Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Международный музыкальный конкурс в формировании имиджа страны проведения (на примере Евровидения 2017)

Аннотация выпускной квалификационной работы Орлов Никита Сергеевич «МЕЖДУНАРОДНЫЙ МУЗЫКАЛЬНЫЙ КОНКУРС В ФОРМИРОВАНИИ ИМИДЖА СТРАНЫ ПРОВЕДЕНИЯ (НА ПРИМЕРЕ ЕВРОВИДЕНИЯ-2017)» Н. рук. - Быкова Елена Владимировна, доктор филологических наук, доцент Кафедра связей с общественностью Очная форма обучения Актуальность: международный музыкальный конкурс Евровидение как самое масштабное регулярное высокотехнологичное телевизионное и медиа-событие, которое . Е ежегодно акцентирует внимание аудитории на национально-культурных особенностях страны-организатора конкурса, формирует значительные туристические потоки и тем самым способствует формированию имиджа территории. Более того, победа страны-участницы конкурса Евровидения зачастую отражает идеолого-политический вектор Европы и по сути дела выполняет функцию политического PR страны-победителя и страны-хозяйки мероприятия. Следовательно анализ используемых на мероприятии коммуникативных технологий является актуальным и востребованным для событийного и устроительного PR Объект исследования: коммуникационные активности международного музыкального конкурса (на примере Евровидения в Киеве в 2017 г.). Предмет исследования: функция статусного PR-мероприятия в формировании имиджа страны. Цель исследования: доказать, что международный музыкальный конкурс Евровидение способствует формированию имиджа страны проведения. Задачи исследования: разработать терминологический аппарат исследования на основе научной литературы по имиджмейкингу, брендингу и ивент-менеджменту; определить актуальные коммуникационные технологии, применяемые в рамках специальных событий для формирования имиджа страны; описать роль Европейского Вещательного Союза как организатора Евровидения в формировании имиджа страны проведения конкурса; оценить эффективность реализованных коммуникативных технологий формирования имиджа страны в рамках Евровидения; дать рекомендации по формированию имиджа страны с помощью Евровидения. Теоретическая база: научные труды Е. Быковой, Д. Гавры, А. Панкрухина, Б. Дженеса, Е. Кавериной, У. Хальцбаура, Дж. Голдблатта а также труды Д. Пассмана о музыкальном бизнесе, П. Джордана о продвижении имиджа стран с помощью Евровидения и др. Эмпирическая база: PR-документы, размещенные на сайте Евровидения и Европейского Вещательного Союза; более полутора миллиона статей об Украине в европейских СМИ, размещенные в базе проекта мониторинга международного имиджа Украины «Oko»; данные базы материалов СМИ и социальных медиа Factiva; данные Google.Analytics. Практическая значимость: исследование доказывает, что международный музыкальный конкурс Евровидение формирует имидж страны проведения независимо от успешности использования конкретных технологий формирования имиджа страны. Тезисы исследования были апробированы на международном научном форуме «Медиа в современном мире. 57-е Петербургские чтения», опубликованы в сборнике материалов статей форума и имеют статус научной статьи, размещенной в базе РИНЦ. Структура работы: Работа состоит из введения, 3 глав: «функция специального события в формировании имиджа страны», «Евровидение как специальное событие Европейского Вещательного Союза» и «коммуникационный потенциал Евровидения как площадки для формирования имиджа страны», заключения, списка использованной литературы из 67 позиций и 12 приложений. Общий объем 76 страниц.Abstract of graduating qualification thesis Mikita Arlou INTERNATIONAL MUSIC CONTEST IN HOST COUNTRY IMAGE FORMATION (ON THE EXAMPLE OF EUROVISION 2017) Supervisor associate professor Elena Bykova, doctor of philology Department of PR in business full-time study Relevance: the international music contest Eurovision as the most wide scale regular high tech TV and Media event which annually emphasizes audience attention on national cultural features of the host country, forms tourist flows which have huge influence on territorial image formation. Besides the win of a participating in the Eurovision country often shows the ideological and political European vector and in fact serves as political PR of the winning or host country. Consequently the analysis of applied communication technologies is relevant and in-demand for event PR. Research object: communication activities of international music contest (on the example of Eurovision in Kyiv in 2017). Research subject: function of status PR event in country image formation. The aim of research: to prove that international music contest Eurovision contributes host country image formation. The tasks of research: to develop research terminology based on scientific literature on image making, branding and event management; to define actual communication technologies applied in special PR events on country image formation; to describe European Broadcasting Union role in host country image formation; to appreciate effectiveness of applied communication technologies on host country image formation in Eurovision; to give recommendations for host country image formation with the help of Eurovision. Theoretical base: scientific works written by E. Bykova, D. Gavra, A. Pankrukhin, B. Jenes, E. Kaverina, U. Halcbaur, J. Goldblatt and D. Passman´s works on music business and P. Jordan on county image building with the help of Eurovision, etc. The empirical base: PR documents from official Eurovision and European Broadcasting Union websites; more than 1.5 million articles on Ukraine in European media stored in the base of international Ukrainian image monitoring project Oko; content of the mass media and social media base Factiva; Google.Analytics data. Practical significance: the research proves that international music contest Eurovision is relevant for the host country image formation independently of the success level of applied country image formation communication technologies. Approbation: General positions of current thesis were aprobated on international scientific forum Media in modern world and were published at the collection of articles of the forum and have the status of a scientific article posted in the RINC database. Thesis structure: Research consists of introduction, 3 chapters: Special event function in country image formation, Eurovision as EBU special event and communication potential of Eurovision as a platform for image formation; conclusion, literature list from 67 positions and 12 attachments. The total volume is 76 pages

