Portal vein resection in pancreatic neuroendocrine neoplasms.

BACKGROUND: Surgery offers the only cure for borderline resectable or locally advanced pancreatic neuroendocrine neoplasms. Data on incidence, perioperative and long-term outcomes of portal vein resection for pancreatic neuroendocrine neoplasms are scarce. This study aimed to analyze the outcome and prognostic factors of portal vein resection in surgery for pancreatic neuroendocrine neoplasms. METHODS: Consecutive patients were analyzed. Portal vein resection was classified according to the International Study Group of Pancreatic Surgery. Clinicopathologic features and overall and disease-free survival were assessed and compared with standard resection in a matched-pair analysis. RESULTS: A total of 54 of 666 (8%) resected pancreatic neuroendocrine neoplasms patients underwent portal vein resection, including 7 (13%) tangential resections with venorrhaphy (type 1), 2 (4%) patch reconstructions (type 2), 35 (65%) end-to-end anastomoses (type 3), and 10 (19%) graft interpositions (type 4); 52% of those underwent pancreatoduodenectomy, 22% distal pancreatectomy, and 26% total pancreatectomy. Postoperative portal vein thrombosis occurred in 19%. Postoperative pancreatic fistula grades B and C (9% vs 16%; P = .357), complications Clavien-Dindo grade ≥IIIb (28% vs 13%; P = .071), and 90-day mortality rate (2% each) were not significantly different compared with 108 matched patients. The 5-year overall survival was 45% (standard resection: 68%; P = .432), and the 5-year disease-free survival was 25% (standard resection: 34%; P = .716). Radical resection was associated with 5-year overall survival of 51% and 5-year disease-specific survival of 75%. CONCLUSION: This is the largest single-center analysis evaluating perioperative and long-term outcomes of portal vein resection for pancreatic neuroendocrine neoplasms. The postoperative complication rate after portal vein resection is comparable with standard resection. The 90-day mortality is low. Radical resection leads to excellent 5-year oncological survival.

Short-term Outcomes of Robotic Versus Open Pancreatoduodenectomy: Propensity Score-matched Analysis.

OBJECTIVE: The goal of the current study was to investigate the perioperative outcomes of robotic pancreaticoduodenectomy (RPD) and open pancreaticoduodenectomy (OPD) in a high-volume center. BACKGROUND: Despite RPDs prospective advantages over OPD, current evidence comparing the 2 has been limited and has prompted further investigation. The aim of this study was to compare both approaches while including the learning curve phase for RPD. METHODS: A 1:1 propensity score-matched analysis of a prospective database of RPD with OPD (2017-2022) at a high-volume center was performed. The main outcomes were overall- and pancreas-specific complications. RESULTS: Of 375 patients who underwent PD (OPD n=276; RPD n=99), 180 were included in propensity score-matched analysis (90 per group). RPD was associated with less blood loss [500 (300-800) vs 750 (400-1000) mL; P =0.006] and more patients without a complication (50% vs 19%; P <0.001). Operative time was longer [453 (408-529) vs 306 (247-362) min; P <0.001]; in patients with ductal adenocarcinoma, fewer lymph nodes were harvested [24 (18-27) vs 33 (27-39); P <0.001] with RPD versus OPD. There were no significant differences for major complications (38% vs 47%; P =0.291), reoperation rate (14% vs 10%; P =0.495), postoperative pancreatic fistula (21% vs 23%; P =0.858), and patients with the textbook outcome (62% vs 55%; P =0.452). CONCLUSIONS: Including the learning phase, RPD can be safely implemented in high-volume settings and shows potential for improved perioperative outcomes versus OPD. Pancreas-specific morbidity was unaffected by the robotic approach. Randomized trials with specifically trained pancreatic surgeons and expanded indications for the robotic approach are needed.

Impact of circumferential resection margin on survival in ampullary cancer: retrospective analysis.

