Forslag til endring av retningslinje ved konservativ behandling av NSTEMI

Sammendrag Bakgrunn Studier gjort internasjonalt har vist at fondaparinuks gir lavere morbiditet og mortalitet på lang sikt, sammenlignet med det lavmolekylære heparinet enoksaparin, ved konservativ antitrombotisk behandling av NSTEMI. Med bakgrunn i dette har vi sett på nåværende praksis for slik behandling av denne pasientgruppen på hjerteavdelingen på Ullevål Universitetssykehus (UUS). Da det ikke er samsvar mellom praksis på UUS og internasjonale guidelines, ønsket vi å utarbeide en strategi for implementering av en ny retningslinje for antitrombotisk behandling ved NSTEMI, med bytte fra enoksaparin til fondaparinuks. Metode Kunnskapsgrunnlaget ble bekreftet ved søk i medline/pubmed, og det ble gjort en spørreskjemaundersøkelse for å avdekke gjeldende praksis. Videre ble det gjort litteratursøk i Medline/Ovid for å finne dokumenterte implementeringstiltak. Resultater Ved UUS brukes det i hovedsak dalteparin ved konservativ behandling av NSTEMI, hvilket samsvarer med de nasjonale retningslinjer. Flere tiltak for endring av den lokale retningslinjen ble vurdert, og følgende tiltak foreslås: 1. Avdelingsledelsen nedsetter en ansvarlig prosjektgruppe med en prosjektkoordinator. 2. Felles undervisningsmøter med utdeling av spørreskjemaer for tilbakemelding. 3. Muntlig orientering samt informasjonsskriv om det nye tiltaket til personalet. 4. Regelmessige møter i prosjektgruppen med evaluering av resultater samt tilbakemeldinger fra personalet. 5. Kontinuerlig oppdatering om resultatene av prosjektet til personalet både muntlig og via e-post, samt oppfordring til å gi respons på hvordan det fungerer. 6. Evaluering av prosjektet etter ett år. Her benyttes indikatoren ”andelen pasienter med NSTEMI som blir behandlet konservativt i akuttfasen med fondaparinuks ved hjerteavdelingen på UUS.” Konklusjon Kunnskapsgrunnlaget viser at et bytte til fondaparinuks er fordelaktig med tanke på redusert morbiditet og mortalitet på lang sikt, lettere administrasjon og reduserte kostnader. De tiltakene vi har kommet frem til kan være praktisk gjennomførbare i den aktuelle avdelingen, og kan være hensiktsmessige i innføringen av en ny retningslinje

NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma

Ipilimumab; Mesotelioma pleural maligne; Vacuna telomerasaIpilimumab; Mesotelioma pleural maligno; Vacuna de telomerasaIpilimumab; Malignant pleural mesothelioma; Telomerase vaccineBackground Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients. Methods NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy. Discussion Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy.Ultimovacs provides UV1 vaccine and sargramostin for patients treated in arm A and some funding for the clinical trial. BMS provides ipilimumab and nivolumab for all patients. The South-Eastern Norway regional health authority has provided support for the clinical trial, PhD students and research analyses (Grant nos. 2021083 and 2020077)

Biomarkører i blod og cerebrospinalvæske ved Alzheimers sykdom og andre demenssykdommer

Approximately 65 000 people in Norway are suffering from dementia and the prevalence will increase as the population continues to age. The importance of biomarkers of Alzheimer’s disease and other dementias is increasing as well. There is a need for biomarkers to aid the diagnosis and to evaluate progression and the effect of therapeutic strategies. A biomarker may be a genetic trait, a change in structural or functional feature or a biochemical change, such as a protein or metabolite. The purpose of this paper is to review the currently available data on biomarkers assessed in plasma and cerebrospinal fluid in dementias, focusing on Alzheimer’s disease. The most extensively evaluated biomarkers are amyloid-β-proteins and total and phosphorylated tau protein in the cerebrospinal fluid. These markers are shown to differentiate between Alzheimer’s disease and several important differential diagnoses, including normal aging, depression and chronic neurological diseases like Parkinson’s disease. However, the specificity against other dementias is lower. Measures related to lipoprotein metabolism, oxidative stress and inflammation also appear altered in AD relative to controls, but lack sufficient discriminatory power. New proteomic technologies are likely to play an increasing role in identifying potential biomarkers of cognitive decline and dementia syndromes

NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma

Background Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients. Methods NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy. Discussion Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy. Trial registration: ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU&draw=2&rank=1

Atezolizumab and stereotactic body radiotherapy in patients with advanced non-small cell lung cancer: safety, clinical activity and ctDNA responses—the ComIT-1 trial

The introduction of immune checkpoint inhibitors has transformed the treatment landscape of metastatic non-small cell lung cancer. However, challenges remain to increase the fraction of patients achieving durable clinical responses to these drugs and to help monitor the treatment effect. In this phase II trial, we investigated the toxicity, systemic responses and circulating tumour DNA responses in patients (n = 21) with advanced non-small-cell lung cancer treated with atezolizumab and stereotactic body radiotherapy in the second or later line. We found the combined treatment to be safe with grade 3 toxicity reported in three patients. As the best overall response, four patients had a partial response, eight had stable disease and five had progressive disease. Median overall survival time was still not reached after a median follow-up of 26.5 months and 10/15 patients with programmed death-ligand 1 negative tumours were alive >18 months after the start of the study treatment. ctDNA was detectable at baseline in 11 patients. A rapid decline in ctDNA to <30% of baseline levels was seen in three patients, two of which were radiographic responders and one was considered clinically benefiting from therapy for almost 1 year