Futile Therapy Research Articles

Terapia daremna - problemy definicyjne

In my article, I discuss the definitional challenges concerning the concept of futile therapy and review and evaluate the strategies and definitional proposals that have appeared in the literature. Difficulties in adequately defining the concept of futile therapy are typical of the definitional problems encountered in defining medical notions, especially in relation to end-of-life procedures, where we are faced with a field of inadequately defined concepts with overlapping meanings and scopes. In addition to futile therapy, this conceptual field consists of ‘ordinary’ (proportionate) and ‘extraordinary’ (disproportionate) means, as well as the concept of the patient's best interests. In the Polish medical literature, this picture is further complicated by the use of the term ‘overzealous therapy’.

Correlation between Palliative Performance Scale results and observed survival among Mexican patients with advanced cancer.

e24040 Background: Cancer is a common cause of death among Hispanics. Estimating patient survival is critical in cancer care since it allows better shared decision-making and avoids use of futile therapy. Palliative Performance Scale (PPS) has been widely used for survival prediction among patients with cancer. However, its performance has not been validated across populations in Latin America, which could have different outcomes. The aim of this study was to analyze the correlation between PPS score and observed survival among patients with advanced cancer to facilitate physician and patient decision-making near the end of life. Methods: We conducted a retrospective observational analysis of patients with advanced cancer included in “ Te Acompañamos” cohort, a multidisciplinary patient navigator-led supportive care program in a single center in Mexico City. We used descriptive statistics to analyze clinico-demographic variables, PPS score, observed survival in days (from recruitment to death). Pearson correlation coefficients were used for correlating observed survival in days and predicted survival using PPS. U de Mann Whitney was used for comparing survival days between PPS groups. Results: We analyzed 246 patients with advanced cancer included in “Te Acompañamos” who died between August 2017-January 2024. Among these patients, 143 (58%) were women. Mean age was 64 years (SD 13). 153 patients (62%) had gastrointestinal (GI), 43 (17%) gynecologic, 19 (7%) genitourinary, 5 (2%) lung, 5 (2%) thyroid, and 21 (8%) other solid malignancies. Pancreatic cancer was the most common cancer (n = 60, 24%). Patients with GI cancer more frequently reported pain (59%) and had an average PPS of 67.7%. Mean survival was 233 days (SD 247) and mean predicted survival in days according to PPS was 68 days (SD 20). Correlation between observed survival days and PPS-predicted survival was low (R = 0.29). Patients with PPS < 50% had mean survival of 74.6 days while patients with PPS > 50% of 243.2 days (p < 0.05). Patients aged < 60 years with GI tumors had a higher PPS score, while older patients had a lower score (74.6% vs 65%; p < 0.05). No other significant differences were found in other subgroups. Conclusions: Our results show weak correlation between observed and predicted survival in days using PPS. However, lower PPS was associated with decreased survival. Among patients with GI cancers we observed that older patients had the lowest PPS scores. This study emphasizes the need to develop and validate more precise tools for survival prediction across patient populations, including minorities such as the Hispanics. Our study suggests that strategies to diagnose and alleviate pain promptly in patients with advanced cancer near the end of life are urgently required.

A digital microfluidic device integrated with electrochemical sensor and 3D matrix for detecting soluble PD-L1

PD1/PD-L1 checkpoint inhibitors are at the forefront of cancer immunotherapies. However, the overall response rate remains only 10–30%. Even among initial responders, drug resistance often occurs, which can lead to prolonged use of a futile therapy in the race with the fatal disease. It would be ideal to closely monitor key indicators of patients’ immune responsiveness, such as circulating PD-L1 levels. Traditional PD-L1 detection methods, such as ELISA, are limited in sensitivity and rely on core lab facilities, preventing their use for the regular monitoring. Electrochemical sensors exist as an attractive candidate for point-of-care tool, yet, streamlining multiple processes in a single platform remains a challenge. To overcome this challenge, this work integrated electrochemical sensor arrays into a digital microfluidic device to combine their distinct merits, so that soluble PD-L1 (sPD-L1) molecules can be rapidly detected in a programmed and automated manner. This new platform featured microscale electrochemical sensor arrays modified with electrically conductive 3D matrix, and can detect as low as 1 pg/mL sPD-L1 with high specificity. The sensors also have desired repeatability and can obtain reproducible results on different days. To demonstrate the functionality of the device to process more complex biofluids, we used the device to detect sPD-L1 molecules secreted by human breast cancer cell line in culture media directly and observed 2X increase in signal compared with control experiment. This novel platform holds promise for the close monitoring of sPD-L1 level in human physiological fluids to evaluate the efficacy of PD-1/PD-L1 immunotherapy.

