How health care professionals confront and solve ethical dilemmas - a tale of two countries: Slovenia and Croatia.

AIM: To assess the differences in the way how Slovenian and Croatian health care professionals (HCPs) confront ethical dilemmas and perceive the role of hospital ethics committees (HECs). METHODS: This cross-sectional, survey-based study involved HCPs from three Slovenian and five Croatian university medical centers (UMC). The final sample sizes were 308 (244 or 79.2% women) for Slovenia and 485 (398 or 82.1% women) for Croatia. RESULTS: Compared with Croatian physicians, Slovenian physicians reported a higher share of ethical dilemmas regarding waiting periods for diagnostics or treatment, suboptimal working conditions due to interpersonal relationships in the ward, and end-of-life treatment withdrawal, and a lower share regarding access to palliative care and patient information protection. Compared with Croatian nurses, Slovenian nurses reported a lower share of ethical dilemmas regarding the distribution of limited resources, recognizing the patient's best interests, and access to palliative care. Compared with Croatian other HCPs, Slovenian other HCPs reported a lower burden of ethical dilemmas regarding waiting periods for diagnostics or treatment, distribution of limited resources, and access to palliative care. When encountering an ethical dilemma, all HCPs in both countries would first consult their colleagues. Slovenian and Croatian HCPs recognized the importance of the HECs to a similar extent, but viewed their role differently. CONCLUSION: Croatian and Slovenian HCPs are confronted with different ethical dilemmas and perceive the role of HECs differently.

Notes on the Development of the Slovenian Ethical Recommendations for Decision-Making on Treatment and Palliative Care of Patients at the End of Life in Intensive Care Medicine.

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.

Attitudes of Slovene paediatricians to end-of-life care.

AIMS: The aims of this study were to assess the attitudes of Slovene paediatricians to aspects of end-of-life (EOL) care and compare these attitudes between paediatric intensivists, paediatric specialists and paediatric residents. METHODS: We performed a cross-sectional survey, using a specifically designed 43-item anonymous questionnaire. RESULTS: We included 323 out of 586 Slovene paediatricians and residents, while 46.7% (151 of 323) of them responded to our questionnaire. More than half of intensivists (54.2%) had sought counsel from the Committee for Medical Ethics in the past as compared with 12.0% and 12.1% of specialists and residents, respectively (P < 0.001). The decision to limit life-sustaining treatment (LST) was found to be ethically acceptable in all groups of respondents. The highest level of agreement was found in residents (90.2%), followed by 83.3% among intensivists and 73.8% among specialists (P = not statistically significant (NS)). Disagreement with termination of hydration was highest among residents (85%) and intensivists (79.2%) while it was lower among specialists (66.7%) (P = NS). Patient's best interest, good clinical practice and patient's autonomous decision were graded as the top three aspects of the EOL care, while cost effectiveness and availability of patient's bed in intensive care were the least important. CONCLUSIONS: The decision to limit LST measures was found to be ethically acceptable for Slovene paediatricians. No major differences were found among paediatric intensivists, specialist paediatricians and paediatric residents in the attitudes towards the EOL care.

Experiences of Slovene ICU physicians with end-of-life decision making: a nation-wide survey.

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 dilemmas arise in end-of-life (EOL) situations. We aimed to assess intensive care unit (ICU) physicians' experiences with EOL decision making and to compare the responses according to ICU type. MATERIAL AND METHODS: A cross-sectional survey was performed in all 35 Slovene ICUs, using a questionnaire designed to assess ICU physician experiences with EOL decision making, focusing on limitations of life-sustaining treatments (LST). RESULTS: We distributed 370 questionnaires (approximating the number of Slovene ICU physicians) and 267 were returned (72% response rate). The great majority of ICU physicians reported using do-not-resuscitate (DNR) orders (97%), withholding LST (94%), and withdrawing antibiotics (86%) or inotropes (95%). Fewer ICU physicians reported withdrawing mechanical ventilation (52%) or extubating patients (27%). Hydration was reported to be only rarely terminated (76% of participants reported never terminating it). In addition, 63% of participants had never encountered advance directives, and 39% reported to "never" or "rarely" participating in decision making with relatives of patients. Nurses were reported to be "never" or "rarely" involved in the EOL decision making process by 84% of participants. CONCLUSIONS: Limitation of LST was regularly used by Slovene ICU physicians. DNR orders and withholding of LST were the most commonly used measures. Hydration was only rarely terminated. In addition, use of advance directives was almost non-existent in practice, and the patients' relatives and nurses only infrequently participated in the decision making.

