between 1987 and 2017 were retrieved from a prospective database and were retrospectively analysed. RESULTS: Eighty-nine MEN1 patients underwent either TPTX (n = 38, 42.7%), SPTX (n = 23, 25.8%) or SGE (n = 28, 31.5%). The rate of disease persistence after initial surgery was 2.6%, 0% and 14.2% in the TPTX, SPTX and SGE groups, respectively. After median follow-up of 112 (range 7-411) months, the rate of recurrent pHPT was significantly higher in the SGE group (n = 19, 21.3%) compared with the TPTX (n = 4, 4.4%, P = .001) and the SPTX (n = 9, 10.1%, P = .03) groups. Analysis of the recurrence-free time among the surgical groups revealed a significant difference (P = .036). The median time to recurrence was significantly shorter after SGE (101, range 3-301 months) than after SPTX (139, range 28-278 months, P = .018) and TPTX (204, range 75-396 months, P = .049). Twelve (32%) patients who underwent TPTX developed permanent hypoparathyroidism compared with only 4 (17%, P = .06) in the SPTX and 0 in the SGE group (P = .001). CONCLUSION: Given the high rate of postoperative permanent hypoparathyroidism after TPTX and SPTX, SGE is a valid option for the treatment of MEN1-associated pHPT.

Contemporary surgical management of the Zollinger-Ellison syndrome in multiple endocrine neoplasia type 1.

About 30% of patients with MEN1 develop a Zollinger-Ellison syndrome. Meanwhile it is well established that the causative gastrinomas are almost exclusively localized in the duodenum and not in the pancreas, MEN1 gastrinomas occur multicentric and are associated with hyperplastic gastrin cell lesions and tiny gastrin-producing micro tumors in contrast to sporadic duodenal gastrinomas. Regardless of the high prevalence of early lymphatic metastases, the survival is generally good with an aggressive course of disease in only about 20% of patients. Symptoms can be controlled medically. The indication, timing, type, and extent of surgery are highly controversial and are discussed in detail in this article by a thorough and critical review of literature. More radical procedures, like partial pancreaticoduodenectomy, are weighed against less aggressive local excision of gastrinomas and the pros and cons of both approaches are discussed in terms of long-term morbidity, biochemical cure, and survival.

Palliative surgical bypass is superior to palliative endoscopic stenting in patients with malignant gastric outlet obstruction: systematic review and meta-analysis.

BACKGROUND: Gastrojejunostomy (GJ) and self-expanding metal stents (SEMS) are the two most common palliative treatment options for patients with malignant gastric outlet obstruction (GOO). Randomised trials and retrospective studies have shown discrepant results, so that there is still a controversy regarding the optimal treatment of GOO. METHODS: Medline, Web of Science and Cochrane Library were systematically searched for studies comparing GJ to SEMS in patients with malignant GOO. Primary outcomes were survival and postoperative mortality. Secondary outcomes were frequency of re-interventions, major complications, time to oral intake and length of hospital stay. RESULTS: Twenty-seven studies, with a total of 2.354 patients, 1.306 (55.5%) patients in the SEMS and 1.048 (44.5%) patients in the GJ group, were considered suitable for inclusion. GJ was associated with significantly longer survival than SEMS (mean difference 43 days, CI 12.00, 73.70, p = 0.006). Postoperative mortality (OR 0.55, CI 0.27, 1.16, p = 0.12) and major complications (OR 0.73, CI 0.5, 1.06, p = 0.10) were similar in both groups. The frequency of re-interventions, however, was almost three times higher in the SEMS group (OR 2.95, CI: 1.70, 5.14, p < 0.001), whereas the mean time to oral intake and length of hospital stay were shorter in the SEMS group (mean differences - 5 days, CI - 6.75, - 3.05 days, p < 0.001 and - 10 days, CI - 11.6, - 7.9 days, p < 0.001, respectively). CONCLUSIONS: Patients with malignant GOO and acceptable performance status should be primarily considered for a palliative GJ rather than SEMS.