BACKGROUND: Ampullary carcinoma is a clinically variable entity. This study aimed to evaluate prognostic factors for the outcome of resected ampullary carcinoma patients with particular intent to analyse the influence of surgical radicality. METHODS: Patients undergoing resection between 2002 and 2017 were analysed. Clinicopathological parameters, perioperative outcome and survival were examined. Risk factor analysis for postresection survival was performed. Resection margin status was evaluated according to the revised classification for pancreatic adenocarcinoma. RESULTS: A total of 234 patients were identified, 97.9 per cent (n = 229) underwent formal resection, while 2.1 per cent (n = 5) underwent ampullary resection. Histological subtypes were 46.6 per cent (n = 109) pancreatobiliary, 34.2 per cent (n = 80) intestinal, 11.5 per cent (n = 27) mixed, and 7.7 per cent (n = 18) undetermined. In the pancreatobiliary group, tumours were more advanced with more vascular resections, pT4 stage, G3 differentiation and pN+ status. Five-year overall survival was significantly different for pancreatobiliary compared to intestinal (51.7 per cent versus 72.8 per cent, P = 0.0087). In univariable analysis, age, pT4 stage, pN+, pancreatobiliary subtype and positive resection margin were significantly associated with worse overall survival. Long-term outcome was significantly better after true R0 resection (circumferential resection margin-, tumour clearance >1 mm) compared with circumferential resection margin+ (<1 mm) and R1 resections (5-year overall survival: 69.6 per cent, median overall survival 191 months versus 42.4 per cent and 53 months; P = 0.0017). CONCLUSION: Postresection survival of ampullary carcinoma patients is determined by histological subtype and surgical radicality. Intestinal differentiation is associated with less advanced tumour stages and better differentiation, which is reflected in a significantly better overall survival compared to pancreatobiliary differentiation. Despite this, true R0-resection is a prognostic key determinant in both entities, achieving 5-year survival in two-thirds of patients.

Retroperitoneoscopic adrenalectomy may be superior to laparoscopic transperitoneal adrenalectomy in terms of costs and profit: a retrospective pair-matched cohort analysis.

BACKGROUND: A direct comparison of the cost-benefit analysis of retroperitoneoscopic adrenalectomy (RPA) versus the minimally invasive transperitoneal access (LTA) approach is currently lacking. We hypothesized that RPA is more cost effective than LTA; promising significant savings for the healthcare system in an era of ever more limited resources. METHODS: We performed a monocentric retrospective observational cohort study based on data from our Endocrine Surgery Registry. Patients who were operated upon between 2019 and 2022 were included. After pair-matching, both cohorts (RPA vs. LTA) were compared for perioperative variables and treatment costs (process cost calculation), revenue and profit. RESULTS: Two homogenous cohorts of 43 patients each (RPA vs. LTA) were identified following matching. Patient characteristics between the cohorts were comparable. In terms of both treatment-associated costs and profit, the RPA procedure was superior to LTA (costs: US$5789.99 for RPA vs. US$6617.75 for LTA, P = 0.043; profit: US$1235.59 for RPA vs. US$653.33 for LTA, P = 0.027). The duration of inpatient treatment and comorbidities significantly influenced the cost of treatment and the overall profit. CONCLUSIONS: RPA appears not only to offer benefits over LTA in terms of perioperative morbidity and length of hospital stay, but also has a superior financial cost/benefit profile.

Treatment characteristics and outcomes of pure Acinar cell carcinoma of the pancreas - A multicentric European study on radically resected patients.

