Serum proteome modulations upon treatment provides biological insight on response to treatment in relapsed mantle cell lymphoma

Background The possibility to monitor patient's serum proteome during treatment can provide deepened understanding of the biology associated with response to specific drugs. Non-invasive serum sampling provides an opportunity for sustainable repetitive sampling of patients, which allows for more frequent evaluation of the biological response and enhanced flexibility in treatment selection in contrast to tissue biopsies. Aim To pin-point biologically relevant changes in pre- and on-treatment serum proteome samples in relapsed mantle cell lymphoma (MCL) patients, leading to insight into mechanisms behind response to treatment in sub-groups of patients. Methods Pre- and on-treatment serum samples from relapsed MCL patients treated with a triple combination therapy of rituximab, ibrutinib and lenalidomide were available for the study, together with detailed clinicopathological information. A microarray technology targeting 158 serum proteins using 371 antibody-fragments was used to compare the serum proteome at the two time-points. Results Proteins modulated by the treatment were shown to be associated to a MCL sub-group with ATM/TP53 alterations, which emphasizes the importance of treatment stratification. Absolute values of serum protein levels in on-treatment samples were highly variable and showed no correlation to outcome. To circumvent the challenge of variability in absolute serum protein levels, the velocity of change of individual serum proteins was used to identify proteins associated with clinical response. Increased values of TGF-beta 1, CD40 and complement component 4 comparing pre- and on-treatment samples were associated with remaining minimal residual disease (MRD) and increased BTK was associated with short progression-free survival (PFS). Conclusion We show that the genetic sub-type of MCL affects the biological response to treatment in serum and that the change in defined serum proteins reveals the biology associated with clinical response.Peer reviewe

Increased incidence rates of positive blood cultures shortly after chemotherapy compared to radiotherapy among individuals treated for solid malignant tumours

BACKGROUND: Cancer treatments suppress immune function and are associated with increased risk of infections, but the overall burden of serious infectious diseases in treated patients has not been clearly elucidated. METHODS: All patients treated for solid malignant tumours with radiotherapy (RT) and/or standard first-line chemotherapy (C) at the Department of Oncology at Rigshospitalet between 01/1/2010 and 31/12/2016 were included. Patients were followed from treatment initiation until the first of new cancer treatment, 1 year after treatment initiation, end of follow-up or death. Incidence rates (IR) of positive blood culture (PBC) per 1000 person-years follow-up (PYFU) were calculated. FINDINGS: 12,433 individuals were included, 3582 (29%), 6349 (51%), and 2502 (20%) treated with RT, C, or both RT & C, respectively, contributing 8182 PYFU. 429 (3%) individuals experienced 502 unique episodes of PBC, incidence rate (95% CI) 52.43 (47.7, 57.6) per 1000 PYFU. The 30-day mortality rate after PBC was 24% independent of treatment modality. Adjusted incidence rate ratios in the first 3 months (95% CI) after PBC significantly varied by treatment: 2.89 (1.83, 4.55) and 2.52 (1.53, 4.14) for C and RT & C compared to RT. Escherichia coli (n = 127, 25%) was the top microorganism identified. INTERPRETATION: PBCs are not common, but when they occur, mortality is high

Dyspnea, a high-risk symptom in patients suspected of myocardial infarction in the ambulance?:A population-based follow-up study

BACKGROUND: Systematic management of patients suffering high-risk symptoms is essential in emergency medical services. Patients with chest pain receive algorithm-based work-up and treatment. Though dyspnea is recognized as an independent predictor of mortality, no generally accepted prehospital treatment algorithm exists and this may affect outcome. The objective of this study was to compare mortality in patients suspected of myocardial infarction (MI) presenting with dyspnea versus chest pain in the ambulance. METHODS: Follow-up study in patients undergoing electrocardiogram-based telemedical triage because of suspected MI in an ambulance in the Central Denmark Region from 1 June 2008 to 1 January 2013. Primary outcome was 30-day mortality. Secondary outcomes were 4-year mortality and mortality rates in subgroups of patients with and without a confirmed MI. Absolute risk differences adjusted for comorbidity, age, systolic blood pressure and heart rate were calculated by a generalized linear regression model. RESULTS: Of 17,398 patients, 12,230 (70 %) suffered from chest pain, 1464 (8 %) from dyspnea, 3540 (20 %) from other symptoms and 164 (1 %) from cardiac arrest. Among patients with dyspnea, 30-day mortality was 13 % (CI 12–15) and 4-year mortality was 50 % (CI 47–54) compared to 2.9 % (CI 2.6-3.2) and 20 % (CI 19–21) in patients with chest pain. MI was confirmed in 121 (8.3 %) patients with dyspnea and in 2319 (19 %) with chest pain. Patients with dyspnea and confirmed MI had a 30-day and 4-year mortality of 21 % (CI 15–30) and 60 % (CI 50–70) compared to 5.0 % (CI 4.2-5.8) and 23 % (CI 21–25) in patients with chest pain and confirmed MI. Adjusting for age, comorbidity, systolic blood pressure and heart rate did not change these patterns. CONCLUSION: Patients suspected of MI presenting with dyspnea have significantly higher short- and long-term mortality than patients with chest pain irrespective of a confirmed MI diagnosis. Future studies should examine if supplementary prehospital diagnostics can improve triage, facilitate early therapy and improve outcome in patients presenting with dyspnea. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13049-016-0204-9) contains supplementary material, which is available to authorized users

Systematic Literature Review of Economic Evaluations of Treatment Alternatives in Chronic Lymphocytic Leukemia

BackgroundEconomic evaluations are widely used to predict the economic impact of new treatment alternatives. Comprehensive economic reviews in the field of chronic lymphocytic leukemia (CLL) are warranted to supplement the existing analyses focused on specific therapeutic areas.MethodsA systematic literature review was conducted based on literature searches in Medline and EMBASE to summarize the published health economics models related to all types of CLL therapies. Narrative synthesis of relevant studies was performed focusing on compared treatments, patient populations, modelling approaches and key findings.ResultsWe included 29 studies, the majority of which were published between 2016 and 2018, when data from large clinical trials in CLL became available. Treatment regimens were compared in 25 cases, while the remaining four studies considered treatment strategies with more complex patient pathways. Based on the review results, Markov modelling with a simple structure of three health states (progression-free, progressed, death) can be considered as the traditional basis to simulate cost effectiveness. However, more recent studies added further complexity, including additional health states for different therapies (e.g. best supportive care or stem cell transplantation), for progression-free state (e.g. by differentiating between with or without treatment), or for response status (i.e. partial response and complete response).ConclusionsAs personalized medicine is increasingly gaining recognition, we expect that future economic evaluations will also incorporate new solutions, which are necessary to capture a larger number of genetic and molecular markers and more complex patient pathways with individual patient-level allocation of treatment options and thus economic assessments.Peer reviewe