Introduction
Reliable estimates of time from diagnosis until institutionalization and death in people with dementia from routine nationally representative databases are lacking.
Methods
We selected ...9230 people with dementia and 24,624 matched controls from family physicians’ electronic records linked with national administrative databases to analyze time until institutionalization and death and associated factors.
Results
Median time from recorded diagnosis until institutionalization and until death for people with dementia was 3.9 and 5.0 years, respectively, which was considerably shorter than for controls. Once institutionalized, median time to death was longer for persons with dementia (2.5 years) than for controls (1.2 years). Older age and receiving home care were the strongest predictors of shorter time until institutionalization and death in people with dementia. Gender, cohabitation, migration status, frailty, polypharmacy, and dementia medication were other significant factors.
Discussion
The estimates could help to inform patients, their families, and policymakers about probable trajectories.
Patients with Chronic Lymphocytic Leukemia (CLL) have a 29- to 36-fold increased risk of invasive pneumococcal disease (IPD) compared to healthy adults. Therefore, most guidelines recommend ...vaccination with the 13-valent pneumococcal conjugated vaccine (PCV13) followed 2 months later by the 23-valent polysaccharide vaccine (PPSV23). Because both CLL as well as immunosuppressive treatment have been identified as major determinants of immunogenicity, we aimed to assess the vaccination schedule in untreated and treated CLL patients. We quantified pneumococcal IgG concentrations against five serotypes shared across both vaccines, and against four serotypes unique to PPSV23, before and eight weeks after vaccination. In this retrospective cohort study, we included 143 CLL patients, either treated (n = 38) or naive to treatment (n = 105). While antibody concentrations increased significantly after vaccination, the overall serologic response was low (10.5%), defined as a ≥4-fold antibody increase against ≥70% of the measured serotypes, and significantly influenced by treatment status and prior lymphocyte number. The serologic protection rate, defined as an antibody concentration of ≥1.3 µg/mL for ≥70% of serotypes, was 13% in untreated and 3% in treated CLL patients. Future research should focus on vaccine regimens with a higher immunogenic potential, such as multi-dose schedules with higher-valent T cell dependent conjugated vaccines.
Studies which examined the association between sedentary behavior (SB) and cognitive function have presented equivocal findings. Mentally active/inactive sedentary domains may relate differently to ...cognitive function. We examined associations between SB and cognitive function, specifically focusing on different domains. Participants were recruited from the Nijmegen Exercise Study 2018 in the Netherlands. SB (h/day) was measured with the Sedentary Behavior Questionnaire. Cognitive function was assessed with a validated computer self-test (COST-A), and a z-score calculated for global cognitive function. Multivariate linear regression assessed associations between tertiles of sedentary time and cognitive function. Cognition tests were available from 2821 participants, complete data from 2237 participants (43% female), with a median age of 61 IQR 52–67 and a mean sedentary time of 8.3 ± 3.2 h/day. In fully adjusted models, cognitive function was significantly better in participants with the highest total sedentary time (0.07 95% CI 0.02–0.12, P = 0.01), work-related sedentary time (0.13 95% CI 0.07–0.19, P < 0.001), and non-occupational computer time (0.07 95% CI 0.02–0.12, P = 0.01), compared to the least sedentary. Leisure sedentary time and time spent sedentary in the domains TV, reading or creative time showed no association with cognitive function in final models (all P > 0.05). We found a strong, independent positive association between total SB and cognitive function in a heterogenous population. This relation was not consistent across different domains, with especially work- and computer-related SB being positively associated with cognitive function. This highlights the importance of assessing the various sedentary domains in understanding the relation between sedentary time and cognitive function.
•Higher self-rated total sedentary time is associated with better cognitive function.•Distinct sedentary domains relate differently to cognitive function.•Higher work-related sedentary times are associated with better cognitive function.•Higher computer sedentary times are associated with better cognitive function.•Leisure sedentary time is not associated with cognitive function.
Impaired awareness in dementia caused by Alzheimer's disease and related disorders made study partner-report the preferred method of measuring interference in "instrumental activities of daily ...living" (IADL). However, with a shifting focus toward earlier disease stages and prevention, the question arises whether self-report might be equally or even more appropriate. The aim of this study was to investigate how participant- and study partner-report IADL perform in a community-based volunteer population without dementia and which factors relate to differences between participant- and study partner-report.