BACKGROUND: Acinar cell carcinomas (ACC) belong to the exocrine pancreatic malignancies. Due to their rarity, there is no consensus regarding treatment strategies for resectable ACC. METHODS: This is a retrospective multicentric study of radically resected pure pancreatic ACC. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Further endpoints were oncologic outcomes related to tumor stage and therapeutic protocols. RESULTS: 59 patients (44 men) with a median age of 64 years were included. The median tumor size was 45.0 mm. 61.0% were pT3 (n = 36), nodal positivity rate was 37.3% (n = 22), and synchronous distant metastases were present in 10.1% of the patients (n = 6). 5-Years OS was 60.9% and median DFS 30 months. 24 out of 31 recurred systemically (n = 18 only systemic, n = 6 local and systemic). Regarding TNM-staging, only the N2-stage negatively influenced OS and DFS (p = 0.004, p = 0.001). Adjuvant treatment protocols (performed in 62.7%) did neither improve OS (p = 0.542) nor DFS (p = 0.159). In 9 cases, radical resection was achieved following neoadjuvant therapy. DISCUSSION: Radical surgery is currently the mainstay for resectable ACC, even for limited metastatic disease. Novel (neo)adjuvant treatment strategies are needed, since current systemic therapies do not result in a clear survival benefit in the perioperative setting.

Lymph node metastases and recurrence in pancreatic neuroendocrine neoplasms.

BACKGROUND: The impact of lymph node metastasis on survival in pancreatic neuroendocrine neoplasms as well as their best surgical treatment is controversial. We aimed to determine the frequency and prognostic impact of lymph node involvement in pancreatic neuroendocrine neoplasms. METHODS: Patients undergoing pancreatic resections for pancreatic neuroendocrine neoplasms between 2001 and 2019 were retrospectively analyzed based on a prospective database. Clinicopathological parameters and perioperative outcome were assessed. Overall and disease-free survival was analyzed. Subgroup analysis was performed for sporadic, nonfunctional pancreatic neuroendocrine neoplasms without distant metastases and ≥4 analyzed lymph nodes. RESULTS: Of 605 surgically resected pancreatic neuroendocrine neoplasms, 55% were G1, 36% were G2, and 9% were G3 differentiated. At the time of resection, 34% of patients had lymph node metastasis, and 16% had distant metastases. For subgroup analysis, 314 patients were analyzed. Lymph node metastases occurred in 36% of patients and were most frequent in G3 patients (67%). An increase in tumor size and advancement was associated with higher rates of lymph node metastasis, and disease-free survival was significantly impaired. Significant differences in disease-free survival were observed between 1 and 3 (5-year disease-free survival 52%) and ≥4 positive lymph nodes (5-year disease-free survival 28%), as well as when G3 tumors were excluded. In multivariable analysis, grading, tumor stage, and especially lymph node metastases as well as the proposed pN1 and pN2 categories were confirmed as independent predictors of recurrence. CONCLUSION: The presence and extent of lymph node involvement has considerable prognostic impact in pancreatic neuroendocrine neoplasms. This study, for the first time, validated the proposed pN2 stage for well-differentiated pancreatic neuroendocrine neoplasms.

Enucleation Is a Feasible Procedure for Well-Differentiated pNEN-A Matched Pair Analysis.

The extent of surgical resection in the treatment of pancreatic neuroendocrine neoplasms (pNEN) is still controversial. This study aimed to evaluate the outcomes of enucleation for well-differentiated non-functional (nf) pNEN. Patients undergoing enucleation (2001−2020) were analyzed. Clinicopathological parameters, perioperative outcomes and survival were assessed. The analysis was performed as a nested case-control study and matched-pair analysis with formal resection. Sixty-one patients undergoing enucleation were identified. Compared to patients undergoing formal resection, enucleation was associated with a significantly shorter median length of operative time (128 (IQR 95−170) versus 263 (172−337) minutes, p < 0.0001) and a significantly lower rate of postoperative diabetes (2% versus 21%, p = 0.0020). There was no significant difference in postoperative pancreatic fistula rate (18% versus 16% type B/C, p = 1.0), Clavien−Dindo ≥ III complications (20% versus 26%, p = 0.5189), readmission rate (12% versus 15%, p = 0.6022) or length of hospital stay (8 (7−11) versus 10 (8−17) days, p = 0.0652). There was no 30-day mortality after enucleation compared to 1.6% (n = 1) after formal resection. 10-year overall survival (OS) and disease-free survival (DFS) was similar between the two groups (OS: 89% versus 77%, p = 0.2756; DFS: 98% versus 91%, p = 0.0873). Enucleation presents a safe surgical approach for well-differentiated nf-pNEN with good long-term outcomes for selected patients.

