Collaborative Trial Research Articles

Global Representation of Heart Failure Clinical Trial Leaders and Collaborators: A Systematic Bibliometric Review 2000-2020

Global Representation of Heart Failure Clinical Trial Leaders and Collaborators: A Systematic Bibliometric Review 2000-2020

DETECTION OF ACID NEUTRALIZERS IN FRAUDULENT MILK: FULL VALIDATION OF A CLASSICAL QUALITATIVE METHOD

Neutralization with alkaline compounds is one of the most common adulterations in milk. The rosolic acid method is a classical test widely used in different countries for detection of neutralizers in milk. The official and a modified version were validated in a single laboratory validation process considering four adulterants: sodium bicarbonate(BI), sodium carbonate(CA), sodium hydroxide(HY) and sodium citrate(CI). The modified version, which presented better performance was selected for interlaboratory validation. In this process, samples of raw milk with acidities of 0.19% were neutralized with different concentrations of BI, CA, HY and C and tested for homogeneity and stability. Eight laboratories, which represented different sectors of the milk production chain, received and analysed these samples. The collaborative trial results confirmed the method performance, although sensitivity and precision were inferior to those obtained in the intralaboratory process, demonstrating its applications and limitations

Daratumumab for the treatment of multiple myeloma.

Since its initial approval in 2015, daratumumab has had a tremendous impact on the treatment of multiple myeloma. It is a monoclonal antibody that targets CD38, an antigen with high surface expression on multiple myeloma cells. While it initially received approval as a monotherapy for multiply relapsed multiple myeloma, its favorable toxicity profile allowed for combinations with other novel myeloma therapies leading to numerous indications as a component of triplet and quadruplet regimens. These indications now span relapsed/refractory populations and both transplant-eligible and transplant-ineligible patients with newly diagnosed myeloma. Further investigations are underway to continue to expand the reach of daratumumab, including large phase III collaborative trials to assess the efficacy of daratumumab as part of post-transplant maintenance and its impact on smoldering myeloma. The recent introduction of a subcutaneous formulation of daratumumab with proven noninferiority will improve the convenience and accessibility of the drug. In this review, we examine the preclinical development of daratumumab, its pharmacology and clinical investigations that demonstrated its safety and efficacy. Furthermore, we discuss the outstanding questions related to daratumumab and ongoing clinical trials seeking to answer them.

Fluoxetine for stroke recovery improvement - the doubleblind, randomised placebo-controlled FOCUS-Poland trial.

The Fluoxetine Or Control Under Supervision (FOCUS)-Poland trial tested in a Polish cohort the hypothesis that fluoxetine improves recovery after stroke. Some studies have suggested that fluoxetine may improve functional outcomes after stroke, but these results needed confirmation. Between 2012 and 2014, large clinical trials were initiated by the FOCUS Trial Collaboration. Recently, results from the UK, Sweden, Australia, New Zealand and Vietnam have been published. We here present the results of the FOCUS trial conducted in Poland. This was a randomised, double-blind, placebo-controlled study based on the FOCUS trial protocol. Patients who had a persisting neurological deficit were randomly assigned 2-15 days after stroke onset to receive for six months either fluoxetine 20 mg/day or a placebo. The primary outcome was functional status measured using the modified Rankin Scale (mRS) at six months after randomisation. Functional status at 12 months was also assessed, as was neurological deficit at six and 12 months. Data was also collected on adverse events. Between 19 December 2014 and 13 March 2018, 30 patients were given fluoxetine and 31 were given a placebo. For the primary outcome, the distribution across mRS categories was similar for the fluoxetine and placebo groups at six months (common odds ratio 0.88; 95% confidence interval 0.31-2.50; p = 0.81), and there was no difference at 12 months (p = 0.864). There were no differences between groups in stroke recovery or in motor function recovery of the affected hand. There were no significant differences in any other secondary outcomes at six or 12 months. Patients given fluoxetine were less likely than those given the placebo to receive new antidepressant medication within six months (2 [6.67%] vs. 4 [12.90%]). Consistent with other trials based on the FOCUS protocol, fluoxetine did not improve motor recovery or general stroke outcome at six and 12 months in the Polish cohort studied. However, patients receiving fluoxetine required therapy with additional antidepressant medication less frequently.