An assessment of the total cost of pancreatic cancer using real-world evidence.

773 Background: The aggregate health economic implications of pancreatic cancer are poorly understood, especially from the patient perspective. As a preliminary effort, we sought to better understand changes in type and quantity of medical expenditures over time, along with quality of life related costs, from this perspective. This preliminary research is part of a larger effort to understand how the introduction of new treatments affect both the outcome and costs of pancreatic cancer associated with care, patients, survivors, their families, and their communities. Methods: We analyzed patient-level data from the Medical Expenditure Panel Survey (MEPS, 1996- 2017). All analyses were performed using R version 3.6.1 on Ubuntu 19.04. Averages were computed for the total health care costs, including prescription drug costs. Average individual annual cost estimates for the second year excluded individuals that were identified as having died prior to the first round of data collection in the second year. The individual patient level ratios of prescription drug cost to other medical expenses was also computed. All expenditures are adjusted for inflation using 2017 US dollars. Included subjects, N= 80 had a diagnosis of pancreatic cancer and available prescription data. Individual age and employment status were accounted for as covariates. Results: Between 1997 and 2017 inflation adjusted first and second year non-medication spending on pancreatic cancer care averaged $66,999.96 and$105,308.60 respectively. However, inflation-adjusted first and second year charges for hospitalizations and emergency visits fell between 2007-2017. Prescription drug as a proportion of total spending prescription drugs increased during the same time period. Lost work/school days declined between 2007 and 2017. Conclusions: Total inflation adjusted pancreatic cancer care expenses declined over the past decade even as drug costs increased. Quality of life costs declined as well. Further analysis is needed to evaluate the relationship between drug spending, total cost of care and quality of life. </jats:p

Value-based estimate of market size and opportunity for economic benefit through innovative pancreatic cancer (PC) therapies.

e16790 Background: Over the past 20 years, cancer drugs have contributed to increased life expectancy, reduced mortality, decreased hospitalization and decreased use of medical services. The economic value of these improvements is about as large as the value of the increase in the US gross domestic product during that time period. Recently, a health economic study presented at ASCO GI 2020 cited that every $1 (adjusted for inflation) spent on innovative PC treatments reduced non-drug expenditures by$9, thereby lowering the total cost of care for PC patients. Accordingly, the commercial opportunity of a new therapy should be measured by some combination of the clinical, economic and social value generated. We demonstrate the value of a novel PC drug from this perspective. Methods: Analysis of SEER survival and incidence data between 2008 and 2016 shows the introduction of new medicines for PC of all stages was associated with a cumulative increase of 26,456 life years, or 2.52 life years per patient. It was also associated with quality of life improvements, measured by a decline in hospitalizations rates and emergency room visits that can also lead to more days at work, at school and with family. Several studies have suggested the average value of an additional year of life, for the age of a typical patient diagnosed with PC, is at least $250,000. Using this figure, the value of 26,456 life years gained from 2008-2016 is$6.61 billion (26,456*$250,000) to patients, the healthcare system and society, as a result of advancing medical innovation for patients with PC. Results: The median annual list price of a life-enhancing cancer therapy is$150,000 per patient. Using the NCI treatment prevalence estimator (holding incidence constant), we estimate that between 2020-2025, there will be an additional 10,728 advanced PC patients requiring treatment who could benefit from innovative drugs. The total cost of these drugs for these patients would be $1.61 billion. However, the economic value of the life years saved would be$6.76 billion (10,728*2.52 life years*$250,000 =$6.76 billion). A review of cancer medicine payor coverage suggests a new PC therapy that produces such value would be able to obtain coverage from US payors given this value-based price. Conclusions: A value-based approach to estimating the opportunity for clinical and economic benefit reveals significant potential for new PC medicines. </jats:p