[Evidence for Neoadjuvant Therapy in Resectable Pancreatic Cancer]. / Evidenz für neoadjuvante Chemotherapie beim resektablen Pankreaskarzinom.

Pancreatic cancer could be the second leading cause of cancer death in 2030. Even though 5-year survival rates remain poor, substantial progress has been made in recent decades. The use of adjuvant chemotherapy after resection has prolonged survival and neoadjuvant concepts have been introduced to allow proportionately more resections in initially borderline resectable or locally advanced disease. Currently, there is an ongoing debate about the use of neoadjuvant therapy in both resectable and borderline resectable disease, whereas in locally advanced cancer, the use of neoadjuvant therapies is unquestionable. High-level evidence in this area remains scarce, despite numerous studies that have recently been published or are currently recruiting. A key problem is the definition of resectability which was - traditionally - based on anatomical criteria; however, it has become clear that this definition is not adequate as tumour biology as well as patient-related prognostic factors are not taken into consideration. A second unsolved problem is the difficulty to standardise neoadjuvant therapy as - in contrast to the adjuvant setting, where large randomised controlled trials have set clear standards - multiple protocols are used around the world. This does not allow us to give any clear recommendation on which therapy protocol should be chosen for a specific patient if neoadjuvant therapy is considered. Furthermore, success control under neoadjuvant treatment is not effectively defined - usually only CA 19-9 as the most common marker can aid in clinical decision making, as imaging often fails to show actual response. With regard to present guidelines, patients with resectable disease should not be treated with neoadjuvant therapy outside clinical studies, whereas for borderline resectable disease, recommendations vary between different countries and societies.This review summarises the present literature on the topic of neoadjuvant therapy in pancreatic cancer with a focus on resectable disease stage.

The link between menin and pleiotrophin in the tumor biology of pancreatic neuroendocrine neoplasms.

MEN1, which encodes menin protein, is the most frequently mutated gene in pancreatic neuroendocrine neoplasms (pNEN). Pleiotrophin (PTN) has been reported as a downstream factor of menin that promotes metastasis in different tumor entities. In this study, the effect of menin and its link to PTN were assessed using features of pNEN cells and the outcome of patients with pNEN. The expression levels of menin and PTN in tissues from patients with pNEN were examined using qRT-PCR and western blot and compared with their metastasis status. Functional assays, including transwell migration/invasion and scratch wound-healing assays, were performed on specifically designed CRISPR/Cas9-mediated MEN1-knockout (MEN1-KO) pNEN cell lines (BON1MEN1-KO and QGP1MEN1-KO ) to study the metastasis of pNEN. Among 30 patients with menin-negative pNEN, 21 revealed a strong protein expression of PTN. This combination was associated with metastasis and shorter disease-free survival. Accordingly, in BON1MEN1-KO and QGP1MEN1-KO cells, PTN protein expression was positively associated with enhanced cell migration and invasion, which could be reversed using PTN silencing. PTN is a predicting factor of metastatic behavior of menin-deficient-pNEN. In vitro, menin is able to both promote and suppress the metastasis of pNEN by regulating PTN expression depending on the tumoral origin of pNEN cells.

Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

State-of-the-art surgery for pancreatic cancer.

