Antibody-mediated blockade of co-inhibitory molecules such as cytotoxic T lymphocyte-associated protein 4, PD1 and PDL1 elicits potent antitumor responses and improves the prognosis of many patients ...with cancer. As these immune checkpoint inhibitors (ICIs) are increasingly prescribed to a diverse patient population, a broad range of adverse effects is emerging. Atherosclerosis, a lipid-driven chronic inflammatory disease of the large arteries, may be aggravated by ICI treatment. In this review, we discuss recent clinical studies that analyze the correlation between ICI use and atherosclerotic cardiovascular disease (CVD). Indeed, several studies report an increased incidence of atherosclerotic CVD after ICI administration, with the occurrence of pathologies such as myocardial infarction, ischemic stroke and coronary artery disease significantly higher after ICI use. Increased awareness and better monitoring of ICI-treated patients can elucidate risk factors that contribute to ICI-induced aggravation of atherosclerosis and identify promising treatment strategies. For now, optimal cardiovascular risk assessment is required to protect ICI-receiving patients and long-term survivors of cancer from the detrimental effects of ICI therapy on atherosclerotic CVD.
Appropriate use of diagnostic laboratory tests is challenging, and estimates of 20% for overutilization and 45% for underutilization have been reported. Introducing effective and sustainable ...solutions to stimulate optimal use of laboratory testing in clinical practice is a challenge. A recent pilot study from our group, focusing on increasing the awareness about appropriate laboratory testing with the aim of changing the mindset of health care workers, has shown promising results. In this project, we aim to extend this multistep intervention to the internal medicine departments of 4 large Dutch hospitals. We aim to reduce unnecessary laboratory testing by 5%.
Our primary objective is to determine the effect of our intervention on diagnostic laboratory test order volume. Our secondary objectives are to determine the effect of our intervention on laboratory expenditure and order volumes, expenditures for other diagnostic modalities, and clinical patient outcomes. We will also analyze the barriers and facilitators for deimplementation of unnecessary laboratory testing.
The main interventions of this before-after study will be an intensified supervision of residents by experienced physicians regarding test ordering, creating awareness through education and monthly feedback on ordering patterns, and changes in (computerized) order entry systems.
At the time of publication of this protocol, the project is in the phase of data collection. We expect to present data on reduction early in the fourth quarter of 2018.
In this project, we aim to reduce the unnecessary diagnostic testing in the internal medicine departments of 4 teaching hospitals. Although the main interventions will be similar, each clinic is given the opportunity to focus on the specific facets of the interventions as deemed useful according to the local situation. If effective, the study provides a framework for a nationwide initiative for reducing inappropriate laboratory testing.
RR1-10.2106/10473.
Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Studies in childhood cancer survivors have shown that ...doxorubicin exposure may also increase BC risk. Although doxorubicin is the cornerstone of HL chemotherapy, the association between doxorubicin and BC risk has not been examined in HL survivors treated at adult ages.
We assessed BC risk in a cohort of 1,964 female 5-year HL survivors, treated at age 15-50 years in 20 Dutch hospitals between 1975 and 2008. We calculated standardized incidence ratios, absolute excess risks, and cumulative incidences. Doxorubicin exposure was analyzed using multivariable Cox regression analyses.
After a median follow-up of 21.6 years (IQR, 15.8-27.1 years), 252 women had developed invasive BC or ductal carcinoma in situ. The 30-year cumulative incidence was 20.8% (95% CI, 18.2 to 23.4). Survivors treated with a cumulative doxorubicin dose of >200 mg/m
had a 1.5-fold increased BC risk (95% CI, 1.08 to 2.1), compared with survivors not treated with doxorubicin. BC risk increased 1.18-fold (95% CI, 1.05 to 1.32) per additional 100 mg/m
doxorubicin (
= .004). The risk increase associated with doxorubicin (yes
no) was not modified by age at first treatment (hazard ratio HR
, 1.5 95% CI, 0.9 to 2.6; HR
, 1.3 95% CI, 0.9 to 1.9) or chest RT (HR
, 1.9 95% CI, 1.06 to 3.3; HR
, 1.2 95% CI, 0.8 to 1.8).
This study shows that treatment with doxorubicin is associated with increased BC risk in both adolescent and adult HL survivors. Our results have implications for BC surveillance guidelines for HL survivors and treatment strategies for patients with newly diagnosed HL.
The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to ...radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors.
Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression.
After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab.
Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.
•Five-year DLBCL survivors have a higher risk of subsequent solid and hematological malignancies than the general population.•Largest excess risks were observed for subsequent lung and gastrointestinal tract cancer.•Receipt of >4500 mg/m2 cyclophosphamide (versus ≤2250 mg/m2) is associated with a 1.5-fold increased solid malignancy risk.•Risk may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up.
Inappropriate use of laboratory testing is a challenging problem. Estimated overuse rates of approximately 20% have been reported. Effective, sustainable solutions to stimulate optimal use are ...needed.