Participants (
= 3,288; 18-97 years, 70.4% females) and their study partners (
= 1,213; 18-88 years, 45.8% females) were recruited from the Dutch Brain Research Registry. IADL were measured using the Amsterdam IADL Questionnaire. The concordance between participant- and study partner-reported IADL difficulties was examined using intraclass correlation coefficient (ICC). Multinomial logistic regressions were used to investigate which demographic, cognitive, and psychosocial factors related to participant and study partner differences, by looking at the over- and underreport of IADL difficulties by the participant, relative to their study partner.
Most A-IADL-Q scores represented no difficulties for both participants (87.9%) and study partners (89.4%). The concordance between participants and study partners was moderate (ICC = 0.55, 95% confidence interval CI = 0.51, 0.59); 24.5% (
= 297) of participants overreported their IADL difficulties compared with study partners, and 17.8% (
= 216) underreported difficulties. The presence of depressive symptoms (odds ratio OR = 1.31, 95% CI = 1.12, 1.54), as well as memory complaints (OR = 2.45, 95% CI = 1.80, 3.34), increased the odds of participants overreporting their IADL difficulties. Higher IADL ratings decreased the odds of participant underreport (OR = 0.71, 95% CI = 0.67, 0.74).
In this sample of community-based volunteers, most participants and study partners reported no major IADL difficulties. Differences between participant and study partner were, however, quite prevalent, with subjective factors indicative of increased report of IADL difficulties by the participant in particular. These findings suggest that self- and study partner-report measures may not be interchangeable, and that the level of awareness needs to be considered, even in cognitively healthy individuals.
Management of patients with chronic lymphocytic leukemia (CLL) is changing due to considerable advances in the therapeutic armamentarium, and new therapies will possibly continue to emerge in the ...near future. Therefore, the CLL working group of the Dutch-Belgium Haemato-Oncology Cooperative Group for Adults in the Netherlands (HOVON) necessitated revising the Dutch CLL guidelines. The current guideline is based on the expert opinion of the HOVON CLL working group members and focusses on well-designed clinical trials taking into account efficacy with special emphasis on toxicity, treatment duration and treatment intensity. This article provides recommendations on diagnosis, treatment strategies in front-line and relapsed setting and provides supportive care measurements during novel-based therapies as well as for infectious CLL-related complications. The recommendations presented here are intended to provide guidance for the management of CLL patients in the Netherlands, and take into account the availability of treatment strategies at the time of this publication.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib improved undetectable measurable residual disease (MRD) rates and ...progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available.
GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0–2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax–rituximab, venetoclax–obinutuzumab, or venetoclax–obinutuzumab–ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1–2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1–3) and intravenous cyclophosphamide (250 mg/m2, days 1–3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2–6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax–rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2–6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2–6: 1000 mg on day 1). In the venetoclax–obinutuzumab–ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax–rituximab and the venetoclax–obinutuzumab group and between 12 and 36 cycles in the venetoclax–obinutuzumab–ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment.
Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax–rituximab group n=237; venetoclax–obinutuzumab group n=229; and venetoclax–obinutuzumab–ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months IQR 44·6–57·9), patients in the venetoclax–obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio HR 0·47 97·5% CI 0·32–0·69, p<0·0001) and the venetoclax–rituximab group (0·57 0·38–0·84, p=0·0011). The venetoclax–obinutuzumab–ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 0·19–0·47; p<0·0001) and the venetoclax–rituximab group (0·38 0·24–0·59; p<0·0001). There was no difference in progression-free survival between the venetoclax–obinutuzumab–ibrutinib and venetoclax–obinutuzumab groups (0·63 0·39–1·02; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax–rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9–91·1; 37 16% events) in the venetoclax–obinutuzumab–ibrutinib group, 81·8% (75·8–87·8; 55 24% events) in the venetoclax–obinutuzumab group, 70·1% (63·0–77·3; 84 35% events) in the venetoclax–rituximab group, and 62·0% (54·4–69·7; 90 39% events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 53% of 216 patients in the chemoimmunotherapy group, 109 46% of 237 in the venetoclax–rituximab group, 127 56% of 228 in the venetoclax–obinutuzumab group, and 112 48% of 231 in the venetoclax–obinutuzumab–ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax–rituximab and venetoclax–obinutuzumab groups, and four (2%) in the venetoclax–obinutuzumab–ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy).