BACKGROUND: The d evelopment of surgical techniques and specialization and specifically complication management in pancreatic surgery have improved surgical outcomes as well as oncological results in pancreatic surgery in recent decades. Historical morbidity and especially mortality rates of up to 80% have decreased to below 5% today. This review summarizes the current state of the art in pancreatic cancer surgery. METHODS: The present literature and clinical experience are summarized to give an overview of the present best practice in pancreatic surgery as one of the most advanced surgical disciplines today. RESULTS: Based on the available literature, three important aspects contribute to best patient care in pancreatic surgery, namely, surgical progress, interdisciplinary complication management, and multimodal oncological treatment in case of pancreatic cancer. In addition, minimally invasive and robotic procedures are currently fields of development and specific topics of research. CONCLUSION: In experienced hands, pancreatic surgery-despite being one of the most challenging fields of surgery-is a safe domain today. The impact of multimodal, especially adjuvant, therapy for oncological indications is well established and evidence-based. New technologies are evolving and will be evaluated with high-evidence studies in the near future.

C-reactive protein independently predicts survival in pancreatic neuroendocrine neoplasms.

Pancreatic neuroendocrine neoplasms (pNEN) are highly variable in their postresection survival. Determination of preoperative risk factors is essential for treatment strategies. C-reactive protein (CRP) has been implicated in the pathogenesis of pNEN and shown to be associated with survival in different tumour entities. Patients undergoing surgery for pNEN were retrospectively analysed. Patients were divided into three subgroups according to preoperative CRP serum levels. Clinicopathological features, overall and disease-free survival were assessed. Uni- and multivariable survival analyses were performed. 517 surgically resected pNEN patients were analysed. CRP levels were significantly associated with relevant clinicopathological parameters and prognosis and were able to stratify subgroups with significant and clinically relevant differences in overall and disease-free survival. In univariable sensitivity analyses CRP was confirmed as a prognostic factor for overall survival in subgroups with G2 differentiation, T1/T2 and T3/T4 tumour stages, patients with node positive disease and with and without distant metastases. By multivariable analysis, preoperative CRP was confirmed as an independent predictor of postresection survival together with patient age and the established postoperative pathological predictors grading, T-stage and metastases. Preoperative serum CRP is a strong predictive biomarker for both overall and disease free survival of surgically resected pNEN. CRP is associated with prognosis independently of grading and tumour stage and may be of additional use for treatment decisions.

Presentation and outcome of mixed neuroendocrine non-neuroendocrine neoplasms of the pancreas.

BACKGROUND/OBJECTIVES: Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) of the pancreas and periampullary region are extremely rare and heterogeneous malignancies. Literature is sparse, clinical management is not standardized and little is known about survival outcomes. The aim of this study was to identify pathological and radiological features of MiNEN and assess the outcome of surgical management. METHODS: Patients undergoing surgery for pancreatic and periampullary MiNEN between 2001 and 2019 were retrospectively analysed based on a prospective database. Histological, radiological and clinical features were assessed. Survival was analysed in a nested case-control study and matched-pair analyses with pure neuroendocrine neoplasms (pNEN) and ductal adeno- or acinar cell carcinomas of the pancreas. A literature review with focus on survival after surgical resection was additionally performed. RESULTS: Of 13 patients with MiNEN, 5 had acinar-MiNEN and 8 adeno-MiNEN. Two of 5 (40%) acinar-MiNEN and one adeno-MiNEN patients had liver metastases. All but one adeno-MiNEN (88%) showed preoperative radiological features of pancreatic adenocarcinoma, 3 of 5 (60%) acinar-MiNEN exhibited mainly neuroendocrine features. No surgical mortality was observed. The 5-year overall survival rate in all MiNEN was 40%. Five-year survival rate was 58% in adeno-MiNEN and comparable to that of matched ductal adenocarcinomas (36%) and pNEN (48%). Five-year overall survival rate was 20% in acinar-MiNEN, compared to 39% in acinar carcinoma patients and 59% in matched pNEN patients. CONCLUSIONS: MiNEN are rare and difficult to distinguish from pure adenocarcinoma or neuroendocrine neoplasm preoperatively. Surgical resection would therefore be the treatment of choice in localized tumors.