Evidence-Based Approaches to Suicide in Older Adults—Collaborative Care

This individual symposium abstract will focus another evidence-based approach to mental health treatment and in older adults, the collaborative care model. Collaborative care is a consultation-based approach in primary care that has been described with multiple clinical trials, with significant benefit for access and treatment. The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) using the collaborative care model found that those older adults receiving the intervention had a higher utilization of mental health treatment (psychotherapy and/or antidepressant treatment) and had a 2.2 times greater decline in suicidal ideation over 24 months. The authors will describe the utility of using the collaborative care model on the identification of suicidal ideation and subsequent mental health treatment for older adults. The authors will also share about challenges and successes related to collaborative care implementation in healthcare settings for older adults, and relevant policy and financing components for the model.

Chespa: Streamlining Expansive Chemical Space Evaluation of Molecular Sets

Thousands of chemical properties can be calculated for small molecules, which can be used to place the molecules within the context of a broader "chemical space." These definitions vary based on compounds of interest and the goals for the given chemical space definition. Here, we introduce a customizable Python module, chespa, built to easily assess different chemical space definitions through clustering of compounds in these spaces and visualizing trends of these clusters. To demonstrate this, chespa currently streamlines prediction of various molecular descriptors (predicted chemical properties, molecular substructures, AI-based chemical space, and chemical class ontology) in order to test six different chemical space definitions. Furthermore, we investigated how these varying definitions trend with mass spectrometry (MS)-based observability, that is, the ability of a molecule to be observed with MS (e.g., as a function of the molecule ionizability), using an example data set from the U.S. EPA's nontargeted analysis collaborative trial, where blinded samples had been analyzed previously, providing 1398 data points. Improved understanding of observability would offer many advantages in small-molecule identification, such as (i) a priori selection of experimental conditions based on suspected sample composition, (ii) the ability to reduce the number of candidate structures during compound identification by removing those less likely to ionize, and, in turn, (iii) a reduced false discovery rate and increased confidence in identifications. Factors controlling observability are not fully understood, making prediction of this property nontrivial and a prime candidate for chemical space analysis. Chespa is available at github.com/pnnl/chespa.

RARE-34. UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG): GUIDELINES FOR THE MANAGEMENT OF MENINGIOMA IN CHILDREN, TEENAGERS AND YOUNG ADULTS

Primary tumours of the meninges are rare accounting for only 0.4–4.6% of all paediatric tumours of the central nervous system. Due to the rarity of these tumours in children, and the consequent absence of collaborative prospective trials, there is no clear consensus on how the unique characteristics of paediatric meningiomas impact clinical status, management approach, and survival. Much of the evidence and treatment recommendations for paediatric meningiomas are extrapolated from adult data. Translating and adapting adult treatment recommendations into paediatric practice can be challenging and might inadvertently lead to inappropriate management. In 2009 Traunecker et al. published guidelines for the management of intracranial meningioma in children and young people on behalf of UK Children’s Cancer and Leukaemia Group (CCLG). Ten years later we have developed the updated guidelines following a comprehensive appraisal of the literature. Complete surgical resection is the treatment of choice for symptomatic meningiomas, while radiotherapy remains the only available adjuvant therapy and may be necessary for those tumours that cannot be completely removed. However, significant advances have been made in the identification of the genetic and molecular alterations of meningioma, which has not only a potential value in development of therapeutic agents but in surveillance of childhood meningioma survivors. This guideline builds upon the CCLG 2009 guideline. We summarise recommendations for the diagnosis, treatment, surveillance and long-term follow up of children and adolescents with meningioma.

Transcriptomic biomarkers for predicting response to neoadjuvant treatment in oesophageal cancer.

