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Rituximab / Gallium-67 / Radiolabeling / Quality control / DOTASummary. Rituximab was successively labeled with [ 67 Ga]-gallium chloride. The macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 • C using DOTA, N-hydroxy succinimide (NHS) in CH 2 Cl 2 . DOTA-Rituximab was obtained by the addition of 1 mL of a Rituximab pharmaceutical solution (5 mg/mL, in phosphate buffer, pH = 7.8) to a glass tube pre-coated with DOTA-NHS (0.01-0.1 mg) at 25 • C with continuous mild stirring for 15 h. Radiolabeling was performed at 37 • C in 3 h. Radiothin layer chromatography showed an overall radiochemical purity of 90%-95% at optimized conditions (specific activity = 30 GBq/mg, labeling efficacy; 82%). The final isotonic 67 Ga-DOTA-rituximab complex was checked by gel electrophoresis for radiolysis. Radio-TLC was performed to ensure that only one species was present after filtration through a 0.22 µm filter. Preliminary biodistribution studies in normal rat model performed to determine complex distribution of the radioimmunoconjugate up to 28 h.

Background Today, there are a lot of markers on the prognosis and diagnosis of complex diseases such as primary breast cancer. However, our understanding of the drivers that influence cancer aggression is limited. Methods In this work, we study somatic mutation data consists of 450 metastatic breast tumor samples from cBio Cancer Genomics Portal. We use four software tools to extract features from this data. Then, an ensemble classifier (EC) learning algorithm called EARN (Ensemble of Artificial Neural Network, Random Forest, and non-linear Support Vector Machine) is proposed to evaluate plausible driver genes for metastatic breast cancer (MBCA). The decision-making strategy for the proposed ensemble machine is based on the aggregation of the predicted scores obtained from individual learning classifiers to be prioritized homo sapiens genes annotated as protein-coding from NCBI. Results This study is an attempt to focus on the findings in several aspects of MBCA prognosis and diagnosis. First, drivers and passengers predicted by SVM, ANN, RF, and EARN are introduced. Second, biological inferences of predictions are discussed based on gene set enrichment analysis. Third, statistical validation and comparison of all learning methods are performed by some evaluation metrics. Finally, the pathway enrichment analysis (PEA) using ReactomeFIVIz tool (FDR < 0.03) for the top 100 genes predicted by EARN leads us to propose a new gene set panel for MBCA. It includes HDAC3, ABAT, GRIN1, PLCB1, and KPNA2 as well as NCOR1, TBL1XR1, SIRT4, KRAS, CACNA1E, PRKCG, GPS2, SIN3A, ACTB, KDM6B, and PRMT1. Furthermore, we compare results for MBCA to other outputs regarding 983 primary tumor samples of breast invasive carcinoma (BRCA) obtained from the Cancer Genome Atlas (TCGA). The comparison between outputs shows that ROC-AUC reaches 99.24% using EARN for MBCA and 99.79% for BRCA. This statistical result is better than three individual classifiers in each case. Conclusions This research using an integrative approach assists precision oncologists to design compact targeted panels that eliminate the need for whole-genome/exome sequencing. The schematic representation of the proposed model is presented as the Graphic abstract. Graphic abstract

Ensemble methods try to improve performance via integrating different kinds of input data, features or learning algorithms. In addition to other areas, they are finding their applications in cancer prognosis and diagnosis. However, in this area, the research community is lagging behind the technology. A systematic review along with a taxonomy on ensemble methods used in cancer prognosis and diagnosis, can pave the way for the research community to keep pace with the technology and even lead trend. In this paper, we first present an overview on existing relevant surveys, and highlight their shortcomings, which raise the need for a new survey focusing on Ensemble Classifiers (ECs) used for the diagnosis and prognosis of different cancer types. Then we exhaustively review the existing methods, including the traditional ones as well as those based on deep learning. The review leads to a taxonomy as well as the identification of the bast-studied cancer types, the best ensemble methods used for the related purposes, the prevailing input data types, the most common decision making strategies, and the common evaluating methodologies. Moreover, we establish future directions for researchers interested in following existing research trends or working on less-studied aspects of the area.

