T. K. Hoffmann

Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant.

healthy men. Decreased DHEA-S concentration has been recognized in different chronic diseases (2). In particular, it has been suggested that DHEA-S deficiency is a permanent feature of some autoimmune diseases and may contribute to their aetiology and/or pathophysiolgy (4, 5). However, no direct evidence is available to indicate whether reduced circulating concentration of the hormone contributes to the diseases (2, 5). We do not know whether lower serum concentration of DHEA-S observed in CIU patients is the cause or rather the effect of urticarial processes. It has been suggested that, during inflammatory response, the adrenal steroid production is changed in the direction of cortisol, relative to DHEA and DHEA-S, such hormonal changes being probably necessary to achieve adequate cortisol levels at the expense of adrenal androgens (6). It is interesting to speculate that similar abnormalities in steroidogenesis might occur during chronic urticarial inflammation. How does lower circulating DHEA-S actually contribute to CIU pathophysiolgy? The question proves both, difficult and complex as the specific molecular mechanism of action for DHEA-S, including mechanisms of DHEA-S effect upon the immunological function and inflammation, is unclear (2). In conclusion, on the basis of the present study as well as our earlier investigations, it appears probable that circulating DHEA-S concentration may be lower in CIU patients, regardless of their gender. It seems that declining circulating concentration of DHEA-S is a phenomenon accompanying CIU, yet its significance and underlying mechanisms remain unknown. As adrenal androgens have been reported to exert immunoregulatory effects, it is interesting to speculate on DHEA-S deficiency role in urticarial inflammation irrespective of its primary or just secondary character.

Comparative analysis of resection tools suited for transoral robot-assisted surgery

Introduction of transoral robot-assisted surgery (TORS) has a strong potential to facilitate surgical therapy of head and neck squamous cell cancer (HNSCC) by decreasing the indication for an external surgical approach. However, the availability of resection tools is limited and comparative studies in the context of TORS are not available. In the context of the newest da Vinci Si HD® robotic system, various dissection methods were compared in a surgical animal model using porcine tongue at three different sites representing mucosal, muscular and lymphatic tissue. Resection methods included (a) CO2 laser tube, (b) flexible fiber Tm:YAG laser, (c) monopolar blade, and (d) radio frequency (RF) needle. Specimens were formalin-fixed, paraffin-embedded, cut, and stained with haematoxylin–eosin. Dissected tissue was examined for the width of the incision as well as the individual coagulation zone of each tool at various tissue sites. In addition, instrument costs and performance were determined. The incisions made by the RF needle had the most favourable cutting width and also smaller coagulation defects, as opposed to other tools, granting the best preservation of tumour-adjacent structures and improved pathological assessment. Instrument performance was best evaluated for CO2 laser and RF needle, whereas financial expenses were lowest for RF needle and monopolar blade. Improvement and modification of resection tools for TORS become a relevant criterion in order to facilitate routine usage in the surgical therapy of HNSCC. A consequent decrease in surgical mortality and improved precision of surgical tumour resection could lead to a significant clinical growth potential of TORS.

First use of a computer-assisted operator-controlled flexible endoscope for transoral surgery.

Transoral robotic surgery (TORS) has become an accepted treatment option for head and neck cancer. However, anatomical limitations and a relevant financial burden require alternative developments in this field. To this end, a patient presenting with a T2 squamous cell carcinoma of the lower lateral oropharyngeal wall was effectively treated with a new Conformité Européene–certified, computer‐assisted, operator‐controlled flexible endoscope (Flex). Intraoperative visualization and tissue handling were acceptable and safe. Transoral surgery with the flexible endoscope was safely conducted in a clinical setting. The introduction of alternative TORS systems will increase competition, drive scientific improvement, and reduce financial expenses. Laryngoscope, 125:645–648, 2015

Effect of C1-Esterase-inhibitor in angiotensin-converting enzyme inhibitor-induced angioedema.

The study objective was to generate pilot data to evaluate the effectiveness and safety of C1‐esterase‐inhibitor concentrate (C1‐INH) compared to standard treatment in patients with angiotensin‐converting enzyme inhibitor (ACEi)‐induced angioedema affecting the upper aerodigestive tract.

Potential Advantages of a Single-Port, Operator-Controlled Flexible Endoscope System for Transoral Surgery of the Larynx

Introduction: Transoral surgery of the larynx is commonly performed with a rigid laryngoscope, a microscope, and a laser. We investigated the potential utility of a flexible, single-port, robot-assisted and physician-controlled endoscopic system to enable easy, transoral surgical access to the larynx. Methods: Transoral laryngeal surgery was performed in human cadavers (n = 4) using the Flex System and compatible flexible instruments. Anatomical landmarks were identified, and mock surgical procedures were performed. Results: Standard laryngeal surgical procedures were completed successfully in a human cadaver model. The built-in HD digital camera enabled high-quality visualization of the larynx. Epiglottectomy, as well as posterior cordectomy, were performed by laser and radio-frequency resection. The flexible design of the compatible tools enabled a nontraumatic approach. Conclusion: The Flex System has the potential to improve surgical access to the larynx, especially in patients with challenging anatomy. The associated flexible instruments enabled completion of surgical procedures in the larynx in a human cadaveric model. Further clinical studies, as well as the development of supplemental technology and tools, are recommended for future clinical applications.