Oesophageal cancer is a devastating disease with poor outcomes and is the sixth leading cause of cancer death worldwide. In the setting of resectable disease, there is clear evidence that neoadjuvant chemotherapy and chemoradiotherapy result in improved survival. Disappointingly, only 15%–30% of patients obtain a histopathological response to neoadjuvant therapy, often at the expense of significant toxicity. There are no predictive biomarkers in routine clinical use in this setting and the ability to stratify patients for treatment could dramatically improve outcomes. In this review, we aim to outline current progress in evaluating predictive transcriptomic biomarkers for neoadjuvant therapy in oesophageal cancer and discuss the challenges facing biomarker development in this setting. We place these issues in the wider context of recommendations for biomarker development and reporting. The majority of studies focus on messenger RNA (mRNA) and microRNA (miRNA) biomarkers. These studies report a range of different genes involved in a wide variety of pathways and biological processes, and this is explained to a large extent by the different platforms and analysis methods used. Many studies are also vastly underpowered so are not suitable for identifying a candidate biomarker. Multiple molecular subtypes of oesophageal cancer have been proposed, although little is known about how these relate to clinical outcomes. We anticipate that the accumulating wealth of genomic and transcriptomic data and clinical trial collaborations in the coming years will provide unique opportunities to stratify patients in this poor-prognosis disease and recommend that future biomarker development incorporates well-designed retrospective and prospective analyses.

Survival and prognostic factors for childhood malignant liver tumors: analysis of harmonized clinical data

BackgroundDespite overall striking advances in survival of childhood liver tumors, outcomes remain poor for specific patient segments. We aimed to assess overall survival (OS) of this rare disease and evaluate the generalizability of prognostic variables included in international collaborative systems using, for the first time, harmonized clinical data from two geographically different cohorts (Greece and Moscow). MethodsData for children (0-14 years) with liver tumors were retrieved from two Southern-Eastern European areas (Greece; 2001-2019 and Moscow; 2012-2019). Kaplan-Meier curves were constructed, and OS values were derived from Cox proportional models controlling for study variables. ResultsA total of 171 newly diagnosed cases (54.4% males) were included. The OS5-year exceeded 80% in patients <5 years, reaching 85% among 133 patients with hepatoblastoma (HBL). By contrast, children with other than HBL histology, especially hepatocellular carcinoma (HCC) had significantly worse prognosis (hazard ratio [HR] HCC: 7.09, 95% confidence intervals [CI]: 2.56-19.65; HR other liver tumors: 5.18; 95%CI: 2.15-12.49). The OS5-year was poorer (40%-60%) in patients with extensive local, metastatic or relapsed disease. By contrast, a significantly lower risk of death was shown in case of microscopically margin-negative resection (HR: 0.06, 95%CI: 0.02-0.17) and liver transplantation (HR: 0.12, 95% CI: 0.02-0.63) compared to the non- operated group. ConclusionsOutcomes of patients with liver tumors registered in two SEE areas were comparable to those reported by major collaborative trials. Ongoing clinical cancer registration could facilitate comparison of outcomes between different study groups in order to shape state of the art of treatment.

Survival Improvement over Time of 960 s-AML Patients Included in 13 EORTC-GIMEMA-HOVON Trials.