Selective removal of soluble tumor necrosis factor receptors by apheresis as a novel immunotherapy approach for triple-negative breast cancer.

e13065 Background: Although the activity of the cytokine TNF-α against diverse tumor types has been widely documented, safe and effective therapies for augmenting this pathway are lacking. An immunoadsorption device, the LW-02 Column, has been developed as a subtractive immunotherapy approach to remove soluble TNF-α receptors (sTNF-R1 and sTNF-R2) from cancer patients’ plasma using apheresis. Since soluble TNF-α receptors bind to and neutralize the activity of TNF-α, their depletion from plasma is performed to unleash the anti-tumor effects of endogenous TNF-α. The LW-02 Column contains an inert matrix to which a recombinant TNF-α polypeptide (single-chain TNF-α; scTNF) is covalently coupled as a ligand for capturing sTNF-R1 and sTNF-R2. This study evaluated key performance features of the LW-02 Column when used as a monotherapy or with chemotherapy in patients with advanced TNBC [ClinicalTrials.gov Identifier: NCT04004910]. Methods: As part of the ongoing clinical study, 28 patients with advanced TNBC underwent 862 LW-02 Column Immunopheresis procedures at 3 sites (mean=22.5; range=2–109) using the Spectra Optia Apheresis System (Terumo BCT, Inc.); 10 patients received LW-02 Column monotherapy and 18 received LW-02 Column therapy with various chemotherapy regimens. Therapy with the LW-02 Column was performed 3x/week for at least 16 weeks by processing 2 plasma volumes per treatment. Adverse events and tolerability of the therapy were monitored. Assessments were performed to determine the LW-02 Column’s target specificity and capture efficiency. The amount of scTNF ligand that could leach from the column during the procedures was also measured. Results: No serious device-related adverse events have been reported in this study. After 30 minutes of apheresis using the LW-02 Column, the mean capture efficiencies for sTNF-R1 and sTNF-R2 from TNBC patients’ plasma were 95.2% and 79.6%, respectively. The LW-02 Column was highly selective for removing sTNF-R1 and sTNR-R2 from total plasma proteins. The mean total amount of scTNF that may leach from the LW-02 Column (109 ng per apheresis session) is orders of magnitude lower than TNF-α concentrations that are known to trigger clinically meaningful effects. Conclusions: In patients with advanced TNBC, subtractive immunotherapy with the LW-02 Column either as a monotherapy or with chemotherapy is safe and achieves effective depletion of soluble TNF-α receptors from plasma. Evaluation of the safety and efficacy of the LW-02 Column is ongoing in TNBC patients as well as in studies of other solid tumor types. The LW-02 Column provides a novel and promising immunotherapy approach for augmenting the anti-cancer activity of the TNF-α pathway. Clinical trial information: NCT04004910. </jats:p

Abstract CT179: Safety and effectiveness of plasmapheresis-based elimination of soluble TNFα receptors combined with chemotherapy in advanced, chemorefractory triple-negative breast cancer patients - a phase I/II study (CP7-005)

