22 research outputs found
Constitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomised phase III trial
No full textLeveraging adaptive tumour immunity to control mesothelioma via immune checkpoint blockade is now a standard therapeutic approach. However, the determinants of sensitivity remain elusive. Low non-synonymous mutation burden and programmed death-ligand 1 expression, an abundance of immunosuppressive immune cell infiltration, and 9p21 deletion should all mitigate responses to therapy. To address this knowledge gap, we conducted a double blind, placebo-controlled, randomized phase III trial of the PD1 inhibitor, nivolumab (ClinicalTrial.gov registration: NCT03063450). After 37.2 months of follow-up, the primary endpoint of progression free-survival, but not overall survival was met. The nivolumab response rate was 10.3%, and related grade 3 or above adverse events occurred in 20.4% versus 7.2% for placebo. Progression-free and overall survival were longer in nivolumab-treated responders versus non-responders. In an exploratory multiomic analysis, blinded whole exome, transcriptome and multiplex immune profiling were used to interrogate R- versus NR-subgroups. Non-synonymous and neoantigen mutation burden were no different between groups, however R-mesotheliomas were infiltrated with activated CD8+ T- and CD19+ B-lymphocytes, organised into tertiary lymphoid structures. B-cell infiltration correlated with pro-inflammatory chemokines including IL24 and CCL19. Conversely, epithelial-mesenchymal transition and mitosis were associated with resistance to nivolumab. These findings illuminate features which can be leveraged to advance precision immunotherapy in this rare cancer setting
Defense of Superior Orders in International Criminal Law as Portrayed in Three Trials: Eichmann, Calley and England
No full textThe paper is dedicated to the defense of superior orders in international law. The author discusses attempts to use this defense in three trials, - Adolf Eichmann\u27s, William Calley\u27s and Lynndie England\u27s. The paper juxtaposes the trials and provides conclusions on the success of this defense in each case
Central Florida Future, Vol. 04 No. 10, December 3, 1971
No full textBudget program challenged: senator predicts demise of clubs; More credit hours asked; Campus bookstore shows little profit; FuTUre Editorials: Don\u27t stop the buses; Theatre Dept. plans first musical production; Pass-Fail plan discussed as possible for FTU; Unconstitutional bill corrected by senate; \u27Lt. Calley\u27 author [John Sack] tells war horrors (with photo); Excitement is \u27Superstar\u27 live (with photos); Sprites to be selected: Elf, Santa Contest to end at dance; Get out of town, Claus... Or, we don\u27t want any, go away (novel); Computer \u27Downs\u27 slow registration; Future Sports News: Tech kills MacDill, 112-45 (with photos); FuTUre\u27s Friday Girl: [Norma Lee Slayton].https://stars.library.ucf.edu/centralfloridafuture/1110/thumbnail.jp
Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial
No full textBACKGROUND: The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. METHODS: This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing. FINDINGS: Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8–9]) than participants in the placebo group (11 days [10–11]; HR 1·30, 95% credible interval 0·92–1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial. INTERPRETATION: We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive. FUNDING: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust
THE BLUE MOUND CHERT INVESTIGATING A TOPOGRAPHIC ANOMALY IN SOUTHERN WISCONSIN
No full textabstract: Blue Mound State Park, located in the state of Wisconsin (USA), is host to a topographic anomaly known as Blue Mound. This mound is the western of the two mounds that make up the park, and it marks the highest elevation in southern Wisconsin. Unlike its eastern sibling, Blue Mound possesses an unusual chert cap that may have protected it from erosion, thus preserving its stratigraphic integrity. Although Blue Mound's unique chert armor was noted in 1927 by the Wisconsin Geological and Natural History Survey, no published work has satisfactorily explained its origin. As little was known about the formation of cherts until the mid-to-late 1900s, the Blue Mound cap was classified merely as a Silurian dolostone into which chert had somehow become integrated (Steidtmann). However, the published observations of the Blue Mound chert do not necessarily match with the classification granted by the Wisconsin Geological and Natural History Survey, nor were any convincing interpretations offered regarding the presence of the chert. Since 1927, significant progress in the field of sedimentology has been achieved. There now exists knowledge that may fill the gaps between observation and interpretation in the Blue Mound survey. The observations in the 1927 bulletin correspond with modern notions of a paleokarst chert breccia, which forms a chert rubble or residuum. A chert breccia is formed when existing clasts, or pieces, of chert become cemented together by further chert deposition (Kolodny, Chaussidon and Katz). This can form large boulders of chert rubble that resist erosion. Accumulation of chert rubble has been documented to form along old weathering surfaces as an insoluble residue in environments similar to Blue Mound (Kolodny, Chaussidon and Katz). The purpose of this investigation was to verify the observations within the 1927 survey of the Blue Mound chert, and determine through field observations and sample study if the Blue Mound chert fits the model of a paleokarst chert breccia
Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial
No full textBackground
No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.