Surgical resection for duodenal neuroendocrine neoplasia: Outcome, prognostic factors and risk of metastases.

BACKGROUND: Clinical management of duodenal neuroendocrine neoplasms (dNEN) is controversial. The aim of this study was to assess the outcome of surgical management and to identify risk factors for metastatic disease. METHODS: Patients undergoing surgery for dNEN were retrospectively analysed. Clinicopathologic features, perioperative outcome and survival were assessed. A literature review with focus on risk factors for metastatic disease was additionally performed. RESULTS: 24 patients were identified. Out of 22 patients presenting with their primary tumour, 20 patients underwent curative resection and 18 patients received curative resection with systematic lymphadenectomy. 17 patients underwent formal oncological resection. Surgical mortality was 1 out of 24 patients. The 5-year overall survival rate was 67% in the entire cohort, 71% in patients undergoing resection for their primary tumour, 72% for patients undergoing curative resection with systematic lymphadenectomy, 75% for pN0 and 70% for pN1 tumours. Lymph node metastases were identified in 15 patients undergoing systematic lymphadenectomy, including 9 of 14 patients with tumours smaller than 2 cm, and 6 of 10 patients with G1 tumours. Literature review confirmed a high risk of metastases in small (58%) or G1 (24%) tumours. Tumour grade and angioinvasion were significantly associated with overall and disease-free survival. CONCLUSION: Even well differentiated or small dNEN harbour a considerable risk of metastases. These data challenge the concepts of surveillance, local resection and endoscopic management for dNEN based on size and grading. Angioinvasion was identified as a strong negative predictor of overall and disease-free survival in dNEN.

Pre-operative dysglycemia is associated with decreased survival in patients with pancreatic neuroendocrine neoplasms.

BACKGROUND: Diabetes mellitus is associated with increased risk of pancreatic cancer and impaired postresection survival. For pancreatic neuroendocrine neoplasms, no evidence is available for a similar effect of diabetes mellitus. The aim of this study was to evaluate the glycemic profile in patients with pancreatic neuroendocrine neoplasms and to assess the potential impact of glycemic control on the pathology and long-term outcomes in patients undergoing resection of pancreatic neuroendocrine neoplasms. METHODS: Pancreatic resections from 2001 to 2017 for pancreatic neuroendocrine neoplasms were analyzed from prospective databases. Blood glucose and HbA1c levels were collected from preoperative tests. Preoperative dysglycemia was defined as a blood glucose ≥140 mg% and/or HbA1c ≥6.5%. Uni- and multivariate analyses were performed according to the presence of perioperative dysglycemia. Survival analyses were performed by Kaplan-Meier curves and Cox-proportional hazards method. RESULTS: Four hundred and seventeen patients were analyzed. Medical history was positive for diabetes mellitus in 88 (21.1%) patients. Blood glucose evaluation identified 30 additional patients without a prior diagnosis of diabetes mellitus who had preoperative dysglycemia. No differences regarding pathologic characteristics or outcomes were detected between diabetics and non-diabetics. Conversely, patients with dysglycemia had greater rates of metastasis (16.8% vs 27.4%; P = .027) as well as vascular, perineural, and lympho-vascular involvement than those with normal blood glucose (89.2% vs 57.4%; P < .001, 90.0% vs 65.1%; P = .046, and 89.3% vs 61.3; P = .006, respectively). Preoperative dysglycemia was associated with impaired overall survival (hazard ratio = 1.57 [1.01-2.46]) and recurrence-free survival (hazard ratio = 1.78 [1.01-3.12]). By multivariate analysis, preoperative dysglycemia was independently associated with recurrence-free survival (hazard ratio 2.32 [1.29-4.17]), together with lymph-node involvement (hazard ratio = 2.01 [1.14-3.57]) and metastatic disease (hazard ratio = 5.10 [2.73-9.55]). CONCLUSION: Preoperative dysglycemia, but not diabetes mellitus per se, is associated with advanced disease and impaired long-term outcomes in patients undergoing resection for a pancreatic neuroendocrine neoplasm. For those patients, closer surveillance and strict glycemic control are warranted.

