Purpose: Imaging mass cytometry (IMC) uses metalconjugated antibodies to provide multidimensional, objective measurement of protein targets. We used this highthroughput platform to perform an 18-plex assessment of HER2 ICD/ECD, cytotoxic T-cell infiltration and other structural and signaling proteins in a cohort of patients treated with trastuzumab to discover associations with trastuzumab benefit. Experimental Design: An antibody panel for detection of 18 targets (pan-cytokeratin, HER2 ICD, HER2 ECD, CD8, vimentin, cytokeratin 7, b-catenin, HER3, MET, EGFR, ERK 1-2, MEK 1-2, PTEN, PI3K p110 a, Akt, mTOR, Ki67, and Histone H3) was used with a selection of trastuzumab-treated patients from the Hellenic Cooperative Oncology Group 10/ 05 trial (n ¼ 180), and identified a case-control series. Results: Patients that recurred after adjuvant treatment with trastuzumab trended toward a decreased fraction of HER2 ECD pixels over threshold compared with cases without recurrence (P ¼ 0.057). After exclusion of the lowest HER2 expressers, 5-year recurrence events were associated with reduced total extracellular domain (ECD)/intracellular domain (ICD) ratio intensity in tumor (P ¼ 0.044). These observations are consistent with our previous work using quantitative immunofluorescence, but represent the proof on identical cell content. We also describe the association of the ECD of HER2 with CD8 T-cell infiltration on the same slide. Conclusions: The proximity of CD8 cells as a function of the expression of the ECD of HER2 provides further evidence for the role of the immune system in the mechanism of action of trastuzumab.
Context.— Large-cell transformation (LCT) of indolent B-cell lymphomas, such as follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL), signals a worse prognosis, at which point aggressive chemotherapy is initiated. Although LCT is relatively straightforward to diagnose in lymph nodes, a marrow biopsy is often obtained first given its ease of procedure, low cost, and low morbidity. However, consensus criteria for LCT in bone marrow have not been established. Objective.— To study the accuracy and reproducibility of a trained convolutional neural network in identifying LCT, in light of promising machine learning tools that may introduce greater objectivity to morphologic analysis. Design.— We retrospectively identified patients who had a diagnosis of FL or CLL who had undergone bone marrow biopsy for the clinical question of LCT. We scored morphologic criteria and correlated results with clinical disease progression. In addition, whole slide scans were annotated into patches to train convolutional neural networks to discriminate between small and large tumor cells and to predict the patient's probability of transformation. Results.— Using morphologic examination, the proportion of large lymphoma cells (≥10% in FL and ≥30% in CLL), chromatin pattern, distinct nucleoli, and proliferation index were significantly correlated with LCT in FL and CLL. Compared to pathologist-derived estimates, machine generated quantification demonstrated better reproducibility and stronger correlation with final outcome data. Conclusions.— These histologic findings may serve as indications of LCT in bone marrow biopsies. The pathologist—augmented with machine system appeared to be the most predictive, arguing for greater efforts to validate and implement these tools to further enhance physician practice.
Word2vec introduced by Mikolov et al. is a word embedding method that is widely used in natural language processing. Despite its success and frequent use, a strong theoretical justification is still lacking. The main contribution of our paper is to propose a rigorous analysis of the highly nonlinear functional of word2vec. Our results suggest that word2vec may be primarily driven by an underlying spectral method. This insight may open the door to obtaining provable guarantees for word2vec. We support these findings by numerical simulations. One fascinating open question is whether the nonlinear properties of word2vec that are not captured by the spectral method are beneficial and, if so, by what mechanism.
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