Angioedema induced by cardiovascular drugs: new players join old friends.

During the last years, two new cardiovascular drug classes, namely inhibitors of DPP IV or neprilysin, have been developed. In both cases, there is clinical evidence for their potential to induce angioedema as known already from blockers of the renin–angiotensin–aldosterone system (RAAS). The majority of angioedema induced by DPP IV inhibitors occurs during concomitant treatment with ACEi and is therefore likely mediated by overactivation of bradykinin type 2 receptors (B2). In striking contrast, the molecular pathways causing angioedema induced by neprilysin inhibitors, that is, sacubitril, are unclear, although a contribution of bradykinin appears likely. Nevertheless, there is no clinical evidence suggesting that inhibition of B2 might relieve the symptoms and/or prevent invasive treatment including coniotomy or tracheotomy in angioedema caused by these drugs. Therefore, the risk of angioedema should always be considered, especially in ambulatory care situations where patients have no rapid access to intensive care.

Clinical significance of PD-L1+ exosomes in plasma of Head and Neck Cancer patients

Purpose: The microenvironment of head and neck squamous cell carcinomas (HNSCC) is highly immunosuppressive. HNSCCs expressing elevated levels of PD-L1 have especially poor outcome. Exosomes that carry PD-L1 and suppress T-cell functions have been isolated from plasma of patients with HNSCC. The potential contributions of PD-L1+ exosomes to immune suppression and disease activity are evaluated. Experimental Design: Exosomes isolated from plasma of 40 HNSCC patients by size exclusion chromatography were captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. The percentages and mean fluorescence intensities (MFI) of PD-L1+ and PD-1+ exosome/bead complexes were correlated with the patients’ clinicopathologic data. PD-L1high or PD-L1low exosomes were incubated with activated CD69+ human CD8+ T cells ± PD-1 inhibitor. Changes in CD69 expression levels on T cells were measured. Patients’ plasma was tested for soluble PD-L1 (sPD-L1) by ELISA. Results: Levels of PD-L1 carried by exosomes correlated with patients’ disease activity, the UICC stage and the lymph node status (P = 0.0008–0.013). In contrast, plasma levels of sPD-L1 or exosome PD-1 levels did not correlate with any clinicopathologic parameters. CD69 expression levels were inhibited (P < 0.03) by coincubation with PD-L1high but not by PD-L1low exosomes. Blocking of PD-L1+ exosome signaling to PD-1+ T cells attenuated immune suppression. Conclusions: PD-L1 levels on exosomes, but not levels of sPD-L1, associated with disease progression in HNSCC patients. Circulating PD-L1+ exosomes emerge as useful metrics of disease and immune activity in HNSCC patients. Significance: Circulating PD-L1high exosomes in HNC patients’ plasma but not soluble PD-L1 levels associate with disease progression. Clin Cancer Res; 24(4); 896–905. ©2017 AACR.

Treatment of angiotensin receptor blocker-induced Angioedema: A case series

Angiotensin II receptor antagonists have been proposed as a replacement therapy after the occurrence of either an angiotensin converting enzyme (ACE) inhibitor‐induced angioedema or cough. However, recent studies indicate that angioedema is associated with elevated bradykinin levels in a small fraction of patients treated with angiotensin‐II‐receptor blockers, suggesting a common pathophysiological mechanism. To date, a standard treatment for angiotensin II receptor blocker‐induced angioedema does not exist.

Recent advances in robot-assisted head and neck surgery.

This article reviews current clinical applications and experimental developments for robotic surgery in the head and neck with special focus on financial challenges, current clinical trials, and the controversial aspect of haptic and tactile feedback.

Angioedema in the emergency department: a practical guide to differential diagnosis and management

BackgroundAngioedema is a common presentation in the emergency department (ED). Airway angioedema can be fatal; therefore, prompt diagnosis and correct treatment are vital.Objective of the reviewBased on the findings of two expert panels attended by international experts in angioedema and emergency medicine, this review aims to provide practical guidance on the diagnosis, differentiation, and management of histamine- and bradykinin-mediated angioedema in the ED.ReviewThe most common pathophysiology underlying angioedema is mediated by histamine; however, ED staff must be alert for the less common bradykinin-mediated forms of angioedema. Crucially, bradykinin-mediated angioedema does not respond to the same treatment as histamine-mediated angioedema. Bradykinin-mediated angioedema can result from many causes, including hereditary defects in C1 esterase inhibitor (C1-INH), side effects of angiotensin-converting enzyme inhibitors (ACEis), or acquired deficiency in C1-INH. The increased use of ACEis in recent decades has resulted in more frequent encounters with ACEi-induced angioedema in the ED; however, surveys have shown that many ED staff may not know how to recognize or manage bradykinin-mediated angioedema, and hospitals may not have specific medications or protocols in place.ConclusionED physicians must be aware of the different pathophysiologic pathways that lead to angioedema in order to efficiently and effectively manage these potentially fatal conditions.