Abstract Introduction: Tumor necrosis factor-alpha (TNFα) is a pleiotropic cytokine with known antitumor activity, produced mainly by activated immune cells. Cancer cells neutralize TNFα by shedding soluble TNF receptors 1&amp;2 (sTNF-Rs), which act as TNFα-binding decoys, promoting cancer cell proliferation, survival, and chemoresistance. Immunopheresis® employs therapeutic apheresis with the selective immunoadsorption LW-02 column (LW-02) for treating solid malignancies. LW-02-based Immunopheresis (granted FDA Breakthrough Device Designation and a CE Mark for mTNBC) selectively removes sTNF-Rs from plasma, permitting TNFα to bind to membrane-bound TNF-Rs, activating intracellular death pathways, and also modulate T-cell-mediated immune activity. Part A data of our phase I/II clinical trial in metastatic, chemorefractory, triple-negative breast cancer (mTNBC) patients (NCT04004910) confirmed that LW-02-based Immunopheresis monotherapy is safe and well-tolerated, with signs of disease stabilization (SD) in patients treated &amp;gt;4 weeks. Here we present interim data on the safety and preliminary efficacy of LW-02 Immunopheresis combined with chemotherapy. Methods: LW-02 Immunopheresis (3x/week for 16 weeks) is combined with a weekly paclitaxel (80 mg/m2)+carboplatin (AUC 2) regimen in patients with mTNBC; treatment is continued past 16 weeks in clinical and/or objective responders. Primary endpoints are safety and tolerability. Secondary endpoints assessed in patients treated &amp;gt;4 weeks include overall survival, tumor response according to RECIST, rate of CNS progression and quality-of-life. Results: Of 11 patients enrolled in Part B of the study, 7 patients were treated for &amp;gt;4 weeks. The ORR was 18% (1CR, 1PR) with one additional patient experiencing SD; the ORR and CBR in patients treated &amp;gt;4 weeks were 29% and 43%, respectively. The median OS, to date, is 18.6 weeks and 26.7 weeks in the group treated &amp;gt;4 weeks. The rate of CNS progression (new or preexisting lesions) appears lower than expected. The most common adverse events (AEs) were chemotherapy-induced myelotoxicity (anemia, neutropenia, thrombocytopenia) and transient electrolyte abnormalities. Thirty-one serious AEs (SAEs) were reported for all 11 patients, 15 (48.4%) were transfusion requiring anemias. Of the SAEs, 3 (9.6%) were judged to have a potential causal relationship to LW-02 column Immunopheresis. Conclusion: LW-02-based Immunopheresis combined with weekly chemotherapy is generally safe, well-tolerated and highly effective in specific sTNFR subtraction on a longer-term basis, with promising signals of clinical benefit in heavily pretreated mTNBC patients (median 3.3 [2-5] prior lines of systemic therapy). Further clinical evaluation of the antitumor activity of LW-02-based immunopheresis combined with low-dose chemotherapy is ongoing with a focus on quality-of-life and prevention of CNS disease progression, the latter especially important in chemorefractory mTNBC, given the high prevalence of CNS involvement. Citation Format: Piotr Jan Wysocki, Adam Ostrowski, Robert Segal, Victoria Manax, Pawel Potocki, Kamil Konopka, Lukasz Kwinta, Paulina Fraczek, Maciej Lubas, Mateusz Lobacz, Lawrence Florin. Safety and effectiveness of plasmapheresis-based elimination of soluble TNFα receptors combined with chemotherapy in advanced, chemorefractory triple-negative breast cancer patients - a phase I/II study (CP7-005) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT179.</jats:p

Abstract A72: Phase 1 study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (G) in pancreatic cancer (PC): safety evaluation of patients treated with nivo + nab-P in arm A

