<p>Multivariate Cox analysis of the change in fragment length score (FLS) from baseline to cycle 3 of pembrolizumab. Covariates in clude cohort, PD-L1 expression, and tumor mutation burden.</p>
<p>Examples of cancer-specific methylation score calculation. Cancer-specific methylation scores were computed using the sum of inferred absolute methylation values for all reads overlapping an independently-trained cancer-specific signature. Here, we show examples illustrating how absolute methylation levels are inferred from coverage depths in 300 bp bins while adjusting for the density of CpGs.</p>
Abstract Background The objective of this study was to evaluate the contribution of radiation dose to different intracranial structures on changes in intellectual function for children with brain tumors. Methods We evaluated children with brain tumors treated in 2005–2017 who had longitudinal neuropsychological assessments and available photon dosimetric data (if radiation therapy [RT] given). Full Scale Intelligence Quotient (FSIQ) and index scores were evaluated (perceptual reasoning index [PRI], processing speed index [PSI], verbal comprehension index [VCI], and working memory index [WMI]). Multivariable linear mixed effects models were used to model endpoints, with age at RT and dose to different brain regions as fixed effects and patient-specific random intercepts. P-values (P*) were adjusted for multiple comparisons. Results Sixty-nine patients were included, 56 of whom received RT. Median neuropsychological follow-up was 3.2 years. Right temporal lobe mean dose was strongly associated with decline in FSIQ (P* = 0.005); with each gray increase in mean dose, there was a decrease of 0.052 FSIQ points per year. Dose to 50% (D50) of the supratentorial brain was associated with decline in PSI (P* = 0.006) and WMI (P* = 0.001). Right and left hippocampus D50 were individually strongly associated with declines in VCI (P* = 0.009 for each). Presence of a ventriculoperitoneal shunt decreased FSIQ by 10 points. Conclusions We reported associations between dosimetry to specific brain regions and intellectual outcomes, with suggested avoidance structures during RT planning. These models can help clinicians anticipate changes in neurocognition post-RT and guide selection of an optimal RT plan.
The decision on whether to implement a 20-year screening programme for a cancer requires weighing the harms and costs against the health benefits (such as the number of cancer deaths averted every year). The evidence of the benefits is often based on a single-number summary, such as the mortality reduction over the entire follow-up time in a single trial, or an average of such one-number measures from a meta-analysis of several trials. There are several problems associated with using the traditional one-number summaries from trials to deduce the yearly mortality reductions expected from a sustained screening programme. We here propose using a rate ratio curve, and its complement (a mortality reduction curve), to address the mortality impact (timing, magnitude, and duration) of a screening programme. This curve is easy to interpret, as it shows when mortality reductions begin, how big they are, and how long they last. We illustrate when and how such rate ratio curves from screening trials could be computed, and how they could be used to compare reduction patterns expected with different screening regimens. We encourage trialists to report the necessary data to arrive at such projections.
<p>Overall survival (OS) and progression free survival (PFS) in included patients by cohort. (A) Kaplan-meier curves are shown indicating the OS and PFS of patients in five histology-specific cohorts. (B) Forest plot of the hazard ratios for each cohort in a Cox proportional hazards model, with Cohort A as the reference level.</p>
<p>Predicting survival outcomes using fragment length score (FLS) at baseline and cycle 3 of pembrolizumab. FLS was determined as the mean of the log2 transformed cancer-to-normal ratio of the length of each fragment in a given cfMeDIP-seq sample. At both baseline and cycle 3, patients were split into above- or below-median groups. Survival outcomes are shown, with hazard ratios and p-values adjusted for cohort using a Cox model. PFS analysis at cycle 3 excludes one patient who progressed before the collection of cycle 3 sample.</p>
<p>Multivariate Cox analysis of change in cancer mutation concentration (CMC) from baseline to cycle 3 of pembrolizumab. Covariates include cohort, PD-L1 expression, and tumor mutation burden</p>
<p>Non-negative matrix factorization identifies characteristic cancer-associated signatures of shorter fragment lengths and greater nucleosome core occupancy. (A) Genome-wide fragment lengths were used as features in a two-component non-negative matrix factorization analysis. This revealed a longer and a shorter component. The weight of the shorter was elevated in cell-free DNA of cancer patients relative to normal controls. (B) The distances of fragment ends to nucleosome centers were also used as features in two-component non-negative matrix factorization. This revealed two components with different proportions of intra-nucleosomal fragment ends. The signature with more intra-nucleosomal fragment ends was elevated in the cell-free DNA of cancer patients relative to normal controls. (C) A heatmap showing the localization of fragment ends within the nucleosome core, meaning within 50 bp of nucleosome peaks. Arranging by group and total cfMeDIP-seq score, we observe that those with higher estimated ctDNA levels demonstrated a higher fraction of read ends terminating within the nucleosome core.</p>
Abstract Purpose To determine the prognostic value of sarcopenia measurements done on staging [ 18 F] FDG PET/CT together with metabolic activity of the tumor in patients with adenocarcinoma esophagogastric cancer with surgical treatment. Methods Patients with early stage, surgically treated esophageal adenocarcinoma and available pre-treatment PET/CT were included. The standard uptake value (SUV) and SUV normalized by lean body mass (SUL) were recorded. Skeletal muscle index (SMI) was measured at the L3 level on the CT component of the PET/CT. Sarcopenia was defined as SMI < 34.4cm 2 /m 2 in women and < 45.4cm 2 /m 2 in men. Results Of the included 145 patients. 30% were sarcopenic at baseline. On the univariable Cox proportional hazards analysis, ECOG, surgical T and N staging, Lymphovascular Invasion (LVI) positive lymph nodes and sarcopenia were significant prognostic factors concerning RFS, and OS. On multivariable Cox regression analysis, surgical N staging (p = 0.025) and sarcopenia (p = 0.022) remained significant poor prognostic factors for OS and RFS. Combining the clinical parameters with the imaging derived nutritional evaluation of the patient but not metabolic parameters of the tumor showed improved predictive ability for OS and RFS. Conclusion Combining the patients’ imaging derived sarcopenic status with standard clinical data, but not metabolic parameters offered an overall improved prognostic value concerning OS and RFS.
<p>Predicting survival outcomes using cancer-specific methylation (CSM) scores at baseline and cycle 3 of pembrolizumab. We computed CSM scores across the trial cohort. At both baseline and cycle 3, patients were split into above- and below-median groups. Survival outcomes are shown, with hazard ratios and p-values adjusted for cohort using a Cox model. PFS analysis at cycle 3 excludes one patient who progressed before the collection of the cycle 3 sample.</p>