Impact of 18F-flotufolastat PET on management of patients with recurrent prostate cancer: Data from the SPOTLIGHT study.

38 Background: 18F-Flotufolastat (18F-rhPSMA-7.3) is a newly approved high affinity PSMA-targeting PET radiopharmaceutical for diagnostic imaging in patients with prostate cancer (PCa). SPOTLIGHT (NCT04186845) evaluated 18F-flotufolastat in patients with recurrent PCa. Here, we report available SPOTLIGHT data to assess the impact of 18F-flotufolastat on planned treatment after curative-intent primary therapy. Methods: Patients underwent PET 50–70 min after IV administration of 296 MBq 18F-flotufolastat. The protocol instructed onsite investigators to record patients’ management plans (MP) before and after 18F-flotufolastat PET. These MP were compared and categorized as: ‘no change’, ‘major change’, ‘other change’, ‘additional information required’ or ‘intended plan not valid’. A ‘major change’ was defined as a change to treatment modality (e.g., salvage radiation therapy [RT] to systemic therapy), while ‘other change’ represented a change within a modality (e.g., modified RT field). Plans categorized as ‘no change’, ‘major change’ or ‘other change’ were considered evaluable. All imaging data were subsequently submitted for blinded image evaluation (BIE) by 3 central readers. Results: Of 389 patients who had 18F-flotufolastat PET, 97 had sufficient MP data for evaluation. These 97 patients were comparable to the overall population in terms of prior treatment (84% vs 79%, respectively, were post-prostatectomy), Gleason Score (63% vs 60% had Score 7), and median baseline PSA (0.8 vs 1.1 ng/mL). Moreover, BIE data show the detection rate in this subgroup (81/97; 84%) to be equivalent to that in the overall population (322/389; 83%). Most patients, 86/97 (89%) had a change to their MP post-scan. A ‘major change’ was noted for 78 (80%) patients, while 8 (8.2%) had an ‘other change’ (Table). Onsite imaging reads show that both positive and negative 18F-flotufolastat scans influenced MP. While 88% of revisions occurred after a positive scan, 75% of those whose MP were revised to watchful waiting (WW) had negative scans. All patients with MP revised from salvage therapy to non-curative systemic therapy had distant/extrapelvic 18F-flotufolastat-avid lesions. Conclusions: 18F-Flotufolastat located recurrence sites in the majority of patients with recurrent PCa, frequently resulting in major changes to MP. Treatment based on visualization of 18F-flotufolastat-avid lesions may facilitate optimal targeting of recurrence sites and avoid futile salvage therapy. Future studies of the outcome of such MP changes are warranted. Clinical trial information: NCT04186845 . [Table: see text]

Legal Protection for Doctors on Withdrawing or Withholding Futile Therapy in Terminally ill Patients

Legal Protection for Doctors on Withdrawing or Withholding Futile Therapy in Terminally ill Patients

Legal Aspects of Futile Therapy in the Face of the End of Life

Abstract This article presents legal issues related to therapeutic decisions made by doctors and to euthanasia and assisted suicide, which are prohibited and penalized in the Polish legal system. The paper refers to the terms ‘futile therapy’ and ‘over-zealous treatment’. It was also considered appropriate to refer to the concept of resuscitation, which can be understood narrowly as cardiopulmonary resuscitation or broadly as all activities aimed at potentially reversing the dying process. Completion of resuscitation as it is broadly understood means that (unless there has been recovery) it is considered a futile therapy. De lege lata there are no statutory regulations in the Polish legal system that could be directly related to the decision to abandon futile therapy in order to assess its legal legitimacy. The aim of the study is to present the problem of futile therapy de lege lata and de lege ferenda in the face of the end of life. The article also presents the latest draft of legal regulation regarding futile therapy developed by an interdisciplinary team appointed by the Patients’ Rights Ombudsman in the form of ‘Standards of conduct in medical therapies used in the end-of-life period’.