To determine the association of a multifaceted intervention with laboratory test volume.
A before-after quality improvement study was performed between August 1, 2016, and April 30, 2018, in the internal medicine departments of 4 teaching hospitals in the Netherlands. Data on laboratory order volumes from 19 comparable hospitals were used as controls. The participants were clinicians ordering laboratory tests.
The intervention included creating awareness through education and feedback, intensified supervision of residents, and changes in order entry systems. Interventions were performed by local project teams and guided by a central project team during a 6-month period. Sustainability was investigated during an 8-month follow-up period.
The primary outcome was the change in slope for laboratory test volume. Secondary outcomes were change in slope for laboratory expenditure, order volumes and expenditure for other diagnostic procedures, and clinical outcomes. Data were collected on duration of hospital stay, rate of repeated outpatient visits, 30-day readmission rate, and rate of unexpected prolonged duration of hospital stay for patients admitted for pneumonia.
The numbers of internists and residents ordering tests in hospitals 1 to 4 were 16 and 30, 18 and 20, 13 and 17, and 21 and 60, respectively. Statistically significant changes in slope for laboratory test volume per patient contact were found at hospital 1 (change in slope, -1.55; 95% CI, -1.98 to -1.11; P < .001), hospital 3 (change in slope, -0.74; 95% CI, -1.42 to -0.07; P = .03), and hospital 4 (change in slope, -2.18; 95% CI, -3.27 to -1.08; P < .001). At hospital 2, the change in slope was not statistically significant (-0.34; 95% CI, -2.27 to 1.58; P = .73). Laboratory test volume per patient contact decreased by 11.4%, whereas the volume increased by 2.4% in 19 comparable hospitals. Statistically significant changes in slopes for laboratory costs and volumes and costs for other diagnostic procedures were also observed. Clinical outcomes were not associated with negative changes. Important facilitators were education, continuous attention for overuse, feedback, and residents' involvement. Important barriers were difficulties in data retrieval, difficulty in incorporation of principles in daily practice, and high resident turnover.
A set of interventions aimed at changing caregivers' mindset was associated with a reduction in the laboratory test volume in all departments, whereas the volume increased in comparable hospitals in the Netherlands. This study provides a framework for nationwide implementation of interventions to reduce unnecessary laboratory testing.
Considerable progress has been made in treatment of patients with CLL, and new potent drugs have become available. Therefore the Dutch CLL guidelines were revised. Efficacy, quality of life and ...socio-economic impact were taken into account. This has led to guidelines with chemo-immunotherapy still as the cornerstone of CLL treatment and with novel targeted drugs for specific risk-groups.
In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukemia (CLL), and new potent drugs have become available. Therefore, the CLL working party revised the Dutch guidelines. Not only efficacy but also quality of life and socio-economic impact were taken into account in the formulation of treatment recommendations.
The working party discussed a set of questions regarding diagnostic tests and treatment and wrote the draft guideline. This was evidence-based whenever possible, but in cases of low evidence, an expert-based recommendation was formulated with input of the entire working party. The draft guideline was sent to all hematologists in the Netherlands for comment and was subsequently approved.
Recommendations were formulated on diagnostic tests and work-up before treatment. Also, recommendations were made for treatment with fludarabine-cyclophosphamide-rituximab, bendamustine-rituximab, chlorambucil with anti-CD20 antibody, ibrutinib, idelalisib-rituximab, venetoclax, and allogeneic stem cell transplantation.
In the revised Dutch CLL guidelines, chemo-immunotherapy is still the cornerstone of CLL treatment with novel targeted drugs for specific risk groups.
Abstract
Funding Acknowledgements
Type of funding sources: None.
Introduction
Echocardiographic left ventricular (LV) global longitudinal strain (GLS) may be used to detect subclinical ventricular ...dysfunction in patients who have received cardiotoxic chemotherapy. However, in some persons participating in recreational sports, GLS at rest may be lower than normal, but normalizes after a short exercise test as soon as resting heart rate (HR) is reached. The aim of the study was to determine GLS response to a short exercise test in patients treated for aggressive non- Hodgkin Lymphoma (NHL) compared to controls.
Methods
We conducted a cross-sectional study nested in a cohort of NHL survivors and their siblings served as controls . Survivors were treated 5 years ago or longer with a cumulative doxorubicin (anthracycline) dose of at least 250 mg/m2.
Transthoracic Echocardiography (TTE) was performed according to the guidelines.
First, GLS and LV ejection fraction (EF) were measured at rest. After 20 squats, GLS and EF measurements were repeated when the HR was comparable to the HR during rest measurements.
Results
In total 20 survivors (mean age 49 (± 13) years, 11 men (55%) were included and measurements were compared to 14 controls. (mean age 45 (± 8) years, 8 men ( 57 %).