With more than 4 years of follow-up, venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax–rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination.
AbbVie, Janssen, and F Hoffmann-La Roche.
•Geriatric assessments can aid in identifying patients with less physical resilience who are at increased risk of grade ≥3 adverse events.•Fixed-duration Ven-O improves HRQoL in patients with CLL ...with and without geriatric impairments.
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Chronic lymphocytic leukemia (CLL)–related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients’ HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043.
van der Straten and colleagues examined the impact of venetoclax plus obinutuzumab (Ven-O) on 67 previously untreated patients with chronic lymphocytic leukemia (CLL) who were deemed unfit for fludarabine, cyclophosphamide, and rituximab (FCR). They evaluated impact on patient-related outcomes, including geriatric assessments and health-related quality of life (HRQoL). Geriatric impairments were present in 90% of patients at baseline and predicted for nonhematological toxicity. However, Ven-O treatment is associated with decreased impairment and improved HRQoL.
Polycomb group (PcG) proteins are involved in the stable transmittance of the repressive state of their gene targets throughout the cell cycle. Mis‐expression of PcG proteins can lead to ...proliferative defects and tumorigenesis. There are two separate multimeric PcG protein complexes: an EED–EZH2‐containing complex and a BMI1–RING1‐containing complex. In the normal human follicle mantle, both PcG complexes have mutually exclusive expression patterns. BMI1–RING1 is expressed, but EZH2–EED is not. Here, we studied the expression of both complexes in six cases of mantle cell lymphoma (MCL), which is derived from the follicle mantle. MCL cells can be cultured in vitro and stimulated to proliferation. We found that resting MCL cells expressed BMI1–RING1, but not EZH2–EED, like normal mantle cells. Proliferating MCL cells, however, showed strongly enhanced expression of EZH2. Also, BMI1 and RING1 continued to be expressed in proliferating MCL. This is the first demonstration that EZH2 expression can be upregulated in fresh lymphoma cells. To test whether the enhanced EZH2 expression was causal for the increased proliferation in MCL, we overexpressed EZH2 in two different cell lines. In the B cell‐derived Ramos cell line, EZH2 overexpression caused an increase in the proliferation rate. This suggests a possible causal effect between EZH2 upregulation and increased proliferation in haematopoietic cells.
Waldenström macroglobulinemia (WM) is a rare B-cell Non-Hodgkin Lymphoma. There are only few prospective randomized clinical trials to guide treatment recommendations and there is no international ...consensus on a preferred first line treatment approach. In the recently revised Dutch guideline for WM, we describe recommendations for practice based as much as possible on the known data. Here, we summarize the considerations for first-line treatment based on these Dutch guidelines. Available evidence is summarized, including efficacy and toxicity data. Combinations of Rituximab with chemotherapy, proteasome inhibition or BTK-inhibition are all valid first line treatment options. The Dutch WM working group considers Dexamethasone/Rituximab/Cylofosfamide (DRC) a suitable first-line treatment for many WM patients, given the efficacy, the relatively mild toxicity profile and the extensive experience with this regimen. However, the long-term toxicities of DRC are unclear and need further clarification. Other regimens such as R-bendamustine, R-Bortezomib-dexamethason are also effective options, however with specific toxicities. BTK-inhibitors are not a preferred option in first line for most patients in the Dutch WM guidelines because of the need for longterm treatment and toxicities. Based on patient preferences research, future clinical trials should focus on effective fixed-duration regimens with non-cytotoxic therapies that have a favorable toxicity profile. Further development of (combinations with) BCL-2 inhibititors, novel proteasome inhibitors and BTK-inhibition could be interesting. In addition T-cell-directed treatments including bispecific antibodies as a monotherapy or combined with other novel agents deserve further study in WM.
Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 ...cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status.
We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27).
Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 70% men and 20 30% women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35·2 months (IQR 31·5-41·3). 16 (50% 95% CI 32-68) of 32 patients in the consolidation group and 16 (53% 34-72) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two 6% of 32 patients in the consolidation group and one 3% of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two 6% and two 7%). There were no treatment-related deaths.
Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse.
F Hoffmann-La Roche.