Health-related quality of life in men with oligometastatic prostate cancer following metastases-directed stereotactic body radiotherapy: Real-world data from the E2-RADIatE OligoCare cohort.

Objective: To evaluate the impact of metastases-directed stereotactic body radiotherapy (SBRT) on health-related quality of life (HRQoL) in men with oligometastatic prostate cancer (PCa) using real-world data from the OligoCare cohort. Materials and methods: OligoCare is a pragmatic, observational cohort designed to assess the impact of metastases-directed SBRT on patients with oligometastatic disease (OMD). We report an interim analyses of the secondary endpoint HRQoL, assessed using the EORTC QLQ-C30, within six months of metastases-directed SBRT for oligometastatic disease in men with PCa among the first 1600 registered patients. HRQoL data collection was optional within the OligoCare cohort. To compare HRQoL between baseline and first follow-up assessment, a Wilcoxon signed-rank test was used. A multiple linear regression model was used to explore the HRQoL associations with predefined factors. Results: Out of the 1600 registered patients, 658 were treated for oligometastatic PCa, of which 233 had baseline QoL data and 132 patients had both baseline and follow-up HRQoL data. At baseline, most patients had a WHO performance status of 0 or 1 (87 %), were de-novo oligometastatic (79 %), had one metastasis (90 %), and had a good overall global health status (mean 80.81, SD16.11, IQR 75-92). 51 % received hormonal therapy as concomitant systemic treatment. Patients with comorbidities as assessed by the Charlson Comorbidity index had a worse global health status at baseline (-4.88, 95 % CI:-9.35, -0.42). No clinically meaningful significant difference in global health status was observed at first assessment following SBRT (median 3.0 months) compared with baseline (mean difference 2.27, 95 % CI:-1.54, 6.08). Upon evaluating the proportions, meaningful clinically important differences (a 10-point or more difference) was observed in, 17 % and 11 % of the patients reporting deterioration and improvement of global health status, respectively. Conclusion: Metastases-directed stereotactic body radiotherapy had no negative impact on global HRQoL within the first six months after treatment.

Safety of CDK4/6 inhibitors and concomitant radiation therapy in patients affected by metastatic breast cancer.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) currently represent the standard of care for the initial treatment of patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The aim of our study is to evaluate the safety of the use of concomitant radiation therapy (RT) in a consecutive series of HR+/HER2- patients treated in two academic institutions with CDK4/6i in the metastatic setting. METHODS AND MATERIALS: From September 2017 to February 2020, we retrospectively collected and analysed data on a sequential series of patients treated with CDK4/6i, receiving RT or not, at two European institutions. Primary outcome of the study was the association between RT and any adverse events (AEs) ≥ G3. Secondary outcomes were the association between RT and any AEs (any grade), CDK4/6i dose reduction rate, and CDK4/6i treatment discontinuation rate. RESULTS: We analysed a total of 132 consecutive women; RT was prescribed in 57 (43.2%) patients (70 irradiated lesions). The median age of the series was 52.1 years (range 32.3-78.2). Concomitant RT administration was not significantly related to higher AEs ≥ G3 (p = 0.19) and any grade AEs (p = 1.0); there was no association with RT and CDK4/6i dose reduction (p = 0.49) and discontinuation rates (p = 0.14). At a median follow-up of 18.8 months, the progression-free survival (PFS) rate was 35% and the overall survival (OS) rate was 38.7% in the whole group. The use of concomitant RT did not affect both PFS (p = 0.71) and OS rates (p = 0.55). CONCLUSIONS: Our data are encouraging regarding the safety of this combination, showing that concurrent RT did not increase severe toxicity and did not have an impact on systemic treatment conduction.