Simple SummarySecondary acute myeloid leukemia (s-AML) refers to the development of AML following myelodysplatic syndrome or other hematological malignancies, or after a solid tumors, or nonmalignant diseases or following exposure to environmental or occupational carcinogens. Here, we report data from 960 s-AML patients who were treated in 13 EORTC collaborative trials conducted between May 1986 and January 2008. The main aims of our study were (1) to assess whether overall survival of s-AML patients improved over time, (2) to identify initial disease features associated with overall survival. We observed that overall survival of younger patients improved over the years, in parallel with introduction of high-dose cytarabine in induction remission chemotherapy. This suggests that this strategy should be further investigated in younger patients with s-AML. Furthermore, this study confirmed that the sAML patients having adverse cytogenetic risk features and those with high white blood cells at diagnosis had a dismal survival, regardless of their age group.We report the outcomes of secondary acute myeloid leukemia (s-AML) patients included in one of 13 European Organisation for Research and Treatment of Cancer (EORTC) collaborative AML trials using intensive remission-induction chemotherapy. Among 8858 patients treated between May 1986 and January 2008, 960 were identified as having s-AML, either after MDS (cohort A; n = 508), occurring after primary solid tumors or hematologic malignancies other than MDS (cohort B; n = 361), or after non-malignant conditions or with a history of toxic exposure (cohort C; n = 91). Median age was 64 years, 60 years and 61 years in cohort A, B and C, respectively. Among patients ≤60 years and classified in the cohorts A or B (n = 367), the 5-year overall survival (OS) rate was 28%. There was a systematic improvement in the 5-year OS rate over three time periods (p < 0.001): 7.7% (95% CI: 1.3–21.7%) for patients treated before 1990 (period 1: n = 26), 23.3% (95% CI: 17.1–30.0%) for those treated between 1990 and 2000 (period 2: n = 188) and 36.5% (95% CI: 28.7–44.3%) for those treated in 2000 or later (period 3: n = 153). In multivariate analysis, male gender (HR = 1.39; p = 0.01), WBC ≥ 25 × 109/L (HR = 2.00; p < 0.0001), age 46-60 years (HR = 1.65; p < 0.001) and poor-risk cytogenetics (HR = 2.17; p < 0.0001) were independently associated with shorter OS, while being treated during period 2 (HR = 0.50, p = 0.003) or period 3 (HR = 0.43; p = 0.0008). Having received high-dose cytarabine (HD-AraC) (n = 48) in the induction chemotherapy (HR = 0.54, p = 0.012) was associated with a longer OS. In contrast, among patients >60 years of age (n = 502), the OS was dismal, and there was no improvement over time.

Examining association between cohesion and diversity in collaboration networks of pharmaceutical clinical trials with drug approvals.

Clinical trials ensure that pharmaceutical treatments are safe, efficacious, and effective for public consumption, but are extremely complex, taking up to 10 years and $2.6 billion to complete. One main source of complexity arises from the collaboration between actors, and network science methodologies can be leveraged to explore that complexity. We aim to characterize collaborations between actors in the clinical trials context and investigate trends of successful actors. We constructed a temporal network of clinical trial collaborations between large and small-size pharmaceutical companies, academic institutions, nonprofit organizations, hospital systems, and government agencies from public and proprietary data and introduced metrics to quantify actors' collaboration network structure, organizational behavior, and partnership characteristics. A multivariable regression analysis was conducted to determine the metrics' relationship with success. We found a positive correlation between the number of successful approved trials and interdisciplinary collaborations measured by a collaboration diversity metric (P < .01). Our results also showed a negative effect of the local clustering coefficient (P < .01) on the success of clinical trials. Large pharmaceutical companies have the lowest local clustering coefficient and more diversity in partnerships across biomedical specializations. Large pharmaceutical companies are more likely to collaborate with a wider range of actors from other specialties, especially smaller industry actors who are newcomers in clinical research, resulting in exclusive access to smaller actors. Future investigations are needed to show how concentrations of influence and resources might result in diminished gains in treatment development.

Urgent intervention of hemodynamically significant stenosis of the internal carotid artery in the acutest period of an ischaemic stroke

