Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer

Figures

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  Figure 1.. Patients with ischemic stroke associated with active tumor as well as patients with ischemic strokes associated with endocarditis show ischemic strokes affecting multiple territories as well as an increase in inflammatory and cell-lysis indicating blood parameters. The number of large territories affected by ischemic strokes (a), CRP (b), LDH (c), and granulocytes (% GRN, d) in patients without known history of tumor (No. T., green), known neoplastic disease judged as inactive (Inact. T., green), with active tumor (Act. T., blue), or with diagnosis of bacterial endocarditis (Endo, red). Left panels: Stacked box blots with the percentage of patients with ischemic stroke involving >1 territory with the indicated number [progressively darker shades, (a)] or scatter plots (b–d) with CRP in mg/l logarithmized after adding 1 [Ln(CRP + 1), (b)]. Middle panels for (a)–(d): ROC analysis of the number of territories (a), CRP (b), LDH (c), and percent GRN (d). The AUC for active tumors versus no tumor indicated (continuous lines: AUC > 0.5). Right panels: Performance of cutoffs (GRN) to distinguish patients with active tumor from those without known tumor optimized for specificity and…

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  Figure 2.. Performance of the algorithm to identify stroke associated with active cancer based on the previous case-control study and generation of a new algorithm. [(a), left graph] Probabilities for stroke associated with active cancer based on the algorithm of Kassubek et al. 6 in patients without known tumor (No. T., green), with inactive tumor (Inact. T., green), active tumor (Act. T., blue), and endocarditis (Endo., red). The Youden-optimized cutoff generated by comparing strokes without and with active tumor of the present cohort (>0.76) is indicated by the dotted line. (Left middle graph) ROC analysis of the probabilities generated for strokes without active tumor (green line), with active tumor (blue line), or endocarditis (red line) in comparison to the group without cancer. The AUC with 95% confidence interval (95% CI) for patients with active tumor versus no known tumor is indicated. (Middle right panel) Percentage of false-positive (green/red) or correctly positive strokes in each subgroup identified by applying the cutoff of >0.76. (Right panel) Enrichment of stroke associated with active tumor (blue) in the total cohort after exclusion of strokes associated with endocarditis…

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  Figure 3.. Patients with active lung, colorectal, and pancreatic cancer share some characteristics typical of paraneoplastic stroke. (a) Relative frequency of lung, pancreatic and colorectal (blue), as well as breast and prostate cancers (gray) combined from Kassubek et al. 6 and the current cohort compared to the German Cancer Registry. The dotted line indicates no change in frequency. (b) Proportion of multiterritorial strokes in patients without tumors (No. T., green) and with indicated active tumors (lung/colorectal/pancreatic: blue, breast/prostate: gray). Higher numbers of ischemic territories are indicated by darker shades with the number of territories given. (c) Age, (d) blood concentrations of CRP [mg/l, logarithmized after adding the correction factor 1, Ln(CRP + 1)], and (e) LDH and the percentage of GRN among leukocytes in the same groups as in (a). The median and interquartile range in indicated. The median of the cohort without tumors is indicated by dotted lines. Statistical analysis was performed using Bonferroni-corrected Fisher’s exact tests after dichotomization (1–4 territories versus 4 territories) (b) or using Kruskal–Wallis tests with Dunn’s post-tests (c–f) both…

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  Figure 4.. Strokes associated with lung, colorectal, and pancreatic cancer exhibit a unique positive correlation of the number of territories involved with blood CRP levels. The combined cohorts of patients with active lung, colorectal, and pancreatic cancer from Figure 2 were grouped as were the patients with breast and prostate cancers. (a) Proportion of multiterritorial strokes (left panel), age (middle left panel), CRP (middle panel), LDH (middle right panel), as well as the percentage of GRN (right panel) in patients without known tumor and with known inactive tumor (green), breast and prostate cancers combined (breast/prostate, gray), lung, pancreatic and colorectal cancer (Lung/Panc/Colo, blue), and endocarditis (red). The number of territories is indicated by darker shades. For statistical analysis, the exact number of patients with a certain number of territories was used. Statistical analysis was performed using Bonferroni-corrected Fisher’s exact tests after dichotomization [1–2 territories versus 3–4 territories, (a), left panel] or using Kruskal–Wallis tests with Dunn’s post-tests [(a), other panels] both comparing against stroke without tumor. (b) Relationship of the number of…

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  Figure 5.. Optimized model taking into account the differences of mono- and multiterritorial stroke associated with cancer using lung, pancreatic, and colorectal cancer as surrogate parameter to select for paraneoplastic stroke. (a) Distribution of probabilities generated by the multiple logistic regression models for strokes with one territory only (left panel) with CRP and percentage of granulocytes as independent variables or for multiterritorial strokes with number of territories, CRP, age, and sex as independent variables (right panel). Strokes not associated with tumor (No T.) and with inactive Tumor (Inact. T.) are shown in green, strokes either associated with lung, pancreatic, or colorectal cancer (L/P/C) in blue, strokes associated with breast or prostate cancer (Br./Pros.) in gray, and all other active tumors (Oth. act. T.) in brown. The respective cutoffs (1 territory: 0.04131, 2–4 territories: 0.01049) are indicated by dotted lines. The mean and interquartile range for each group is indicated. [(b), left panel] Percentage of strokes with active tumors in the group of strokes with probability below or above the respective cutoff. The percentage of correctly positive strokes…