Legal and Ethical Issues of Discontinuing Futile Therapy in Children

Abstract This article raises the issue of critical medical decisions made in the interest of small children. It seeks answers to the questions of whether there are any differences in this field’s attitude towards adults and what the criteria for life and death decisions should be for persons who are legally dependent and unable to declare their position. The concept of so-called parental autonomy in making treatment decisions for children and situations in which they may be limited by the assessment of doctors and by the supervisory function of the guardianship court. The overriding principle of the best interests of the child is compared with the British concept of best interest and is confronted with the newer concept of threat of serious harm, which is considered better at respecting privacy and giving parents more powers. The mechanism of conflict resolution between parents and doctors is shown through the example of court decisions in the cases of Charlotte Wyatt, also known in Poland, Charlie Gard and Alfie Evans, and then is transferred to the Polish example of Madzia Weakling. The considerations end with the conclusion that the best interests criterion is pragmatic and a non-principal development of the principle of the best interests of the child, within the context of protection against the unbearable suffering of living or dying in agony, which is also important.

“The challenge is the complexity” – A qualitative study about decision-making in advanced lung cancer treatment

IntroductionThe value of shared decision-making and decision aids (DA) has been well documented yet remain difficult to integrate into clinical practice. We wanted to investigate needs and challenges regarding decision-making about advanced lung cancer treatment after first-line therapy, focusing on DA applicability. MethodsQualitative data from separate, semi-structured focus groups with patients/relatives and healthcare professionals were analysed using systematic text condensation. 12 patients with incurable lung cancer, seven relatives, 12 nurses and 18 doctors were recruited from four different hospitals in Norway. ResultsThe participants described the following needs and challenges affecting treatment decisions: 1) Continuity of clinician-patient-relationships as a basic framework for decision-making; 2) barriers to information exchange; 3) negotiation of autonomy; and 4) assessment of uncertainty and how to deal with it. Some clinicians feared DA would steal valuable time and disrupt consultations, arguing that such tools could not incorporate the complexity and uncertainty of decision-making. Patients and relatives reported a need for more information and the possibility both to decline or continue burdensome therapy. Participants welcomed interventions supporting information exchange, like communicative techniques and organizational changes ensuring continuity and more time for dialogue. Doctors called for tools decreasing uncertainty about treatment tolerance and futile therapy. ConclusionOur study suggests it is difficult to develop an applicable DA for advanced lung cancer after first-line therapy that meets the composite requirements of stakeholders. Comprehensive decision support interventions are needed to address organizational structures, communication training including scientific and existential uncertainty, and assessment of frailty and treatment toxicity.

Intermittent inotropic support with levosimendan in advanced heart failure as destination therapy: The LEVO-D registry.