Aim. To assess the results of carotid angioplasty with stenting (CAS) performed in the first 3 h after the onset of ischaemic stroke (the most acute period of acute cerebrovascular accident).Methods. This retrospective study included 312 patients from January 2008 to August 2020 with hemodynamically significant stenosis of the internal carotid arteries (ICA) who underwent CAS within 3 h of stroke onset. After a patient was hospitalised in our emergency department, stroke development was assessed by a neurologist. The level of neurological deficit was determined according to the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin scale, the Barthel scale and the Rivermead Mobility Index. Multispiral computed tomography (MSCT) of the brain was then performed. On condition of visualisation of the ischaemic focus, the patient was sent for screening colour duplex scanning of the brachiocephalic arteries (BCA), arteries of the lower extremities, aortic arch and heart. If hemodynamically significant stenosis in the ICA was visualised, the patient underwent MSCT angiography of the BCA. The degree of stenosis was determined using the North American Symptomatic Trial Collaborators (NASCET) classifications. The on-duty ultidisciplinary council determined the tactics of the patient's treatment. Decisions regarding surgical correction and the choice of revascularisation strategy (CAS or carotid endarterectomy) were made based on stratification of the risk of postoperative complications according to the EuroSCORE II scale and the severity of coronary lesions according to the SYNTAX Score (in the presence of a history of coronary angiography). The time between admission to the emergency department and admission to the operating room was 84.5 ± 9.3 minutes. The inclusion criteria were 1. mild neurological disorders from 3 to 8 points on the NIHSS scale, no more than 2 points on the Rankin modification scale and more than 61 points on the Barthel scale; 2. Indication for CAS according to the current national recommendations; 3. Ischaemic focus in the brain no more than 2.5 cm in diameter according to MSCT; 4. Absence of pronounced calcification of the ICA. The exclusion criteria were: 1. Contraindications for CAS; 2. The presence of thrombosis of the ICA requiring the introduction of fibrinolytics (Alteplase), thromboextraction and thromboaspiration.Results. In the hospital postoperative period, 6 (1.92%) patients had lethal outcomes, 5 (1.6%) had myocardial infarctions, 5 (1.6%) had nonfatal stroke, 7 (2.2%) had asymptomatic ‘silent’ stroke, 2 (0.64%) had haemorrhagic transformations and 1 (0.32%) had ICA thrombosis. The combined endpoint (death + stroke + myocardial infarction) was reached in 7.05% of patients (n = 22).Conclusion. CAS is a safe and effective method of brain revascularisation in the first hours after the onset of ischaemic stroke. Interventional correction of hemodynamically significant stenoses of the ICA had permissible levels of ‘stroke + mortality from stroke’ and lethal outcomes, which reached 3.84% and 1.92%, respectively. Urgent implementation of CAS allows a significant regression of neurological deficit which is stable throughout the entire postoperative period. Received 21 September 2020. Revised 1 October 2020. Accepted 10 October 2020. Funding: The study did not have sponsorship. Conflict of interest: Authors declare no conflict of interest. Author contributionsConception and design: R.A. Vinogradov, M.A. Chernyavsky, V.A. Porkhanov, E.Yu. Kachesov, G.G. KhubulavaData collection and analysis: V.V. Matusevich, K.P. Chernykh, A.B. ZakeryaevDrafting the article: A.N. KazantsevStatistical analysis: G.Sh. Bagdavadze, R.Yu. LeaderFinal approval of the version to be published: A.N. Kazantsev, R.A. Vinogradov, M.A. Chernyavsky, V.V. Matusevich, K.P. Chernykh, A.B. Zakeryaev, G.Sh. Bagdavadze, R.Yu. Leader, E.Yu. Kachesov, V.A. Porkhanov, G.G. Khubulava

Prognostic Value of DNA Ploidy By Flow Cytometry for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Peruvian Cohort Study

