Bone metastases from renal cell carcinoma: A case report and literature review

Management of bone metastases from Renal Cell Carcinoma (RCC) has significantly changed after the era of targeted therapy that improved the overall survival. This has sucked the different interveners in their management to push the surgical indications in order to improve outcome and quality of life for these patients. In case of a solitary metastasis or a limited number of resectable metastases wide resections have to be considered according to patient profile, comorbidities, localization, heaviness of the surgery and to benefit –risk balance. However such surgeries are highly demanding procedures that must be carefully planned and discussed in multidisciplinary team and with patient. Thus, surgical decision-making for a second metastasis and according to what criteria remains a subject of controversy. We report a case of an aggressive metastatic renal cell carcinoma with good functional and oncologic outcomes 3 years after surgery coupled with anti-angiogenic treatment. A review of the literature concerning recent attitudes in the management of bony metastatic renal carcinoma was carried out. Keywords: renal cell carcinoma; bone metastases; surgery; targeted therapy.

Patient and Citizen Participation in the Identification of Ethical Considerations Aiming to Address Uncertainty in the Evaluation of Promising Interventions in a Pandemic Context

Since the beginning of the COVID-19 pandemic, numerous studies have been conducted to identify interventions that could contribute to alleviating the burden it has caused. The Institut national d'excellence en santé et en services sociaux (INESSS) has played a key role in informing the government of Québec regarding the evaluation of specific pandemic-related interventions. This process took place in a context characterized by a sense of urgency to assess and recommend potential interventions that could save lives and reduce the effects of the disease on populations and healthcare systems, which increased the pressure on the regulatory agencies leading these evaluations. While some of the interventions examined were considered promising, results from COVID-19 studies often led to uncertainty regarding their efficacy or safety. Regulatory agencies evaluating the value of promising interventions thus face challenges in deciding whether these should be made available to the population, particularly when assessing their benefit-risk balance. To shed light on these challenges, we identified underlying ethical considerations that can influence such an assessment. A rapid literature review was conducted in February 2021, to identify the main challenges associated with the benefit-risk balance assessment of promising interventions. To reinforce our understanding of the underlying ethical considerations, we initiated a discussion among various social actors involved in critical thinking surrounding the evaluation of promising interventions, including ethicists, clinicians and researchers involved in clinical or public health practice, as well as patients and citizens. This discussion allowed us to create a space for exchange and mutual understanding among these various actors who contributed equally to the identification of ethical considerations. The knowledge and perspectives stemming from the scientific literature and those consulted were integrated in a common reflection on these ethical considerations. This allowed patients and citizens, directly affected by the evaluation of pandemic-related interventions and the resulting social choices, to contribute to the identification of the relevant ethical considerations. It also allowed for reflection on the responsibilities of the various actors involved in the development, evaluation, and distribution of promising interventions in a setting of urgency and uncertainty, such as that brought about by the COVID-19 pandemic.

Classification of Companion Diagnostics: A New Framework for Biomarker-Driven Patient Selection

Background Modern personalized medicine strategies builds on therapy companion diagnostics to stratify patients into subgroups with differential benefit/risk. In general, stratification for drug response implies a treatment-by-subgroup interaction. This interaction is usually suggested by the drug’s mechanism of action and investigated in pharmacological research or in clinical studies. In these candidate genes or pathway approaches, either biological reasons for a differential benefit/risk or statistical interaction regarding a pharmacological or clinical endpoint or both may be given. For successful drug approval, demonstration of a positive benefit/risk balance in the intended patient population is required. This also applies to situations with biomarker-selected populations. However, further regulatory considerations relate to the usefulness and plausibility of the selected patients and benefit/risk extrapolations or alternative therapy options in biomarker-negative populations. Methods To facilitate the specification of regulatory requirements and support the design of clinical development programmes, a systematic classification of biomarker-drug pairs is needed, in particular with regard to the expected underlying molecular mechanism and the clinical evidence. Results A classification of five biomarker-drug categories is proposed related to increasing evidence on the biomarker’s predictive value in relation to a specific drug. We classified biomarkers into five ascending categories with increasing evidence on the predictive nature of the biomarker in relation to a specific drug according to the comparative pharmacological and clinical evidence. Conclusions The proposed classification will facilitate regulatory decision-making and support drug development with respect to biomarker-related subgrouping, both, during clinical programme and at the time of marketing authorization application, since the grade of evidence on the differential power of the biomarker can be considered as an indicator for the usefulness of a biomarker-related subgrouping.

