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.

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 dosedependent manner. The combination of AdMPs and raised IFN-α concentrations resulted in an increase in the secretion of proinflammatory 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.

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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) CD127 (IL-7Rα) 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 CD25 CD127 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.

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on behalf of the NEKAR study groupObjective: 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 ¼ 0.04). In multivariate analysis low T status [odds ratio (OR) ¼ 2.65, 95% confidence interval (CI) 1.02-6.88, P ¼ 0.045], N0 stage at initial diagnosis (OR ¼ 6.32, 95% CI 1.33-30.01, P ¼ 0.02), Ki-67 <10% (OR ¼ 14.07, 95% CI 2.09-94.9, P ¼ 0.007), and postoperative biochemical remission (OR ¼ 0.023, 95% CI 0.001-0.52, P ¼ 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.

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.