5 research outputs found
Predicting sinusoidal obstruction syndrome after allogeneic stem cell transplantation with the EASIX biomarker panel
No biomarker panel is established for prediction of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), a major complication of allogeneic stem cell transplantation (alloSCT). We compared the potential of the Endothelial Activation and Stress Index (EASIX), based on lactate dehydrogenase, creatinine, and thrombocytes, with that of the SOS/VOD CIBMTR clinical risk score to predict SOS/VOD in two independent cohorts. In a third cohort, we studied the impact of endothelium-active prophylaxis with pravastatin and ursodeoxycholic acid (UDA) on SOS/VOD risk. The cumulative incidence of SOS/VOD within 28 days after alloSCT in the training cohort (Berlin, 2013-2015, n=446) and in the validation cohort (Heidelberg, 2002-2009, n=380) was 9.6% and 8.4%, respectively. In both cohorts, EASIX assessed at the day of alloSCT (EASIX-d0) was significantly associated with SOS/VOD incidence (p<0.0001), overall survival (OS) and non-relapse mortality (NRM). In contrast, the CIBMTR score showed no statistically significant association with SOS/VOD incidence, and did not predict OS and NRM. In patients receiving pravastatin/UDA, the cumulative incidence of SOS/VOD was significantly lower at 1.7% (p<0.0001, Heidelberg, 2010-2015, n=359) than in the two cohorts not receiving pravastatin/UDA. The protective effect was most pronounced in patients with high EASIX-d0. The cumulative SOS/VOD incidence in the highest EASIX-d0 quartiles were 18.1% and 16.8% in both cohorts without endothelial prophylaxis as compared to 2.2% in patients with pravastatin/UDA prophylaxis (p<0.0001). EASIX-d0 is the first validated biomarker for defining a subpopulation of alloSCT recipients at high risk for SOS/VOD. Statin/UDA endothelial prophylaxis could constitute a prophylactic measure for patients at increased SOS/VOD risk
Validation of a proxyâreported SARCâF questionnaire for current and retrospective screening of sarcopeniaârelated functional impairments
BACKGROUND: The strength, assistance walking, rise from a chair, climb stairs, and falls (SARCâF) questionnaire is a wellâestablished instrument for screening of sarcopenia and sarcopeniaârelated functional impairments. As it is based on selfâreporting, its use precludes patients who are unable to answer the questionnaire as a consequence of severe acute diseases or cognitive impairment. Therefore, we aimed to validate a proxyâreported version of the SARCâF for both adâhoc as well as retrospective screening for severe sarcopeniaârelated functional impairments. METHODS: Patients aged â„60 years completed the SARCâF and performed the short physical performance battery (SPPB) at baseline (T1). Proxies in Cohort A gave a simultaneous assessment of the patients' functional status with the proxyâreported SARCâF at T1 and again, retrospectively, after 3 months (T2). Proxies in Cohort B only completed the SARCâF retrospectively at T2. The questionnaires' performances were assessed through sensitivity/specificity analyses and receiver operating characteristic (ROC) curves. For nonâinferiority analyses, results of both the patientâreported and proxyâreported SARCâF were correlated with the SPPB total score as well as the results of the chairârise test subcategory; the respective correlation coefficients were tested against each other. RESULTS: One hundred and four patients and 135 proxies participated. Using a SPPB score < 9 points as the reference standard, the proxyâreported SARCâF identified patients at high risk for sarcopeniaârelated functional impairment with a sensitivity of 0.81 (adâhoc), 0.88 (retrospective Cohort A), and 0.87 (retrospective Cohort B) as well as a specificity of 0.89 (adâhoc), 0.78 (retrospective Cohort A), and 0.64 (retrospective Cohort B). Areas under the ROC curves were â„ 0.9 for the adâhoc proxyâreported SARCâF and the retrospective proxyâreported SARCâF in both cohorts. The proxyâreported SARCâF showed a nonâinferior correlation with the SPPB compared with the patientâreported SARCâF for adâhoc (P = <0.001) as well as retrospective screening for severe sarcopeniaârelated functional impairment in both Cohorts A (P = 0.007) and B (P = 0.026). CONCLUSIONS: Proxyâreported SARCâF is a valid instrument for both adâhoc as well as retrospective screening for sarcopeniaârelated functional impairment and could become the standard tool for evaluating this risk in older adults with severe acute disease, for example, in patients with quickly evolving haematological conditions
Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial
Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint to provide drug response profiling reports within 7âd was met in 91% of all study participants (Nâ=â80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers
Comparison of Proteomic Technologies for Blood-Based Detection of Colorectal Cancer
Blood-based protein biomarkers are increasingly being explored as supplementary or efficient alternatives for population-based screening of colorectal cancer (CRC). The objective of the current study was to compare the diagnostic potential of proteins measured with different proteomic technologies. The concentrations of protein biomarkers were measured using proximity extension assays (PEAs), liquid chromatography/multiple reaction monitoring–mass spectrometry (LC/MRM-MS) and quantibody microarrays (QMAs) in plasma samples of 56 CRC patients and 99 participants free of neoplasms. In another approach, proteins were measured in serum samples of 30 CRC cases and 30 participants free of neoplasm using immunome full-length functional protein arrays (IpAs). From all the measurements, 9, 6, 35 and 14 protein biomarkers overlapped for comparative evaluation of (a) PEA and LC/MRM-MS, (b) PEA and QMA, (c) PEA and IpA, and (d) LC/MRM-MS and IpA measurements, respectively. Correlation analysis was performed, along with calculation of the area under the curve (AUC) for assessing the diagnostic potential of each biomarker. DeLong’s test was performed to assess the differences in AUC. Evaluation of the nine biomarkers measured with PEA and LC/MRM-MS displayed correlation coefficients >+0.6, similar AUCs and DeLong’s p-values indicating no differences in AUCs for biomarkers like insulin-like growth factor binding protein 2 (IGFBP2), matrix metalloproteinase 9 (MMP9) and serum paraoxonase lactonase 3 (PON3). Comparing six proteins measured with PEA and QMA showed good correlation and similar diagnostic performance for only one protein, growth differentiation factor 15 (GDF15). The comparison of 35 proteins measured with IpA and PEA and 14 proteins analyzed with IpA and LC/MRM-MS revealed poor concordance and comparatively better AUCs when measured with PEA and LC/MRM-MS. The comparison of different proteomic technologies suggests the superior performance of novel technologies like PEA and LC/MRM-MS over the assessed array-based technologies in blood-protein-based early detection of CRC
Confirmatory adaptive group sequential designs for single-arm phase II studies with multiple time-to-event endpoints
Existing methods concerning the assessment of long-term survival outcomes in one-armed trials are commonly restricted to one primary endpoint. Corresponding adaptive designs suffer from limitations regarding the use of information from other endpoints in interim design changes. Here we provide adaptive group sequential one-sample tests for testing hypotheses on the multivariate survival distribution derived from multi-state models, while making provision for data-dependent design modifications based on all involved time-to-event endpoints. We explicitly elaborate application of the methodology to one-sample tests for the joint distribution of (i) progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model, and (ii) time to toxicity and time to progression while accounting for death as a competing event. Large sample distributions are derived using a counting process approach. Small sample properties are studied by simulation. An already established multi-state model for non-small cell lung cancer is used to illustrate the adaptive procedure