Chemoprevention with Somatuline© Delays the Progression of Pancreatic Neuroendocrine Neoplasms in a Mouse Model of Multiple Endocrine Neoplasia Type 1 (MEN1).

OBJECTIVE: Long-acting synthetic somatostatin analogues (SSA) are an essential part of the treatment of neuroendocrine neoplasms. We evaluated the chemopreventive effects of a long-acting somatostatin analogue on the development of pancreatic neuroendocrine neoplasms (pNENs) in a genetically engineered MEN1 knockout mouse model. MATERIALS AND METHODS: Heterozygote MEN1 knockout mice were injected every 28 days subcutaneously with the somatostatin analogue lanreotide (Somatuline Autogel©; Ipsen Pharma) or a placebo starting at day 35 after birth. Mice were euthanized after 6, 9, 12, 15 and 18 months, and the size and number of pNENs were measured due histological analysis and compared to the placebo group. RESULTS: The median tumor size of pNENs was statistically significantly smaller after 9 (control group vs. SSA group; 706.476 µm2 vs. 195.271 µm2; p = 0.0012), 12 (placebo group vs. SSA group 822.022 vs. 255.482; p ≤ 0.001), 15 (placebo group vs. SSA group 1192.568 vs. 273.533; p ≤ 0.001) and after 18 months (placebo group vs. SSA group 1328.299 vs. 864.587; p ≤ 0.001) in the SSA group. Comparing the amount of tumors in both groups, a significant reduction was achieved in treated Men1(+/-) mice (41%, p = 0.002). Immunostaining showed, however, no significant difference in the expression of the apoptosis marker caspase-3, but a significant difference in Ki67 index as a marker for tumor cell proliferation (p ≤ 0.005). CONCLUSION: Long-acting somatostatin analogues may be an effective chemopreventive approach to delay the progression of MEN1-associated pNENs. After our preclinical results, we would recommend to evaluate the effects of long-acting SSA in a prospective clinical trial.

Results of Duodenopancreatic Reoperations in Multiple Endocrine Neoplasia Type 1.

BACKGROUND: To evaluate the outcome of duodenopancreatic reoperations in patients with multiple endocrine neoplasia type 1 (MEN1). METHODS: MEN1 patients who underwent reoperations for duodenopancreatic neuroendocrine neoplasms (dpNENs) were retrieved from a prospective database and retrospectively analyzed. RESULTS: Twelve of 101 MEN1 patients underwent up to three reoperations, resulting in a total of 18 reoperations for dpNEN recurrence. Patients initially underwent either formal pancreatic resections (n = 7), enucleations (n = 3), or duodenotomy with lymphadenectomy for either NF-pNEN (seven patients), Zollinger-Ellison syndrome (ZES, three patients), organic hyperinsulinism (one patient) or VIPoma (one patient). Six patients had malignant dpNENs with lymph node (n = 5) and/or liver metastases (n = 2). The indication of reoperations was NF-pNEN (five patients), ZES (five patients), organic hyperinsulinism (one patient), and recurrent VIPoma (one patient). Median time to first reoperation was 67.5 (range 6-251) months. Five patients required a second duodenopancreatic reoperation for 60-384 months after initial surgery, and one patient underwent a third reoperation after 249 months. The rate of complications (Clavien-Dindo ≥3) was 28%. Four patients required completion pancreatectomy. Six patients developed pancreoprivic diabetes. After a median follow-up of 18 (6-34) years after initial surgery, ten of 12 patients are alive, one died of metastatic pancreatic VIPoma, and one died of metastatic thymic NEN. CONCLUSION: Reoperations are frequently necessary for dpNEN in MEN1 patients, but are not associated with an increased perioperative morbidity in specialized centers. Organ-sparing resections should be preferred as initial duodenopancreatic procedures to maintain pancreatic function and avoid completion pancreatectomy.