Four-year safety and effectiveness data from patients with multiple sclerosis treated with fingolimod: The Spanish GILENYA registry

Objective To describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. Methods An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. Results Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p<0.001). This significant reduction in the ARR continued to be observed in all subgroups. After 4 years, the EDSS showed a minimal deterioration, with the EDSS scores from year 1 to year 4 remaining mostly stable. The percentage of patients without T1 Gd+ lesions progressively increased from 45.6% during the year prior to fingolimod initiation to 88.2% at year 4. The proportion of patients free from new/enlarged T2 lesions after 4 years of fingolimod treatment was 80.3%. This trend in both radiological measures was also observed in the subgroups. Adverse events (AEs) were experienced by up to 41.6% of patients (most commonly: lymphopenia [12.5%] and urinary tract infection [3.7%]). Most AEs were mild in severity, 3.6% of patients had serious AEs. Conclusions The patient profile was similar to other observational studies. The results obtained from the long-term use of fingolimod showed that it was effective, regardless of prior DMT, and it had adequate safety results, with a positive benefit-risk balance.

Quantifying healthcare and welfare sector workers’ preferences around COVID-19 vaccination: a cross-sectional, single-profile discrete-choice experiment in France

ObjectivesTo analyse preferences around promotion of COVID-19 vaccination among workers in the healthcare and welfare sector in Fance at the start of the vaccination campaign.DesignSingle-profile discrete-choice experiment. Respondents in three random blocks chose between accepting or rejecting eight hypothetical COVID-19 vaccination scenarios.Setting4346 healthcare and welfare sector workers in France, recruited through nation-wide snowball sampling, December 2020 to January 2021.OutcomeThe primary outcomes were the effects of attributes’ levels on hypothetical acceptance, expressed as ORs relative to the reference level. The secondary outcome was vaccine eagerness as certainty of decision, ranging from −10 to +10.ResultsAmong all participants, 61.1% made uniform decisions, including 17.2% always refusing vaccination across all scenarios (serial non-demanders). Among 1691 respondents making variable decisions, a strong negative impact on acceptance was observed with 50% vaccine efficacy (compared with 90% efficacy: OR 0.05, 95% CI 0.04 to 0.06) and the mention of a positive benefit–risk balance (compared with absence of severe and frequent side effects: OR 0.40, 0.34 to 0.46). The highest positive impact was the prospect of safely meeting older people and contributing to epidemic control (compared with no indirect protection: OR 4.10, 3.49 to 4.82 and 2.87, 2.34 to 3.50, respectively). Predicted acceptance was 93.8% for optimised communication on messenger RNA vaccines and 16.0% for vector-based vaccines recommended to ≥55-year-old persons. Vaccine eagerness among serial non-demanders slightly but significantly increased with the prospect of safely meeting older people and epidemic control and reduced with lower vaccine efficacy.DiscussionVaccine promotion towards healthcare and welfare sector workers who hesitate or refuse vaccination should avoid the notion of benefit–risk balance, while collective benefit communication with personal utility can lever acceptance. Vaccines with limited efficacy will unlikely achieve high uptake.

Immunomodulatory treatment and surgical management of idiopathic uveitis and juvenile idiopathic arthritis-associated uveitis in children: a French survey practice

Background Surgeries for idiopathic uveitis and juvenile idiopathic arthritis-associated uveitis in children are complex because of the high risk of inflammatory postoperative complications. There is no consensus about treatment adaptation during the perioperative period. The objectives of this study are to report the therapeutic changes made in France and to determine whether maintaining or stopping immunosuppressive therapies is associated with an increased risk of surgical site infection or an increased risk of uveitis or arthritis flare-up. Methods We conducted a retrospective cohort study between January 1, 2006 and December 31, 2018 in six large University Hospitals in France. Inclusion criteria were chronic idiopathic uveitis or chronic uveitis associated with juvenile idiopathic arthritis under immunosuppressive therapies at the time of the surgical procedure, operated before the age of 16. Data on perioperative treatments, inflammatory relapses and post-operative infections were collected. Results A total of 76 surgeries (42% cataract surgeries, 30% glaucoma surgeries and 16% posterior capsule opacification surgeries) were performed on 37 children. Adaptation protocols were different in the six hospitals. Immunosuppressive therapies were discontinued in five cases (7%) before surgery. All the children in the discontinuation group had an inflammatory relapse within 3 months after surgery compared to only 25% in the other group. There were no postoperative infections. Conclusions The results of this study show varying practices between centres. The benefit-risk balance seems to favour maintaining immunosuppressive therapies during surgery. Further studies are needed to determine the optimal perioperative treatments required to limit post-operative inflammatory relapses.