Microvesicles released by apoptotic human neutrophils suppress proliferation and IL-2/IL-2 receptor expression of resting T helper cells.

Membrane-coated microvesicles (MVs) have been identified as important mediators in intercellular communication. During the process of apoptosis, dying cells dynamically release MVs. Neutrophils are the most abundant type of leukocytes in the circulation. Due to their very short lifespan, it is likely that they are the source of large amounts of apoptotic cell-derived MVs. Here, we show that MVs released by apoptotic human polymorphonuclear neutrophils (apoPMN-MVs), but not the apoptotic neutrophils themselves, selectively suppress the proliferation of CD25 (IL-2Rα)neg CD127 (IL-7Rα)pos Th cells in a dose-dependent manner. In contrast, the proliferation of total T cells is not affected by MVs. Importantly, apoPMN-MVs suppress the secretion of IL-2 as well as the expression of and signaling via the IL-2 receptor (IL-2R) by CD25neg CD127pos Th cells. Addition of IL-7 strongly reduced the suppression of T-cell proliferation by MVs and the addition of IL-2 completely abrogated the suppressive effect. Thus, apoPMN-MVs suppressed a subset of Th cells by downregulating IL-2 and IL-2R expression and signaling. This may represent an important mechanism to prevent the activation and expansion of resting T cells in the absence of sufficient cytokine stimulation, and thereby maintaining immune tolerance.

Apoptotic-cell-derived membrane microparticles and IFN-α induce an inflammatory immune response.

A dysregulation in the clearance of apoptotic material is considered a major pathogenetic factor for the emergence of autoimmune diseases. Apoptotic-cell-derived membrane microparticles (AdMPs), which are released from the cell surface during apoptosis, have been implicated in the pathogenesis of autoimmunity. Also of importance are cytokines, such as interferon-α (IFN-α), which is known to be a major player in patients with systemic lupus erythematosus (SLE). This study investigates the combined effect of AdMPs and IFN-α on professional phagocytes. In the presence of IFN-α, phagocytosis of AdMPs by human monocytes was significantly increased in a dose-dependent manner. The combination of AdMPs and raised IFN-α concentrations resulted in an increase in the secretion of pro-inflammatory cytokines and an upregulation of surface molecule expression involved in antigen uptake. In addition, macrophage polarisation was shifted towards a more inflammatory type of cell. The synergism between IFN-α and AdMPs seemed to be mediated by an upregulation of phosphorylated STAT1. Our results indicate that IFN-α, together with AdMPs, amplify the initiation and maintenance of inflammation. This mechanism might especially play a crucial role in disorders with a defective clearance of apoptotic material.

During apoptosis HMGB1 is translocated into apoptotic cell-derived membranous vesicles.

High mobility group box protein B1 (HMGB1), a nuclear protein reportedly involved in the structural organisation of DNA, is released from necrotic cells or upon cellular activation. After its release into the extracellular space, HMGB1 serves as a mediator of inflammation. In contrast to necrotic cells, apoptotic ones usually do not release HMGB1. Formation and release of membranous vesicles is a well-known feature of apoptotic cell death. Only recently, subcellular membrane vesicles, such as those released during apoptotic cell death have been identified as immune regulators and as mediators of cell to cell communication. We and others have previously detected nuclear antigens within apoptosis-released membranous vesicles and HMGB1 together with nuclear antigens has been discussed to be a key player in etiology and pathogenesis of autoimmune diseases. On this background, we analysed whether HMGB1 is included in the membranous vesicles generated by apoptosing cells. Employing immune blots we observed abundand amounts of HMGB1 in the fraction of the small membraneous particles isolated from cell culture supernatants and conclude that HMGB1 is translocated into vesicles generated during apoptosis.