Patients with advanced heart failure (AHF) who are not candidates to advanced therapies have poor prognosis. Some trials have shown that intermittent levosimendan can reduce HF hospitalizations in AHF in the short term. In this real-life registry, we describe the patterns of use, safety and factors related to the response to intermittent levosimendan infusions in AHF patients not candidates to advanced therapies. Multicentre retrospective study of patients diagnosed with advanced heart failure, not HT or LVAD candidates. Patients needed to be on the optimal medical therapy according to their treating physician. Patients with de novo heart failure or who underwent any procedure that could improve prognosis were not included in the registry. Four hundred three patients were included; 77.9% needed at least one admission the year before levosimendan was first administered because of heart failure. Death rate at 1year was 26.8% and median survival was 24.7 [95% CI: 20.4-26.9] months, and 43.7% of patients fulfilled the criteria for being considered a responder lo levosimendan (no death, heart failure admission or unplanned HF visit at 1year after first levosimendan administration). Compared with the year before there was a significant reduction in HF admissions (38.7% vs. 77.9%; P<0.0001), unplanned HF visits (22.7% vs. 43.7%; P<0.0001) or the combined event including deaths (56.3% vs. 81.4%; P<0.0001) during the year after. We created a score that helps predicting the responder status at 1year after levosimendan, resulting in a score summatory of five variables: TEER (+2), treatment with beta-blockers (+1.5), Haemoglobin >12g/dL (+1.5), amiodarone use (-1.5) HF visit 1year before levosimendan (-1.5) and heart rate >70b.p.m. (-2). Patients with a score less than -1 had a very low probability of response (21.5% free of death or HF event at 1year) meanwhile those with a score over 1.5 had the better chance of response (68.4% free of death or HF event at 1year). LEVO-D score performed well in the ROC analysis. In this large real-life series of AHF patients treated with levosimendan as destination therapy, we show a significant decrease of heart failure events during the year after the first administration. The simple LEVO-D Score could be of help when deciding about futile therapy in this population.

Limitation of Futile Therapy in the Opinion of Nursing Staff Employed in Polish Hospitals—Results of a Cross-Sectional Study

The debate on limiting futile therapy in the aspect of End of Life (EoL) care has been going on in Poland over the last decade. The growing demand for EoL care resulting from the aging of societies corresponds to the expectation of a satisfactory quality of life and self-determination. The authors designed a cross-sectional study using a newly designed questionnaire to assess the opinions of 190 nurses employed in intensive care units (ICUs) on futile therapy, practices, and the respondents' approach to the issue. The problem of futile therapy and its clinical implications are known to the nursing community. Among the most common reasons for undertaking futile therapy in adult patients, the respondents declared fear of legal liability for not taking such actions (71.58%), as well as fear of being accused of unethical conduct (56.32%), and fear of talking to the patient/patient's family and their reaction (43.16%). In the case of adult patients, the respondents believed that discontinuation of futile therapy should be decided by the patient (84.21%), followed by a doctor (64.21%). As for paediatric patients, two-thirds of the respondents mentioned a doctor and a court (64.74% and 64.21%, respectively). Overall, 65.26% of the respondents believe and agree that the comfort of the patient's last days is more important than the persistent continuation of therapy and prolonging life at all costs. The presented results clearly show the attitude of the respondents who defend the patient's dignity and autonomy.

Futile therapy in the conditions of the Covid-19 pandemic

Futile therapy is the prolonged maintenance of organ function. This process in this case does not bring therapeutic benefits, and its task is to maintain the failed organs. The article aims to present the differences between influenza and Covid-19 and to draw attention to the problem of the futility of therapy in the context of a pandemic.

Longitudinal profile of neutralizing and binding antibodies in vaccinated and convalescent COVID-19 cohorts by chemiluminescent immunoassays.