Methods
This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.
Findings
Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2–16·8). Median progression-free survival was 3·0 months (95% CI 2·8–4·1) in the nivolumab group versus 1·8 months (1·4–2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53–0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5–12·1) in the nivolumab group versus 6·9 months (5·0–8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52–0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group.
Interpretation
Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.
Funding
Stand up to Cancer–Cancer Research UK and Bristol Myers Squibb
Tachykinin receptor-selectivity of the potential glioblastoma-targeted therapy, DOTA-[Thi8,Met(O2)11]-substance P
No full textThe data presented in this study are available on request from the corresponding author (C.L.N.).Please read abstract in article.The Technology Innovation Agency South Africa.https://www.mdpi.com/journal/ijmsImmunologyNuclear MedicinePhysiologySDG-03:Good heatlh and well-beingSDG-09: Industry, innovation and infrastructur
Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial
No full textMolnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations
CLUSTER RANDOMIZED CONTROLLED TRIAL TO EVALUATE THE EFFECTIVENESS OF A MULTIFACETED ACTIVE STRATEGY TO IMPLEMENT LOW BACK PAIN PRACTICE GUIDELINES; EFFECT ON COMPETENCE, PROCESS OF CARE AND PATIENT OUTCOMES IN PHYSICAL THERAPY
No full textThe study was a cluster randomized controlled trial designed to evaluate the effectiveness of an active strategy to implement practice guidelines for low back pain in physical therapy. Physical therapy clinics (clinics=28, therapists=41) were randomized to receive a multifaceted active intervention (education, audit, feedback) (clinics=16, therapists=24) to increase awareness regarding key recommendations in guidelines or mailed guidelines (clinics=12, therapists=18). Primary outcome measures were change in pre to post intervention competence score (18 clinical vignettes), adherence to guidelines and change in patient Oswestry scores from first to last visit. The competence test was administered at baseline and on completion of the education course. Data on LBP patients treated by participating therapists in a 12-week pre (therapists=41, patients=50) and post (therapists=41, patients=107) intervention period (education, audit and feedback) was extracted from the UPMC electronic database. Patient care was classified as being adherent or non-adherent using 6 quality indicators developed to reflect recommendations in the guidelines. Overall percentage of adherence and adherence to individual criterion on the guidelines were also calculated. The results of the study indicated that education did not have an effect improving knowledge measured by change in total competence score. However, there were significant differences between groups on the ability to appropriately identify directional preference with movement testing, where the intervention group did better than the control. Adherence to guidelines and patient outcomes did not improve as a result of the active intervention strategy. The groups were not significantly different when comparing overall adherence to guidelines or to individual criterion on guidelines. There was an underutilization of mobilization thrust (82.3%), traction (78.5%) and graded exercises (47.6%) for fear avoidant patients, while stabilization was over-utilized in 51% of patients. Although therapists demonstrated moderate to high scores on the competence test, they failed to apply this knowledge in clinical practice. Future research should focus on a qualitative inquiry into organizational and environmental barriers to adoption of clinical practice guidelines. These include evaluating if payment policies and reimbursement from providers are aligned with guidelines and also assessing the extent to which patient demands and compliance influences adherence to guidelines
Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial
No full textBackgroundNo phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.MethodsThis was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.FindingsBetween May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2–16·8). Median progression-free survival was 3·0 months (95% CI 2·8–4·1) in the nivolumab group versus 1·8 months (1·4–2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53–0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5–12·1) in the nivolumab group versus 6·9 months (5·0–8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52–0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group.InterpretationNivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.</div