Background: B-cell Acute Lymphoblastic Leukemia (B-ALL) represents an aggressive malignancy but highly curable in children. Currently, pediatric collaborative clinical trials have reported survival rates that exceed 90%, and DNA ploidy by flow cytometry (FC) has been pointed for risk stratification and prognosis in these clinical trials. However, its generalized use remains controversial as few studies reported no impact in real-world populations. We aimed to evaluate prognostic value of DNA ploidy measured by FC in a large cohort of Peruvian children with B-ALL. Methods: We evaluated prospectively DNA-ploidy by FC in bone marrow diagnostic samples from newly diagnosed children (&amp;lt;15 years) with B-ALL treated at Instituto Nacional de Enfermedades Neoplasicas (Lima-Peru) between 2017-2019. DNA-ploidy was evaluated using Propidium Iodide and calculated as the mean ratio between fluorescence of pathologic B blasts and normal marrow cells. Ploidy categories were established based on previous reports of DNA-index(DI): Diploid + Low-Hyperdiploidy (DLH; DI: 0.95 - 1.15), hypo-diploid (HD; DI&amp;lt;0.95) and High-hyperdiploidy (HH; DI&amp;gt;1.15), and recalculated using maximally selected rank statistics. Samples were analyzed in a FacsCanto II flow cytometer (BD) and Infinicyt software (Cytognos). All patients received BFM-2009 protocol and had minimal residual disease evaluation at the end of IA and IB induction. Minimal residual disease (MRD) was evaluated with FC using a detection threshold of 0.0025% and considering positive ≥0.01%. Survival curves (event-free and overall survival) were estimated using the Kaplan-Meier method and compared with the Log-rank test. Results: A total of 192 children were included (2 HD, 141 DLH and 49 HH cases according to DNA ploidy by FC). Clinical characteristics and outcomes are shown in Table 1. Median age at diagnosis was 5 years (Range:1-14), 10 years for HD, 6 and 3 years for DLH and HH, respectively (p=0.002). F/M ratio was 1:1.3 for all cases, but 1:2 in HH group. Most karyotypes (62%) had unsatisfactory or poor-quality result, 29% were considered normal, and only 9 hyperdiploidy and 2 hypodiploidy cases were detected by conventional karyotyping. Regarding genetics, 21 TEL/AML, 19 E2A/PBX1 and 9 BCR/ABL cases were detected by multiplex-PCR and most balanced alterations had DLH subtype and only one HD case had TEL/AML. MRD positivity after Induction IA was 35% without difference between groups (50% HD, 36% DLH and 31% HH, p=0.77), however after Induction IB, MRD was positive in 50% of HD, 12% of DLH and 5% of HH (p=0.048). At eight-teen months of follow-up, one relapse was seen in HD cases, and 11% DLH and 10% in HH. Median EFS and OS was not reached, however one-year EFS and OS were 86% for both without significant differences between groups. Multivariate analysis showed that MRD positivity remains as the principal independent prognostic factor and ploidy by DNA did not show any impact in terms of MRD, EFS and OS. Conclusion: High-Hyperdiploidy by DNA ploidy was associated to better MRD negativity rate after induction IB but without impact in short-term EFS and OS. DNA ploidy did not represent a prognostic factor in our study cohort, however long-term follow-up is warranted. Additionally, a better genetic risk stratification is necessary to improve outcomes in Latino high-risk population. Disclosures No relevant conflicts of interest to declare.

Abstract IA11: AYA lymphomas: Bridging the divide

Abstract Lymphomas account for approximately 20-25% of annual cancer diagnoses in the adolescent and young adult (AYA) population, defined as ages 15–39 years. Despite continued improvements in lymphoma outcomes, AYAs have not exhibited survival gains to the same extent as other age groups. At present, this survival gap is a manifestation of many compounding factors including a lack of sufficient understanding of the tumor biology or the optimal therapeutic approaches, as well as delays in diagnosis, the supportive care needs, long-term toxicity risk, developmental stage of the AYA, and socioeconomic factors. There is no established standard of care for AYA lymphomas, and there is significant divergence in treatment approaches between medical and pediatric oncology. Data on the heterogeneity of lymphoid malignancies in the AYA population as compared with younger pediatric and older adult groups will be reviewed. The highest proportion (35-70%) of lymphoid malignancies are due to Hodgkin lymphoma and lymphoblastic leukemia/lymphoma, followed by diffuse large B-cell lymphoma (10%-20%). Sex, race, and ethnic differences in the AYA lymphomas are also observed. These findings suggest that AYA lymphomas are biologically distinct from those present in the pediatric and adult populations. Factors that may contribute to the observed age-based variation in disease include evolution of the immune system with age, changes in the impact of genetic susceptibility, and viral and/or environmental exposures. There is a marked difference between the pediatric and adult approaches for AYA lymphomas. The example of AYA Hodgkin lymphoma will be reviewed. The pediatric backbone chemotherapy regimen has been doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC), whereas the adult regimen has been doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Radiation therapy is incorporated more often in pediatric high-risk regimens and adult low-risk approaches. Because disease biology does not conform to an 18-year-old cutoff, which of these approaches is most appropriate for AYAs has not been established. Treatment approach is not standard and is often driven by the experience of the physician. Recent progress in developing collaborative clinical trials through the North American National Clinical Trials Network will be reviewed. Citation Format: Kara Kelly. AYA lymphomas: Bridging the divide [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA11.