IntroductionSurrogate rapid serological assay was urgently demanded for accessibly interpretation of immunity potency and duration of neutralizing antibody against SARS‐CoV‐2. The longitudinal trajectory of antibody profile with a reliable large‐scale assay was crucial to judge the protective immune status, avoid futile therapy and provide insight into the booster vaccination minimizing the risk of COVID‐19.MethodsA total of 195 volunteers were enrolled for a two‐doses procedure (0 and 28 days) of inactive vaccination, as well as ten COVID‐19 convalescents. The serum was collected at six time point and detected by chemiluminescent immunoassay with SARS‐CoV‐2 neutralizing antibody (Nab), SARS‐CoV‐2 RBD immunoglobulin G (IgG) antibody (RBD IgG) and RBD total antibody. The diagnostic results and the correlation of antibody level were evaluated among three serological (Nab, RBD IgG, and RBD total antibody) assay, as well as with an authorized cPass kit (Nab). Referred to the assay‐specific threshold, the seroconversion rate and dynamic titer of antibody were exhibited from 0 to 56 days since vaccination.ResultsThere was no difference observed with diagnostic results between neutralizing and RBD IgG antibody (p > 0.05). Both diagnostic results of neutralizing and RBD IgG antibody testing differentiated from RBD total antibody assay (p < 0.05). The coefficient of correlation (R) was above 0.90 among the levels of those three antibodies, more than 0.60 in comparison with neutralizing antibody by cPass enzyme‐linked immunoassay. The “S” varying pattern for various antibodies level was observed with time extension after vaccination. The seroconversion rate was below 11.1% in 2 weeks after the priming dose, while the value climbed to 81% in 1 week after the boosting dose. The seroconversion rate was maintained around 91%. The inactive vaccine elicited 81‐fold higher antibody levels after finished the vaccination schedule than that at the basic point. Besides, the level of neutralizing antibody induced by vaccine was found with a 0.2‐fold ratio by comparison with that in COVID‐19 convalescents.ConclusionThe humoral immune response products including SARS‐CoV‐2 neutralizing, RBD IgG antibody and total antibody and the varying pattern of the antibody profile could be rapidly detected by CILA method. Meanwhile, the continuing and dynamic determination was attributed to evaluate the protection effect of humoral immunity against the SARS‐CoV‐2 infection.

Abstract P3-03-05: The budget impact of the DiviTum®TKa assay in postmenopausal women with hormone receptor positive metastatic breast cancer

Abstract Background. Management of postmenopausal women with HR+ mBC includes monitoring with tumor markers, CT scans, and bone scans. DiviTum®TKa is a blood-based biomarker assay developed to monitor and predict treatment response in hormone receptor positive metastatic breast cancer (HR+ mBC). Uptake of DiviTum®TKa monitoring may decrease usage of traditional monitoring technologies and potentially avoid prolongation of futile treatments. Our objective was to estimate budget impacts of the assay on monitoring utilization and cancer treatment on a postmenopausal HR+ mBC population in a 1,000,000 member U.S. health plan. Methods. We developed a budget impact model comparing inclusion of DiviTum®TKa to standard monitoring practices vs. standard monitoring practices alone. The modeled population was post-menopausal women with HR+ mBC who receive 1st-line treatment with CDK4/6 inhibitors (CDK4/6i) + an aromatase inhibitor (AI). We explored two scenarios: (1) uptake of DiviTum®TKa reduces the frequency of traditional mBC monitoring tools, and 2) in addition to scenario 1, DiviTum®TKa predicts treatment futility 1 month in advance of radiological disease progression. We assumed patients were 100% adherent to DiviTum®TKa and traditional monitoring schedules, which were based on clinical guidelines and expert opinion. DiviTum®TKa’s impact on therapy utilization was based on published literature and expert opinion. Modeled costs included DiviTum®TKa, NCCN-recommended treatments, imaging, biomarker testing, and adverse events. Unit costs were based on CMS fee schedules and wholesale acquisition costs. Annual rates of incident and recurrent post-menopausal HR+ mBC were estimated from SEER and publicly available data. We calculated total and per-member per-month (PMPM) costs with a 3-year time horizon. Results. Each year, 17 women who progressed to mBC and 4 who developed de novo mBC were treated 1st-line with CDK4/6i+AI. In scenario 1 (monitoring only), addition of 404 DiviTum®TKa assays led to 203 fewer CT scans, 93 fewer bone scans, and 60 fewer biomarker tests over 3 years. In scenario 2 (impact on therapy), mean time on treatment with CDK 4/6i + AI therapy was 28 months without DiviTum®TKa testing; with DiviTum®TKa, 27 months; this led to treatment-related cost savings due to avoidance of time on futile therapy. Spend on DiviTum®TKa testing was $161,600. Accounting only for test costs (Scenario 1) resulted in incremental cost of $38,000 and a PMPM of $0.001. Accounting for time spent on futile therapy (Scenario 2) resulted in incremental cost savings of $465,600 and a PMPM cost-savings of $0.013. In one-way sensitivity analysis, results were most sensitive to DiviTum®TKa and CT scan costs, the proportion of mBC patients treated with CDK4/6i+AI, and CDK4/6i costs. Conclusions. In this analysis, use of DiviTum®TKa reduced use of a substantial proportion of traditional monitoring. If use of DiviTum®TKa can also predict lack of benefit from costly CDK4/6i therapy and clinicians act on that information in a timely fashion, this can result in substantial cost savings to patients and health plans. In this 2nd scenario, net savings on adding a new test to care were ~3X the spend on the test itself. Following approval and commercial introduction of DiviTum®TKa, future research on practice patterns will be necessary to validate our analysis. Scenario 1WithoutDiviTum®TKaWithDiviTum®TKaDifferenceDifferencePMPMTotal Cost$14,518,998$14,556,984$37,986$0.001Monitoring$284,680$322,666$37,986$0.001Treatment$13,703,867$13,703,867$0$0.000Adverse Events$530,451$530,451$0$0.000Scenario 2WithoutDiviTum®TKaWithDiviTum®TKaDifferenceDifferencePMPMTotal Cost$14,518,998$14,053,431-$465,567-$0.013Monitoring$284,680$311,179$26,500$0.001Treatment$13,703,867$13,209,240-$494,627-$0.014Adverse Events$530,451$533,013$2,561$0.000 Citation Format: Gregory F. Guzauskas, Josh J. Carlson, Robert A. Dann, Scott D. Ramsey. The budget impact of the DiviTum®TKa assay in postmenopausal women with hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-03-05.