A fatal wound complication following sequential anti-angiogenesis, immune checkpoint inhibition and ultra-hypofractionated radiotherapy.

PURPOSE: Multimodality treatments combining radiotherapy, immune therapy and/or targeted therapy are under heavy investigation. Promising data from clinical trials are emerging, nevertheless unexpected interactions and adverse events should not be overlooked. CASE PRESENTATION: Here we present a case study of a patient with metastatic colon adenocarcinoma treated sequentially with a chemotherapy/targeted therapy combination, immune checkpoint inhibitors and ultra-hypofractionated radiotherapy. After radiation treatment, the patient developed extensive posterior abdominal wall wounds coinciding with regression of the irradiated metastatic tumour mass and marked elevation of the inflammation parameters. CONCLUSION: This case represents an unusual fatal wound complication after palliative ultra-hypofractionated radiotherapy. Further research into synergistic effects of sequential radiotherapy and anti-angiogenesis therapy may provide an advantage in anticipating severe sequelae.

Economic and social impacts of COVID-19 and public health measures: results from an anonymous online survey in Thailand, Malaysia, the UK, Italy and Slovenia.

OBJECTIVES: To understand the impact of COVID-19 and public health measures on different social groups, we conducted a mixed-methods study in five countries ('SEBCOV-social, ethical and behavioural aspects of COVID-19'). Here, we report the results of the online survey. STUDY DESIGN AND STATISTICAL ANALYSIS: Overall, 5058 respondents from Thailand, Malaysia, the UK, Italy and Slovenia completed the self-administered survey between May and June 2020. Poststratification weighting was applied, and associations between categorical variables assessed. Frequency counts and percentages were used to summarise categorical data. Associations between categorical variables were assessed using Pearson's χ2 test. Data were analysed in Stata 15.0 RESULTS: Among the five countries, Thai respondents reported having been most, and Slovenian respondents least, affected economically. The following factors were associated with greater negative economic impacts: being 18-24 years or 65 years or older; lower education levels; larger households; having children under 18 in the household and and having flexible/no income. Regarding social impact, respondents expressed most concern about their social life, physical health, mental health and well-being.There were large differences between countries in terms of voluntary behavioural change, and in compliance and agreement with COVID-19 restrictions. Overall, self-reported compliance was higher among respondents who self-reported a high understanding of COVID-19. UK respondents felt able to cope the longest and Thai respondents the shortest with only going out for essential needs or work. Many respondents reported seeing news perceived to be fake, the proportion varying between countries, with education level and self-reported levels of understanding of COVID-19. CONCLUSIONS: Our data showed that COVID-19 and public health measures have uneven economic and social impacts on people from different countries and social groups. Understanding the factors associated with these impacts can help to inform future public health interventions and mitigate their negative consequences. TRIAL REGISTRATION NUMBER: TCTR20200401002.

Telemedicine in Radiation Oncology Post-COVID-19 Pandemic: There Is No Turning Back.

PURPOSE: We aimed to assess patients' and physicians' perspectives on wider implementation of telemedicine in radiation oncology practice, disrupted by the novel coronavirus disease 2019 (COVID-19). METHODS: Quantitative questionnaires were prepared and distributed between May 27 and June 11, 2020. A 29-question survey targeting patients with cancer was distributed electronically via cancer support organizations. Cross-sectional data from a selected weekday at a radiation oncology department were also analyzed. In addition, a 25-question survey was distributed to 168 physicians employed by a comprehensive cancer center. RESULTS: In total, we have analyzed 468 patients' and 101 physicians' responses. Among responding patients, 310 were undergoing active treatment and 158 were in follow-up care. Both patients and physicians reported no experiences with video consultations during the COVID-19 pandemic, but 15% of patients stated that they missed telemedicine services that would include a video call. Overall, 30.6% of patients expressed interest in more frequent usage of telemedicine and 23.3% would start using it. Sixty-seven percent of radiation oncologists expressed interest in more frequent usage of telemedicine, and 14% would use it similarly as in the past. For patients treated with radiation therapy (RT), 59.9% and 63.4% of the responding patients acknowledged that video consultations would be an important addition to medical care during RT course or after the completion of RT, respectively. Comparably, 61.1% and 63.9% of radiation oncologists believed video consultations would be useful or extremely useful for patients undergoing RT or for patients in the follow-up setting, respectively. CONCLUSIONS: The post-COVID-19 era represents a unique chance to improve and guarantee continuity of cancer care via telemedicine solutions, when appropriate.

