Immunotherapy with immune checkpoint inhibitors (ICI) has recently become a standard part of the treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), although the response rates are low. Numerous preclinical and clinical studies have now illuminated several mechanisms by which radiotherapy (RT) enhances the effect of ICI. From RT-induced immunogenic cancer cell death to its effect on the tumor microenvironment and vasculature, the involved mechanisms are diverse and intertwined. Moreover, the research of these interactions is challenging because of the thin line between immunostimulatory and the immunosuppressive effect of RT. In the era of active research of immunoradiotherapy combinations, the significance of treatment and host-related factors that were previously seen as being less important is being revealed. The impact of dose and fractionation of RT is now well established, whereas selection of the number and location of the lesions to be irradiated in a multi-metastatic setting is something that is only now beginning to be understood. In addition to spatial factors, the timing of irradiation is as equally important and is heavily dependent on the type of ICI used. Interestingly, using smaller-than-conventional RT fields or even partial tumor volume RT could be beneficial in this setting. Among host-related factors, the role of the microbiome on immunotherapy efficacy must not be overlooked nor can we neglect the role of gut irradiation in a combined RT and ICI setting. In this review we elaborate on synergistic mechanisms of immunoradiotherapy combinations, in addition to important factors to consider in future immunoradiotherapy trial designs in R/M HNSCC.

Actin nucleators initiate formation of actin filaments. Among them, the Arp2/3 complex has the ability to form branched actin networks. This complex is regulated by members of the Wiscott-Aldrich syndrome protein (WASp) family. Polymerization of actin filaments can be evaluated through flow cytometry by fluorescent phalloidin staining before and after stimulation with N-formyl-methionyl-leucyl-phenylalanine (fMLP). We identified a missense mutation in the gene ARPC1B (Arp2/3 activator subunit) resulting in defective actin polymerization in four patients (three of them were related). All patients (1 male, 3 female) developed microthrombocytopenia, cellular immune deficiency, eczema, various autoimmune manifestations, recurrent skin abscesses and elevated IgE antibodies. Besides four patients with homozygous mutation in ARPC1B, we also identified six heterozygous carriers without clinical disease (3 males, 3 females) within the same family. We developed a functional test to evaluate Arp2/3 complex function, which consists of flow cytometric detection of intracellular polymerized actin after in vitro fMLP stimulation of leukocytes. Median fluorescence intensities of FITC-phalloidin stained actin were measured in monocytes, neutrophils and lymphocytes of patients, carriers, and healthy control subjects. We detected non-efficient actin polymerization in monocytes and neutrophils of homozygous patients compared to carriers or the healthy subjects. In monocytes, the increase in median fluorescence intensities was significantly lower in patients compared to carriers (104 vs. 213%; p < 0.01) and healthy controls (104 vs. 289%; p < 0.01). Similarly, the increase in median fluorescence intensities in neutrophils was significantly increased in the group with carriers (208%; p < 0.01) and healthy controls (238%; p < 0.01) and significantly decreased in the patient's group (94%). Our functional fMLP/phalloidin test can therefore be used as a practical tool to separate symptomatic patients from asymptomatic mutation associated to actin polymerization.

Background:Advances in intensive care medicine have enormously improved ability to successfully treat seriously ill patients. However, intensive treatment and prolongation of life is not always in the patient’s best interest, and many ethical dilem...

Healthcare professionals (HCPs), patients and families are often faced with ethical dilemmas. The role of healthcare ethics committees (HECs) is to offer support in these situations. The primary objective was to study how often HCPs encounter ethical dilemmas. The secondary objective was to identify the main types of ethical dilemmas encountered and how HCPs solve them. We conducted a cross-sectional, survey-based study among HCPs in 14 Slovenian hospitals. A questionnaire was designed and validated by HCPs who were selected by proportional stratified sampling. Data collection took place between April 2015 and April 2016. The final sample size was n = 485 (385 or 79.4%, female). The response rates for HCPs working in secondary and tertiary level institutions were 45% and 51%, respectively. Three hundred and forty (70.4%) of 485 HCPs (very) frequently encountered ethical dilemmas. Frequent ethical dilemmas were waiting periods for diagnostics or treatment, suboptimal working conditions due to poor interpersonal relations on the ward, preserving patients’ dignity, and relations between HCPs and patients. Physicians and nurses working in secondary level institutions, compared to their colleagues working in tertiary level institutions, more frequently encountered ethical dilemmas with respect to preserving patients’ dignity, protecting patients’ information, and relations between HCPs and patients. In terms of solutions, all HCPs most frequently discussed ethical dilemmas with co-workers (colleagues), and with the head of the department. According to HCPs, the most important role of HECs is staff education, followed by improving communication, and reviewing difficult ethical cases. Waiting periods for diagnostics and treatment and suboptimal working conditions due to poor interpersonal relations are considered to be among the most important ethical issues by HCPs in Slovenian hospitals. The most important role of HECs is staff education, improving communication, and reviewing difficult ethical cases.

Objectives: To describe the process of development of “Slovenian Ethical Recommendations for Decision-Making on Treatment and Palliative Care of Patients at the End of Life in Intensive Care Medicine” and its final outcomes. Data Sources: Personal experience and reflection, complemented by published data. Study Selection: Not applicable. Data Extraction: Not applicable. Data Synthesis: Narrative, experiential reflection, literature review. Conclusions: Slovenian ethical recommendations bring a small piece to a long tradition of ethical practice in a small European country. Despite the availability of informative international guiding documents on the issue, there are several specific good reasons for a small country or a region to develop its own unique guidelines (i.e., lack of local directives and legislation, unique cultural and political situation, need for development of professional expertise and terminology, and to educate healthcare providers). The authors strongly believe that our recommendations positively impact practice and will support best possible integrated palliative and end-of-life quality care with the ICU.