Limiting futile therapy as part of end-of-life care in intensive care units.

The debate about medical futility often involves intensive care units where life-support procedures are routinely applied. Futile therapy is part of end-of-life therapy. In the discussion about medical futility it is important to distinguish the effect of therapy from the benefit for the patient. The goal of treatment is not to maintain the function of an organ, body part or physiological activity, but to maintain health as a whole. Prolonging ineffective treatment violates the standard of good medical practice. In 2014, the first Polish guidelines on limiting futile therapy in patients treated in intensive care units were published. This document presents the official position of intensive care experts consulted by medical societies of other medical disciplines. Limitation of futile therapy by withdrawing from already used treatments or withholding new therapies does not mean that the role of medical personnel has ended. Intensive care turns into palliative care. The list of comorbidities showing a statistically significant correlation with medical futility has been refined. These include heart failure (NYHA III/IV), neoplastic disease and disseminated neoplastic process, and failure of two or more organs. The published survey results are devastating; 66-89% of intensive care nurses have provided futile treatment in their careers. Intensivists estimated that, on average, 20% of patients in intensive care units receive futile therapy. There is a need to disseminate standards and procedures related to end-of-life care in Polish intensive care units.

Nuclear medicine theranostics comes of age.

Personalised medicine is widely discussed, but only intermittently implemented. The use of theranostics by whole body molecular imaging modalities (eg, 68Ga-prostate-specific membrane antigen [PSMA]-PET/CT or 68Ga-DOTATATE-PET/CT) allows assessment of druggable target expression as well as target accessibility of all lesions, defining patient populations that most likely benefit from radioligand therapy with their therapeutic counterparts 177Lu-PSMA and 177Lu-DOTATATE, respectively. Molecular imaging-based theranostics exclude patients from being exposed to a priori futile therapy. In the NETTER-1 trial 1 Strosberg J El-Haddad G Wolin E et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017; 376: 125-135 Crossref PubMed Scopus (1354) Google Scholar 177Lu-DOTATATE proved efficacious in rare neuroendocrine tumours, whereas the VISION trial 2 Sartor O de Bono J Chi KN et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021; 385: 1091-1103 Crossref PubMed Scopus (170) Google Scholar studied a far more common cancer—prostate cancer, which is the second most common cause of cancer death in men—and showed 177Lu-PSMA was efficacious in this setting. Now that a significant benefit of 177Lu-PSMA has been shown in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer, with a median overall survival of 15·3 months versus 11·3 months for standard care (HR 0·62; 95% CI 0·52–0·74; p<0·001), 2 Sartor O de Bono J Chi KN et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021; 385: 1091-1103 Crossref PubMed Scopus (170) Google Scholar the tone of the discussions around treatment has changed, with some advocating the disruption of the molecular imaging theranostic concept by discarding 68Ga-PSMA-PET/CT for patient selection. Correction to Lancet Oncol 2021; 22: 1497–98Herrmann K, Krause BJ, Hadaschik B, et al. Nuclear medicine theranostics comes of age. Lancet Oncol 2021; 22: 1497–98—In this Comment, the spelling of author Bernd Joachim Krause's surname was incorrectly spelt as “Kraus” and has been corrected to “Krause”. This correction has been made to the online version as of Nov 29, 2021. Full-Text PDF