Abstract Background: Cytotoxic chemotherapy activates the immune system through multiple mechanisms, including stress signaling, antigen release by dying tumor cells, and modulation of immune cell populations. Nivo, an anti–PD-1 antibody, has demonstrated activity in other solid tumors but has not yet demonstrated activity in PC. The combination of nab-P + G is approved by the US Food and Drug Administration as first-line therapy for metastatic PC (MPC). nab-P does not require corticosteroid pretreatment, which makes it a suitable combination partner with nivo to test for safety and efficacy in PC. Here we report interim results from the first of 2 PC cohorts of a Phase 1 study of nivo + the standard dose and schedule of nab-P. Methods: The 2 PC cohorts (arms A and B) were to be initiated sequentially. In arm A, patients with locally advanced PC (LAPC) or MPC who had received 1 prior chemotherapy regimen received nab-P 125 mg/m2 on days 1, 8, and 15 of a 28-day cycle (qw 3/4) in combination with nivo 3 mg/kg on days 1 and 15 of the 28-day cycle starting with cycle 1. The primary objective of part 1 was to identify dose-limiting toxicities (DLTs). Patients treated with ≥ 2 cycles of nivo + nab-P or who discontinued due to a DLT prior to completing 2 cycles of nivo + nab-P were considered DLT evaluable. If arm A is deemed safe per DLT evaluation, arm B will enroll chemotherapy-naive patients, who will receive G 1000 mg/m2 qw 3/4 in addition to nivo + nab-P. Results: Between February 24 and December 3, 2015, 11 patients were enrolled in arm A. Most patients were &amp;lt; 75 years of age (82%) and male (55%). No DLTs were observed, and no grade 3/4 AEs occurred in &amp;gt; 1 patient. Among 8 response-evaluable patients, 1 had a partial response and 4 achieved stable disease. Eight patients discontinued treatment due to disease progression. Conclusions: In arm A of the PC cohort, the addition of nivo to nab-P did not appear to increase safety/tolerability concerns. Based on safety observed in arm A, arm B will enroll patients with MPC for first-line treatment with nivo + nab-P + G. ClinicalTrials.gov: NCT02309177. Citation Format: Howard S. Hochster, Zev A. Wainberg, Martin Gutierrez, David Waterhouse, E Gabriela Chiorean, Ben George, Amy Ko, Victoria Manax, Sotirios Stergiopoulos, Peter O’Dwyer.{Authors}. Phase 1 study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (G) in pancreatic cancer (PC): safety evaluation of patients treated with nivo + nab-P in arm A. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A72.</jats:p

Phase I study of nivolumab (nivo) + <i>nab</i>-paclitaxel (<i>nab</i>-P) ± gemcitabine (Gem) in solid tumors: Interim results from the pancreatic cancer (PC) cohorts.

412 Background: Immune checkpoint inhibitors, such as nivo, an anti−PD-1 antibody, have demonstrated antitumor activity in various cancers. Chemotherapy has demonstrated immune system activation via multiple mechanisms, providing a rationale for combination approaches. nab-P + Gem is a standard of care in PC which does not require immunosuppressive corticosteroids. Here we report interim results from 2 PC cohorts (Arms A and B) of a phase I study in patients (pts) receiving nivo + nab-P ± Gem for locally advanced or metastatic PC. Methods: This 2-part study was designed to identify dose-limiting toxicities (DLTs) of nivo + nab-P ± Gem in Part 1 and assess tolerability and efficacy in Part 2 dose expansion (+ Gem). Pts were DLT evaluable if they received ≥ 2 cycles of treatment and remained on study for 14 days after last dose or discontinued due to a DLT prior to completing 2 cycles. After Arm A, Part 1 was deemed safe, Arm B, Part 1 was initiated. In Arm A, pts with 1 prior chemotherapy regimen received nab-P 125 mg/m2 on days 1, 8, and 15 of a 28-day cycle (qw 3/4) + nivo 3 mg/kg on days 1 and 15 of a 28-day cycle starting with cycle 1. In Arm B, treatment-naive pts received the same regimen in Arm A + Gem 1000 mg/m2qw 3/4. Results: As of June 28, 2016, 11 and 6 pts were treated in Arms A and B in Part 1, respectively. No DLTs were reported in Arm A, and 1 in Arm B (nonimmune hepatitis, suspected to be due to Gem; resolved and pt continued nivo + nab-P without Gem). The most common grade 3/4 teatment-emergent AEs were pulmonary embolism, neutropenia, and anemia in 2/11 pts (18%) in Arm A and anemia in 2/6 pts (33%) in Arm B. Nine patients discontinued due to progressive disease (8 in Arm A, 1 in Arm B). Best overall response is shown in the Table. Median treatment duration was 12.6 and 15.5 weeks for Arms A and B, respectively. Clinical trial information: NCT02309177. Conclusions: These results indicate that adding nivo to nab-P ± Gem is feasible for pts with advanced PC, and antitumor activity of this regimen appears to be encouraging. Based on promising results from Part 1, Arm B, Part 2, is enrolling pts.[Table: see text] </jats:p