In patients at rest, the EF was 52.6% ( ± 8.0%) and the GLS −16.1% ( ± 2.9%), compared to controls with an EF of 56.2% (± 3.4% ) (p-value 0.13) and GLS −18.0% (± 1.4 %) (p-value 0.031). All patients performed 20 squats and their EF increased to 55.0% (± 6.8%) and GLS −18.7% (± 3.8%) compared to controls in whom the EF increased to 62% (± 4.7%) (p-value 0.002) and GLS −21.3% (± 2.5%) (p-value 0.037) (Figure 1).
Conclusion
In addition to GLS measurement at rest, GLS after a short exercise test seems to be a promising tool to detect subclinical LV dysfunction in non-Hodgkin Lymphoma survivors. Further research in larger studies is needed to confirm these findings and to assess the association with clinical parameters.
To describe how utility weights and disability weights have been used in the context of quality-adjusted life-years (QALYs) and disability-adjusted life-years (DALYs)-based cost-effectiveness ...analysis (CEA) of pediatric vaccines for infectious diseases and assess the comparability between weights.
A systematic review was conducted of CEAs of pediatric vaccines for 16 infectious diseases, published between January 2013 and December 2020 and using QALYs or DALYs as outcome measure. Data on values and sources of weights for the estimation of QALYs and DALYs were extracted from studies and compared across similar health states. Reporting was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.
Out of 2154 articles identified, 216 CEAs met our inclusion criteria. Of the included studies, 157 used utility weights and 59 used disability weights in their valuation of health states. In QALY studies, the source, background, who’s preferences (adults’/children’s) were applied and adjustments made to utility weights were poorly reported. In DALY studies, the Global Burden of Disease study was most often referenced. Valuation weights for similar health states varied within QALY studies and between DALY and QALY studies, but no systematic differences were identified.
This review identified considerable gaps in the way valuation weights are used and reported on in CEA. The nonstandardized use of weights may lead to different conclusions about cost-effectiveness of vaccines and policy decisions.
•Cost-effectiveness analysis using quality-adjusted life-year and disability-adjusted life-year as outcome measures require valuation weights in the form of utility weights and disability weights. The level of agreement between these weights remains unclear.•This article describes how utility and disability weights have been used to estimate quality-adjusted life-year and disability-adjusted life-year outcomes in economic evaluations of pediatric vaccines conducted in low-, middle-, and high-income countries and assesses the comparability between valuation weights.•This review identified that the current use of weights in pediatric vaccine cost-effectiveness analysis is not standardized, leading to diverging valuation weights for the same health states, which could affect conclusions and policy decisions.
The coadjutant method for denture cleansing most used by denture wearers is immersion in chemical agents, which are toxic when in direct contact with cells. However, clinically, the contact between ...these chemical agents and prosthetic tissues does not occur directly, but rather with what remained impregnated into acrylic bases, even after rinsing the disinfected dentures. This study evaluated the antimicrobial and cytotoxic effects of a denture acrylic resin after successive cycles of daily overnight immersion in 1% sodium hypochlorite (1%NaClO) and 2% chlorhexidine digluconate (2%CHX), simulating the periods of 9 months or 1.5 year. Microbiological and cytotoxic assays were performed, respectively, by broth microdilution method (Candida albicans or Staphylococcus aureus) and MTT assay. Chemical residues of 2%CHX impregnated into the denture acrylic resin had an antimicrobial effect on both immersion periods, which was not observed with those of 1%NaClO. However, residues of 2%CHX were severely cytotoxic to human gingival fibroblasts compared to those of 1%NaClO and acrylic resin (not submitted to the denture cleansers), which were slightly cytotoxic. Even at low concentrations recommended for overnight soaking of removable dentures, the chemical residues of CHX may result in some degree of toxicity to the denture-bearing mucosa after long-term daily immersion.
•Chemical residues of denture cleansers remain impregnated into acrylic bases even after rinsing the disinfected dentures.•2%CHX impregnated into acrylic resin was severely cytotoxic to human gingival fibroblasts after long-term immersion.•Residues of 2%CHX may result in toxicity to the denture-bearing mucosa after long periods of daily overnight denture-soaking.
In healthy individuals, Candida species are considered commensal yeasts of the oral cavity. However, these microorganisms can also act as opportunist pathogens, particularly the so‐called ...non‐albicans Candida species that are increasingly recognized as important agents of human infection. Several surveys have documented increased rates of C. glabrata, C. tropicalis, C. guilliermondii, C. dubliniensis, C. parapsilosis, and C. krusei in local and systemic fungal infections. Some of these species are resistant to antifungal agents. Consequently, rapid and correct identification of species can play an important role in the management of candidiasis. Conventional methods for identification of Candida species are based on morphological and physiological attributes. However, accurate identification of all isolates from clinical samples is often complex and time‐consuming. Hence, several manual and automated rapid commercial systems for identifying these organisms have been developed, some of which may have significant sensitivity issues. To overcome these limitations, newer molecular typing techniques have been developed that allow accurate and rapid identification of Candida species. This study reviewed the current state of identification methods for yeasts, particularly Candida species.
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