What is the potential cardiovascular risk reduction associated with achieving LDL-C levels recommended in the ESC/EAS guidelines for very high-risk patients? Data from 18 European countries

Abstract Background/Introduction For patients at very-high risk of cardiovascular (CV) events, the 2016 ESC/EAS dyslipidaemia guidelines recommended lipid-lowering therapy (LLT) to achieve an LDL-C level below 70 mg/dL. This was lowered to an LDL-C level below 55 mg/dL in the 2019 guidelines. Purpose To assess: 1) the risk profile of European patients with established atherosclerotic CV disease (ASCVD) receiving LLT; and 2) the treatment gap between the estimated risk and the population benefits if all patients were to achieve LDL-C levels of 70 mg/dL and 55 mg/dL. Methods We used data from Da Vinci, an observational cross-sectional study conducted across 18 European countries. Data were collected at a single visit between June 2017 and November 2018, for consented adults who had received any LLT in the prior 12 months and had an LDL-C measurement in the prior 14 months. LDL-C level was assessed at least 28 days after starting the most recent LLT (stabilised LLT). For each patient with established ASCVD receiving stabilised LLT, we: 1) calculated their absolute LDL-C reduction required to achieve LDL-C levels of 70 mg/dL and 55 mg/dL; 2) predicted their 10-year CV risk using the REACH score based on demographic and medical history; 3) simulated their relative risk reduction (RRR) by randomly sampling from the probability distribution of the rate ratio per 38.7 mg/dL (1 mmol/L) estimated by the Cholesterol Treatment Trialists Collaboration meta-analysis; and 4) calculated their absolute risk reduction (ARR) achieved by meeting LDL-C levels of 70 mg/dL and 55 mg/dL. Results A total of 2039 patients with established ASCVD were included in the analysis. Mean (SD) LDL-C was 83.1 (35.2) mg/dL. 40.4% and 19.3% of patients achieved LDL-C levels of 70 mg/dL and 55 mg/dL, respectively. Mean (SD) 10-year CV risk calculated using the REACH score was 36.3% (15.4%). Mean absolute LDL-C reductions of 19.6 mg/dL and 30.4 mg/dL were needed to reach LDL-C levels of 70 mg/dL and 55 mg/dL, respectively. When adjusted for the LDL-C reduction required to achieve an LDL-C level of 70 mg/dL, mean ARR was 3.0%, leaving a mean (SD) residual 10-year CV risk of 33.3% (15.5%). When adjusted for the LDL-C reduction required to achieve an LDL-C level of 55 mg/dL, mean ARR was 4.6%, leaving a mean (SD) residual 10-year CV risk of 31.7% (15.2%). Conclusion(s) In a contemporary European cohort with ASCVD receiving LLT, the 10-year risk of CV events is high and many patients do not achieve LDL-C levels of 55 mg/dL or even of 70 mg/dL. Moreover, even if all patients were to achieve recommended LDL-C levels, they would still remain at a high residual risk of CV events. These data suggest these patients require even more intensive LLT. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen

The Development of the Australian National Palliative Care Clinical Studies Collaborative "Integrating Qualitative Research into Clinical Trials Framework".

