Cooperation between geriatricians and general practitioners for improved pharmacotherapy in home-dwelling elderly people receiving polypharmacy - the COOP Study : study protocol for a cluster randomised controlled trial

Background: Polypharmacy and inappropriate drug use is associated with negative health outcomes among older people. Various interventions for improving drug treatment have been evaluated, but the majority of studies are limited by the use of surrogate outcomes or suboptimal design. Thus, the potential for clinically significant improvements from different interventions is still unclear. The main objective of this study is therefore to evaluate the effect upon patient-relevant endpoints of a cooperation between geriatricians and general practitioners on complex drug regimens in home-dwelling elderly people. Methods: This is a cluster randomised, single-blind, controlled trial where general practitioners are invited to participate with patients from their lists. The patients must be 70 years or older, use at least seven different medications and have their medications administered by the home nursing service. We plan to recruit 200 patients, with randomisation at physician level. The intervention consists of three main parts: ( 1) clinical geriatric assessment of the patient, combined with a thorough review of their medications; ( 2) a meeting between the geriatrician and general practitioner, where the two physicians combine their competence and knowledge and discuss the drug list systematically; ( 3) clinical follow-up, depending on the medication changes that have been done. The study period is 24 weeks, and the patients are assessed at baseline, 16 and 24 weeks. The primary outcome measure is health-related quality of life according to the 15D instrument. Secondary outcome measures include physical and cognitive functioning, medication appropriateness, falls, carer burden, use of health services ( hospital or nursing home admissions, use of home nursing services) and mortality. Discussion: Our choice of patient-relevant outcome measures will hopefully provide new knowledge on the potential for clinical improvements after performing comprehensive medication reviews in home-dwelling elderly people receiving polypharmacy.Peer reviewe

Effect of Clinical Geriatric Assessments and Collaborative Medication Reviews by Geriatrician and Family Physician for Improving Health-Related Quality of Life in Home-Dwelling Older Patients Receiving Polypharmacy: A Cluster Randomized Clinical Trial.

IMPORTANCE Polypharmacy and inappropriate drug regimens are major health concerns among older adults. Various interventions focused on medication optimization strategies have been carried out, but the effect on patient-relevant outcomes remains uncertain. Objective To investigate the effect of clinical geriatric assessments and collaborative medication reviews by geriatrician and family physician (FP) on health-related quality of life and other patient-relevant outcomes in home-dwelling older patients receiving polypharmacy. Design, Setting, and Participants Cluster randomized, single-blind, clinical trial. Norwegian FPs were recruited from March 17, 2015, to March 16, 2017, to participate in the trial with their eligible patients. Participants were home-dwelling patients 70 years or older, using at least 7 medications regularly, and having their medications administered by the home nursing service. Patients in the control group received usual care. Randomization occurred at the FP level. A modified intent-to-treat analysis was used. Intervention The intervention consisted of 3 main parts: (1) clinical geriatric assessment of the patients combined with a thorough review of their medications; (2) a meeting between the geriatrician and the FP; and (3) clinical follow-up. Main Outcomes and Measures The primary outcome was health-related quality of life as assessed by the 15D instrument (score range, 0-1; higher scores indicate better quality of life, with a minimum clinically important change of +/- 0.015) at week 16. Secondary outcomes included changes in medication appropriateness, physical and cognitive functioning, use of health services, and mortality. Results Among 174 patients (mean [SD] age, 83.3 [7.3] years; 67.8% women; 87 randomized to the intervention group and 87 randomized to the control [usual care] group) in 70 FP clusters (36 intervention and 34 control), 158 (90.8%) completed the trial. The mean (SD) 15D instrument score at baseline was 0.708 (0.121) in the intervention group and 0.714 (0.113) in the control group. At week 16, the mean (SD) 15D instrument score was 0.698 (0.164) in the intervention group and 0.655 (0.184) in the control group, with an estimated between-group difference of 0.045 (95% CI, 0.004-0.086; P = .03). Several secondary outcomes were also in favor of the intervention. There were more drug withdrawals, reduced dosages, and new drug regimens started in the intervention group. Conclusions and Relevance This study's findings indicate that, among older patients exposed to polypharmacy, clinical geriatric assessments and collaborative medication reviews carried out by a geriatrician in cooperation with the patient's FP can result in positive effects on health-related quality of life.Peer reviewe

Mutation Spectrum in Liquid Versus Solid Biopsies From Patients With Advanced Gastroenteropancreatic Neuroendocrine Carcinoma.

PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor prognosis. Most GEP-NEC are diagnosed with metastatic disease, with only minor biopsies available for molecular diagnostics. We assessed the applicability of liquid biopsies for molecular profiling of GEP-NEC. MATERIALS AND METHODS We performed massive parallel sequencing of 76 cancer-related genes in circulating tumor DNA from 50 patients with advanced GEP-NEC and compared findings to previous analyses of solid tumor biopsies from the same patients. Plasma samples were collected before therapy, and the median time span between blood and tissue sampling was 25 days. RESULTS We detected 178 somatic mutations in the liquid biopsies, 127 (71%) were also detected in the solid biopsies, whereas 51 (29%) were unique to the liquid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (single nucleotide variants) in solid biopsies, of which 127 (64%) were also now detected in liquid biopsies. In exploratory subgroup assessments, concordance was higher in patients with liver metastases (P = 1.5 × 10-5) and increasing with level of liver involvement (P = 1.2 × 10-4). The concordance was similar between GEP-NEC with different primary sites, except being lower in esophageal cases (P = .001). Concordance was not associated with tumor mutation burden. Tumor tissue mutations also detected in liquid biopsies was lower for MSI (40%) versus MSS tumors (70%; P = 7.8 × 10-4). We identified potentially targetable mutations in plasma of 26 (52%) of patients with GEP-NEC; nine patients (18%) had potentially targetable mutation detected only in liquid biopsies. CONCLUSION Liquid biopsy analyses may be an applicable alternative to solid biopsies in GEP-NEC. Liquid biopsies may add additional mutations compared with tumor biopsies alone and could be useful for biomarker assessment in clinical trials for these patients

Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms.

High-grade gastroenteropancreatic (HG-GEP) NEN are highly aggressive cancers. The molecular etiology of these tumors remains unclear and the prevalence of pathogenic germline variants in patients with HG-GEP-NEN is unknown. We assessed sequencing data of 360 cancer genes in normal tissue, from 240 patients with HG GEP-NEN; 198 patients with NEC and 42 with NET G3. Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in 3 patients and a recurrent MUTYH variant in 2 patients, indicating that these genes may be important underlying risk factors for HG-GEP-NEN, when mutated. Further, germline variants were found in canonical tumor suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in-silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP-NEC. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG GEP-NEN with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG GEP-NEN

Ipilimumab in a real-world population: A prospective Phase IV trial with long-term follow-up

Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real-world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost-benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real-world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment-associated grade 3 to 4 toxicity was observed in 28% of patients, and immune-related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3-15.9); and progression-free survival 2.7 months (95% CI: 2.6-2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C-reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow-up of a real-world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III trials and suggest that the use of ipilimumab can be based on current cost-benefit estimates.publishedVersio

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.Peer reviewe

Brief Tests such as the Clock Drawing Test or Cognistat Can Be Useful Predictors of Conversion from MCI to Dementia in the Clinical Assessment of Outpatients

Background: The identification of patients with mild cognitive impairment (MCI) who are at high risk of conversion to dementia is a challenging clinical task. Aims: To investigate whether simple cognitive screening tests can predict the conversion from MCI to dementia and to study the impact of different patient characteristics on the progression rate. Methods: A retrospective, longitudinal study of 90 outpatients diagnosed with MCI at a psychogeriatric clinic in Norway was conducted. Baseline scores on the Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), and Neurobehavioral Cognitive Status Examination (Cognistat) were related to ICD-10 diagnosis during 46 months. The influence of demographic, life situational, and clinical data were analyzed. Results: Sixty-four patients were diagnosed with dementia, significantly more females (82%) than males (50%) (p Conclusions: A high proportion of patients converted from MCI to dementia within 46 months, and females seem to be at higher risk. CDT and Cognistat significantly predicted the conversion from MCI to dementia and are therefore considered appropriate tests in clinical practice

Farmakoterapi i sykehjem

Beskriver en sammenlignende studie hvor hensikten var å undersøke legemiddelforbruk og kvalitet i to sykehjem med ulik legedekning.Bakgrunn. Sykehjemspasientenes polyfarmasi, multimorbiditet og fysiologiske aldersforandringer gir høy risiko for legemiddelrelaterte problemer. Vi beskriver legemiddelforbruket og sammenlikner legemiddelbehandlingen ved to sykehjem med ulik legedekning. Materiale og metode. Vi inkluderte 48 langtidspasienter fra to sykehjem i Oslo, sykehjem A (24 pasienter) og sykehjem B (24 pasienter). En farmasøyt innhentet informasjon om legemiddelbruk, identifiserte og klassifiserte legemiddelrelaterte problemer og graderte legemidlene etter antikolinerg aktivitet. To leger med erfaring fra geriatri og sykehjemsmedisin vurderte, uavhengig av hverandre og blindet for hvilket sykehjem pasientene tilhørte, den kliniske betydningen av de legemiddelrelaterte problemene. Resultater. Pasientene i sykehjem A brukte median (interkvartilavstand) 7,0 (5,3–11,0) legemidler, sammenliknet med 9,5 (8,0–12,8) i sykehjem B (median differanse 2,0, 95 % KI 1,0–4,0, p = 0,006). Pasientene i sykehjem A hadde også lavere antikolinerg skår enn pasientene i sykehjem B – 1,0 (0,0–2,0) mot 2,0 (2,0–3,8) (median differanse 1,0, 95 % KI 0,0–2,0, p = 0,009) – og færre legemiddelrelaterte problemer – 3,0 (2,0–4,0) versus 5,5 (3,3–8,0) (median differanse 2,0, 95 % KI 0,0–3,0, p = 0,007). Det var ingen signifikante forskjeller mellom sykehjemmene i pasientenes alder, komorbiditet, nyrefunksjon eller demensstatus, men legebemanningen var bedre i sykehjem A. Fortolkning. Legemiddelforbruket så vel som kvalitetsindikatorene varierer betydelig mellom sykehjem. Ulik legedekning er én mulig forklaring på forskjellene. Undersøkelsen synliggjør behovet for tverrfaglige legemiddelgjennomganger som kvalitetshevende tiltak i sykehjemsmedisinen