Conventional analysis of host chimerism (HC) frequently fails to detect relapse before its clinical manifestation in patients with hematological malignancies after allogeneic stem cell transplantation (allo-SCT). Quantitative PCR (qPCR)-based highly-sensitive chimerism analysis extends the detection limit of conventional (short tandem repeats-based) chimerism analysis from 1 to 0.01% host cells in whole blood. To date, the diagnostic value of highly-sensitive chimerism analysis is hardly defined. Here, we applied qPCR-based chimerism analysis to 901 blood samples of 71 out-patients with hematological malignancies after allo-SCT. Receiver operating characteristics (ROC) curves were calculated for absolute HC values and for the increments of HC before relapse. Using the best cut-offs, relapse was detected with sensitivities of 74 or 85% and specificities of 69 or 75%, respectively. Positive predictive values (PPVs) were only 12 or 18%, but the respective negative predictive values were 98 or 99%. Relapse was detected median 38 or 45 days prior to clinical diagnosis, respectively. Considering also durations of steadily increasing HC of more than 28 days improved PPVs to more than 28 or 59%, respectively. Overall, highly-sensitive chimerism analysis excludes relapses with high certainty and predicts relapses with high sensitivity and specificity more than a month prior to clinical diagnosis.
In this report, we describe four cases of small-cell carcinoma of the lung manifesting as acute hepatic failure. These cases were noteworthy for the presence of hepatomegaly and substantially increased serum lactate dehydrogenase and uric acid levels. The ratio of normalized serum lactate dehydrogenase to normalized serum alanine aminotransferase from the 4 cases reported herein (mean +/- SE, 3.63 +/- 1.10) was significantly greater than the ratio obtained from the 12 cases of nonmalignant fulminant hepatic failure (mean +/- SE, 0.46 +/- 0.18; P < 0.001). Chest radiographs and abdominal imaging studies showed no neoplastic process in three of the four cases. Postmortem examinations disclosed extensive infiltration of the liver by metastatic small-cell carcinoma of the lung. A review of the literature revealed 13 additional similar cases. We conclude that metastatic small-cell carcinoma of the lung should be considered in cases of acute hepatic failure associated with hepatomegaly, substantially increased lactate dehydrogenase levels in comparison with alanine aminotransferase values, and increased uric acid levels even if imaging studies show no lesion. A liver biopsy done early during the hospital course is appropriate for diagnosis and for prevention of inappropriate transfer of the patient to a liver transplant center.
The HercepTest was approved 20 + years ago as the companion diagnostic test for trastuzumab in HER2 amplified/overexpressing breast cancers. Subsequent HER2 immunohistochemistry (IHC) assays followed, including the now most common Ventana 4B5 assay. While this IHC assay has become the clinical standard, its reliability, reproducibility, and accuracy have largely been approved and accepted based on concordance between small numbers of pathologists without validation in a real-world setting. In this study, we evaluate the concordance and inter-rater reliability of scoring HER2 IHC in 170 breast cancer biopsies by 18 breast cancer-specialized pathologists from 15 institutions. We used the ONEST (Observers Needed to Evaluate Subjective Tests) method to determine the plateau of concordance and the minimum number of pathologists needed to estimate inter-rater agreement values for large numbers of raters, as seen in the real-world setting. We report substantial discordance within the intermediate categories (< 1% agreement for 1 + and 3.6% agreement for 2+) in the four-category HER2 IHC scoring system. The discordance within the IHC 0 cases is also substantial with an overall percent agreement (OPA) of only 25% and poor inter-rater reliability metrics (0.49 Fleiss’ kappa, 0.55 intraclass correlation coefficient). This discordance can be partially reduced by using a three-category system (28.8% vs. 46.5% OPA for four and three-category scoring systems respectively). ONEST plots suggest that the OPA for the task of determining a HER2 IHC score 0 from not 0 plateaus statistically around 59.4% at 10 raters. Conversely, at the task of scoring HER2 IHC as 3 + or not 3 + pathologists’ concordance was much higher with an OPA that plateaus at 87.1% with 6 raters. This suggests that legacy HER2 IHC remains valuable for finding HER2 gene amplified patients, but unacceptably discordant in assigning HER2-low or negative status for emerging HER2-low therapies.
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