Qualitative methodologies have multiple contributions to health research, including improving baseline understanding in new areas of enquiry; questioning existing assumptions; understanding viewpoints of specific subgroups; and offering complex, contextual information. While the role of qualitative research within mixed methods approaches is well documented, the contribution to clinical trial design and conduct is less well recognized. The Australian Palliative Care Clinical Studies Collaborative and Cancer Symptom Trials have developed a framework to detail how qualitative research might contribute to each key aspect of clinical trials. This practical framework provides real-world examples, including sample qualitative questions, to consider at each phase of controlled clinical trial development. As the number of randomized clinical trials in palliative care increases, a readily accessible approach to integrating qualitative research into clinical trial design and conduct is needed so that its full potential for improving study recruitment, conduct, outcomes, interpretation, and implementation may be realized.

In adults with severe acute GI bleeding, tranexamic acid did not reduce death due to bleeding at 5 days

The HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395:1927-36. 32563378.

Care manager perspectives on integrating an mHealth app system into clinical workflows: A mixed methods study

mHealth can be a valuable means of monitoring symptoms and supporting care for rural patients, but barriers to implementation remain. This study aimed to examine care manager perspectives on the adoption, use and impact of an mHealth system deployed within a pragmatic Collaborative Care trial for rural patients with PTSD and/or Bipolar Disorder. Sixteen care managers at 12 Federally Qualified Health Centers in 3 states participated in semi-structured interviews. Interviews were transcribed, coded, and thematically analyzed using the Unified Theory of Adoption and Use of Technology as a conceptual framework. App metadata was used to assess the frequency of a care manager reported phenomenon, clinically disengaged app use. 4 themes were identified: infrastructural limitations; redundant and incompatible clinical and mHealth workflows; cross platform and web access; and patient engagement and clinically disengaged app use. Most users had a period of consistently submitting symptom measures via the app while disengaged from care for >4 weeks.

Importance and Evidence of Extent of Resection in Glioblastoma.

Maximal safe resection is an essential part of the multidisciplinary care of patients with glioblastoma. A growing body of data shows that gross total resection is an independent prognostic factor associated with improved clinical outcome. The relationship between extent of glioblastoma (GB) resection and clinical benefit depends critically on the balance between cytoreduction and avoiding neurologic morbidity. The definition of the extent of tumor resection, how this is best measured pre- and postoperatively, and its relation to volume of residual tumor is still discussed. We review the literature supporting extent of resection in GB, highlighting the importance of a standardized definition and measurement of extent of resection to allow greater collaboration in research projects and trials. Recent developments in neurosurgical techniques and technologies focused on maximizing extent of resection and safety are discussed.

Anticoagulation in splanchnic and cerebral vein thrombosis: An international vignette‐based survey

BackgroundAnticoagulant treatment of splanchnic (SVT) and cerebral vein thrombosis (CVT) can be challenging due to the rarity of these conditions, the concomitantly high thrombotic and bleeding risks, and the available low‐quality evidence. ObjectivesTo explore the current therapeutic approaches to SVT and CVT, and the rationale behind the anticoagulant treatment choice. MethodsA cross‐sectional survey was conducted (October 2018‐April 2019) among members of three thrombosis and hemostasis societies. The survey consisted of four vignette cases: (i) SVT secondary to transient risk factor; (ii) cirrhotic SVT with esophageal varices; (iii) CVT secondary to transient risk factor; and (iv) unprovoked CVT with intracranial hemorrhage. ResultsA total of 397 physicians responded to the survey. There was wide variability in anticoagulant treatment options, starting time, and duration. Vitamin K antagonists were the commonest choice across the four vignette cases (44.2%‐63.0%). The direct oral anticoagulants (DOACs) were the second commonest choice in low‐bleeding‐risk scenarios (27.7% in case 1, 22.9% in case 3), while parenteral anticoagulation alone was the second commonest choice in high‐bleeding‐risk scenarios (39.9% in case 2, 39.8% in case 4). The most frequent reasons for selecting DOACs were oral route of administration (50.6%), lack of need for laboratory monitoring (48.1%), and favorable safety profile of these drugs (43.4%). ConclusionsThe results of our study showed that, despite being off‐label, the DOACs were considered for the treatment of unusual‐site venous thromboembolism. The wide variability among different physicians reflected the clinical difficulties and raised the need for more collaborative trials on these disorders.