Challenges in Combining Immunotherapy with Radiotherapy in Recurrent/Metastatic Head and Neck Cancer.

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.

The first nationwide study on facing and solving ethical dilemmas among healthcare professionals in Slovenia.

BACKGROUND: 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. AIM: 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. SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cyclin-Dependent Kinase 4/6 Inhibitors Combined With Radiotherapy for Patients With Metastatic Breast Cancer.

BACKGROUND: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the standard treatment for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Data about the balance between efficacy and toxicity of combined palliative radiotherapy (RT) and CDK4/6 inhibition are lacking. PATIENTS AND METHODS: We undertook a review of 46 patients with metastatic breast cancer on systemic treatment with CDK4/6i who underwent 62 metastases-directed RT. Clinical, laboratory, and RT treatment planning data were collected. Statistical analyses included Student t test, paired sample t test, and logistic regression modeling. RESULTS: Thirty patients (65.2%) received palbociclib, 15 (32.6%) received ribociclib, and one patient received abemaciclib (2.2%). Median total prescribed RT dose was 20 Gy (range, 8-63 Gy). Sites of RT were bone (n = 50; 80.7%), visceral (n = 7; 11.3%), or brain metastases (n = 3; 4.8%), as well as primary tumor of the breast (n = 2; 3.2%). Overall, the rates of grade 3 or higher adverse events (AEs) were 6.5%, 4.3%, 15.2%, and 23.9% before the start of RT, during RT, 2 and 6 weeks after RT completion, respectively. We found no correlation between dose distribution to organs at risk and the development of AEs. The local control rates for the entire cohort were 98% at 6 months and 90% at 12 months. Overall, pain relief (complete or partial) was experienced by 80% (24/30) of patients who initially reported pain at the treated metastatic site. CONCLUSION: We observed a modest increase in the rates of grade 3 or higher AEs after combined RT and CDK4/6i, with maintained efficacy of concomitant RT.

Flow Cytometric Determination of Actin Polymerization in Peripheral Blood Leukocytes Effectively Discriminate Patients With Homozygous Mutation in ARPC1B From Asymptomatic Carriers and Normal Controls.

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.

End-of-life decisions in 34 Slovene Intensive Care Units: a nationwide prospective clinical study.

BACKGROUND: The aim of this study was to determine how end-of-life decisions (EOLD) on limitations of life-sustaining treatment (LST) are made in three different types of intensive care units (ICUs) in Slovenia. METHODS: A national multicenter prospective study among 31 adult and three pediatric/neonatal ICUs (PICUs). The questionnaire form on EOLD was designed to assess the clinical practice. Data were collected between January 1, 2013, and March 31, 2013. For statistical analysis we used IBM® SPSS® Statistics 20 software package. RESULTS: Overall, of 4226 patients were admitted to ICUs, the EOLD on limitation of LST were performed in 112 patients (23.9%) out of 468 patients, which had died and/or had been subject to EOLD on limitation of LST. In 86.2% of the cases, patients had impaired competence. Advance directives were available only in 1.9% (2 out of 106 patients) of the cases. In the majority of cases, the EOLD was taken by the physicians (96.2%). In 61.8% of the cases, patient representatives were involved in the discussion about limitation of LST. The do-not-resuscitate order and withholding of inotropes/vasopressors were the most common measures to limit LST. Most commonly withdrawn were inotropes/vasopressors and antibiotics. Palliative care was included in 72.3% of the cases (80 out of 112 patients), however, palliative care team was only included in 4% of the cases. CONCLUSIONS: No differences were found between the three different types of ICUs in EOLD on limitation of LST even though limitation of LST was provided regularly. The most commonly limited LST measures include mechanical ventilation, inotropes/vasopressors, hemodialysis, and antibiotics. Almost none of the patients had advance directives in place. Palliative care team was available in only few cases.