Spór o zaprzestanie daremnej terapii oraz sztucznego odżywiania i nawadniania na przykładzie sprawy polskiego pacjenta RS w Wielkiej Brytanii

The article describes and comments upon a recent decision of the British Court of Protection which authorised the cessation of futile life-sustaining therapy including clinically assisted nutrition and hydration (CANH) from RS, a middle-aged Polish patient who fell into the permanent vegetative state (PVS) caused by severe brain damage. The authors scrutinize the legal proceedings and discuss the “best interests” criterion applied by Mr. Judge Cohen (the famous Bland case as well as the Mental Capacity Act of 2005 are evoked in this context). Several terminological and ethical issues are also explained, including the concepts of “passive euthanasia”, “futile therapy”, “over-zealous treatment”, and CANH withdrawal. The authors reflect upon the role of family in decision-making concerning the withdrawal of futile treatment from PVS patients, recalling the notorious cases of Terri Schiavo, Vincent Lambert, and Eluana Englaro. Furthermore, in view of the public outrage caused by the RS case in Poland, the authors comment upon the alleged cultural differences in legal regulations and social attitudes towards the approach to the end of life treatment in Poland and United Kingdom, speculating on the possible way of handling RS’s case in his homeland.

Abstract 1426: Multiomic analysis identifies CPT1A and fatty acid oxidation as a potential therapeutic target in platinum-refractory high grade serous ovarian cancer

Abstract Platinum-based DNA cross-linking agents are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). Remarkably, despite &amp;gt;30 years of literature on platinum responses in human cancer, none of these findings is used clinically as a predictive biomarker to stratify patients for platinum resistance, nor exploited therapeutically to treat platinum-resistant disease. Thus, understanding mechanisms of platinum resistance is an urgent goal, both to identify predictive biomarkers of platinum response (to spare patients with platinum-resistant tumors futile platinum therapy) and to develop efficacious therapies for platinum-resistant disease. To better understand mechanisms underlying platinum resistance in HGSOC, we performed comprehensive, dynamic (+/-carboplatin), multiomic profiling of DNA, RNA, protein and post-translational modifications (phosphorylation, ubiquitination, acetylation) to identify the cellular networks that respond to platinum treatment and associate with platinum resistance in three HGSOC intra-patient cell line pairs (PEA1S/PEA2R, PEO1S/PEO4R, PEO14S/PEO23R). The cell line pairs were derived from ascites or pleural effusions (Langdon et al., 1988) from three patients both before (PEA1S, PEO1S, PEO14S) and after (PEA2R, PEO4R, PEO23R, respectively) their tumors became clinically platinum resistant (i.e., in vivo development of resistance). The molecular profiles revealed extensive responses to carboplatin and differential responses between platinum-sensitive and platinum-resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that pharmacologic inhibition or CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO, and CPT1A in particular, represent a candidate therapeutic target to overcome platinum resistance in HGSOC. Citation Format: Hong Wang, Dongqing Hugang, Shrabanti Chowdhury, Sara Savage, Richard Ivey, Jacob Kennedy, Jeffrey Whiteaker, Chenwei Lin, Xiaonan Hou, Catherine Huntoon, Uliana Voytovich, Zahra Shire, Qing Yu, Steven Gygi, Andrew Hoofnagle, Zachary Herbert, Anna Calinawan, Larry Karnitz, S. John Weroha, Scott Kaufmann, Bing Zhang, Pei Wang, Michael Birrer, Amanda Paulovich. Multiomic analysis identifies CPT1A and fatty acid oxidation as a potential therapeutic target in platinum-refractory high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1426.