BackgroundToday, there are a lot of markers on the prognosis and diagnosis of complex diseases such as primary breast cancer. However, our understanding of the drivers that influence cancer aggression is limited.MethodsIn this work, we study somatic mutation data consists of 450 metastatic breast tumor samples from cBio Cancer Genomics Portal. We use four software tools to extract features from this data. Then, an ensemble classifier (EC) learning algorithm called EARN (Ensemble of Artificial Neural Network, Random Forest, and non-linear Support Vector Machine) is proposed to evaluate plausible driver genes for metastatic breast cancer (MBCA). ResultsThis study is an attempt to focus on the findings in several aspects of MBCA prognosis and diagnosis. First, drivers and passengers predicted by SVM, ANN, RF, and EARN are introduced. Second, biological inferences of predictions based on gene set enrichment analysis are discussed. Third, statistical validation and comparison of all learning methods based on evaluation metrics are done. Finally, the pathway enrichment analysis (PEA) using ReactomeFIVIz tool (FDR<0.03) for the top 100 genes predicted by EARN leads us to propose a new gene set panel for MBCA, including HDAC3, ABAT, GRIN1, PLCB1, and KPNA2 as well as NCOR1, TBL1XR1, SIRT4, KRAS, CACNA1E, PRKCG, GPS2, SIN3A, ACTB, KDM6B, and PRMT1. Furthermore, we compare results for MBCA to other outputs regarding 983 primary tumor samples of breast invasive carcinoma (BRCA) obtained from the Cancer Genome Atlas (TCGA). The comparison between outputs shows that ROC-AUC reached 99.24% using EARN for MBCA and 99.79% for BRCA. This statistical result is better than three individual classifiers in each case.ConclusionsThis research using an integrative approach assists precision oncologists to design compact targeted panels that eliminate the need for whole-genome/exome sequencing.

Background: Ensemble methods are supervised learning approaches that integrate different types of data or multiple individual classifiers. It has been shown that these methods can improve professional performance.Methods: This study is an attempt to provide an in-depth review on 45 most relevant articles and aims to introduce 42 ensemble classifier (EC) machine learning methods used for the detection of 18 different types of cancer. Compared to other types of cancer, breast cancer, and the 22 ensemble methods introduced for its identification, is extensively investigated. The purpose of this study is to identify, map, and analyze the current academic discourse on EC machine learning methods in order to: 1. identify overarching themes emerging from empirical studies as regards EC methods, 2. determine their input data and decision-making strategies, and 3. evaluate relevant statistical procedures.Results: By comparing various approaches, we can introduce Relevance Vector Machine (RVM)-based ensemble learning method that can provide optimal solutions for problems such as curse the dimensionality and high-dimensionality of feature space without missing data values.Conclusions: To obtain robust performance and achieve better results, it is tactfully suggested to use multi-omics data integration, which has demonstrated to identify cancers and their subtypes more efficiently.

Background Ensemble methods are supervised learning approaches that integrate different types of data or multiple individual classifiers. It has been shown that these methods can improve professional performance. Methods This study is an attempt to provide an in-depth review on 45 most relevant articles and aims to introduce 42 ensemble classifier (EC) machine learning methods used for the detection of 18 different types of cancer. Compared to other types of cancer, breast cancer, and the 22 ensemble methods introduced for its identification, is extensively investigated. The purpose of this study was to identify, map, and analyze the current academic discourse on EC machine learning methods in order to: 1. identify overarching themes emerging from empirical studies regarding EC methods, 2. determine their input data and decision-making strategies, and 3. evaluate relevant statistical procedures. Results By comparing various approaches, we can introduce Relevance Vector Machine (RVM)-based ensemble learning method that can provide optimal solutions for problems such as curse the dimensionality and high-dimensionality of feature space without missing data values. Conclusions To obtain robust performance and achieve better results, it is tactfully suggested to use multi-omics data integration, which has demonstrated to identify cancers and their subtypes more efficiently.