Ethics of HIV cure research: an unfinished agenda

Background The pursuit of a cure for HIV is a high priority for researchers, funding agencies, governments and people living with HIV (PLWH). To date, over 250 biomedical studies worldwide are or have been related to discovering a safe, effective, and scalable HIV cure, most of which are early translational research and experimental medicine. As HIV cure research increases, it is critical to identify and address the ethical challenges posed by this research. Methods We conducted a scoping review of the growing HIV cure research ethics literature, focusing on articles published in English peer-reviewed journals from 2013 to 2021. We extracted and summarized key developments in the ethics of HIV cure research. Twelve community advocates actively engaged in HIV cure research provided input on this summary and suggested areas warranting further ethical inquiry and foresight via email exchange and video conferencing. Discussion Despite substantial scholarship related to the ethics of HIV cure research, additional attention should focus on emerging issues in six categories of ethical issues: (1) social value (ongoing and emerging biomedical research and scalability considerations); (2) scientific validity (study design issues, such as the use of analytical treatment interruptions and placebos); (3) fair selection of participants (equity and justice considerations); (4) favorable benefit/risk balance (early phase research, benefit-risk balance, risk perception, psychological risks, and pediatric research); (5) informed consent (attention to language, decision-making, informed consent processes and scientific uncertainty); and (6) respect for enrolled participants and community (perspectives of people living with HIV and affected communities and representation). Conclusion HIV cure research ethics has an unfinished agenda. Scientific research and bioethics should work in tandem to advance ethical HIV cure research. Because the science of HIV cure research will continue to rapidly advance, ethical considerations of the major themes we identified will need to be revisited and refined over time.

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics

Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of life.

REFRAMING OF THE TOURIST BRANDING CONCEPT

Background. The use of innovative tools in various spheres of Ukraine’s tourist sys­tem, including in particular its branding, will provide new development opportunities in the context of the global pandemic COVID-19. Analysis of recent research and publications has shown that the problems of for­ma­tion Ukraine’s national tourism brand require systematic comprehensive research despite scientific interest and practical necessity. The aim of the article is to substantiate the peculiarities of reframing concept (from English reframe – to do over, to change) of tourism branding on the basis of the holistic approach. Materials and methods. The portfolio tools and methods of scientific research such as analysis, synthesis, analytical researches; systematization, decomposition and generali­za­tion were used to substantiate the concept of the national tourist brand of Ukraine, structuring of the process of tourist brand formation, descriptors identification of the brand semantic model. Results. Scientific hypotheses about the correlation between the share of problem loans in the total volume of issued loans and the ratio of individual macroeconomic indi­cators of the country’s development were suggested; their empirical testing was carried out. The range of proposals, based on the results of this study, was developed. It included res­triction of high-risk balance and off-balance banks credit operations; introduction of the mechanism for mandatory stress testing of credit risk, taking into account key indicators that characterize the level of global misbalances; establishment of a direct relationship bet­ween the level of credit rating of the country and the degree of credit activity of its banks; establishment by the mega-regulator of the critical value of the ratio between the volume of financial assets and GDP; determination of tight credit risk standards, etc. The implement­tation of these proposals will stabilize the situation in global financial markets. Conclusion. The generated national brand is a means of increasing tourist interest in Ukraine and a prerequisite for the tourist flows growth. The national brand value is not only in the feasibility to create a positive image, increase the benefits of activities in global, regional and national markets, but also in strengthening the country’s position at the inter­national level. Global economic asymmetries in tourism are not homogeneous, therefore new impul­ses and new quality of tourism can be obtained through the development of the tourism branding concept, which depends on the socio-economic and cultural impact of the tourist destina­tion, its attractiveness to potential tourists and export-oriented development model of tourism.