Efficacy and safety of Cerebrolysin after futile recanalisation therapy in patients with severe stroke

IntroductionGolden standard of acute stroke treatment is recanalisation therapy. However, opening the occluded blood vessel sometimes does not show the expected clinical result or leads to haemorrhagic complications. As neuroinflammation and neurotoxicity play an important role in the pathophysiology of stroke, neuroprotective agents might preserve brain tissue after futile recanalisation. Patients and methodsAfter recanalisation therapy and not later than 24 h after symptoms onset, patients with initial NIHSS of ≥ 8 were assigned to the investigational and control group. The investigational group received intravenous Cerebrolysin as add-on therapy. The primary objective was to assess the clinical efficacy of Cerebrolysin. The secondary objective was to investigate its effect on haemorrhagic transition and to confirm its safety profile. ResultsBaseline characteristics of patients showed no significant differences between the two groups. No difference could be detected between the two groups in the mRS scale though the Cerebrolysin group showed descriptive superiority over the control group. We found a statistically significant difference considering haemorrhagic transition and mortality rate in favour of the Cerebrolysin group. DiscussionThe multimodal neurotrophic agent Cerebrolysin holds promise to impact on the late consequences of a reperfusion syndrome. Its influence on reducing neuroinflammation, promoting neuronal cell viability and neurogenesis as well as the stabilising effect on the blood-brain barrier suggests a protective effect on the neurovascular unit even when no recanalisation occurs. We confirmed the excellent safety profile of Cerebrolysin. ConclusionCerebrolysin as add-on therapy might be beneficial and safe for patients with acute stroke in terms of lowering risk for haemorrhagic complications after recanalisation therapy.

PCN190 Budget Impact of the DiviTum®Tka Assay in Postmenopausal Women with Hormone Receptor Positive Metastatic Breast Cancer

DiviTum®TKa, a blood-based biomarker assay developed to monitor and predict treatment response in hormone receptor positive metastatic breast cancer (HR+ mBC), may decrease traditional disease monitoring assessments and avoid prolongation of futile treatments. Our objective was to estimate the diagnostic- and treatment budget impact of the assay on a postmenopausal HR+ mBC population in a one-million-member U.S. health plan. We developed a budget impact model comparing inclusion and exclusion of DiviTum®TKa to standard care under which DiviTum®TKa 1) reduces frequency of traditional mBC monitoring tools, and 2) predicts treatment futility in advance of radiological disease progression. Traditional disease monitoring assessment schedules were based on guidelines and expert opinion. DiviTum®TKA’s impact on therapy utilization was based on published literature and expert opinion. Modeled costs included DiviTum®TKa, NCCN-recommended treatments, imaging, biomarker testing, and adverse events. Unit costs were based on CMS fee schedules and wholesale acquisition costs. Annual rates of incident and recurrent postmenopausal HR+ mBC were estimated from SEER and publicly available data. We calculated total and per-member per-month (PMPM) costs with a 3-year time horizon. Inclusion of DiviTum®TKa resulted in total cost-savings of $439,700, equaling PMPM cost-savings of $0.013. Looking at 3-year diagnostic and treatment impacts separately, addition of DiviTum®TKa (+$166,400) to monitoring was offset by reductions to other tests (-$144,800): CT scans (-203), bone scans (-93), and biomarker tests (-180), with a PMPM of +$0.001. Treatment-related cost-savings were $465,300. Results were most sensitive to DiviTum®TKa cost, population parameters, and treatment costs. Clinical use of DiviTum®TKa is expected to decrease traditional imaging and monitoring and may reduce overall costs of managing mBC if it leads to clinical decisions to avoid futile therapy. Post-coverage, real world monitoring of palliative therapies among postmenopausal mBC populations is needed to better categorize cost savings over time.

Pregnancy Clauses

Pregnancy Clauses