Computational methods for metastasis detection in lymph nodes and characterization of the metastasis-free lymph node microarchitecture: A systematic-narrative hybrid review.

Background: Histological examination of tumor draining lymph nodes (LNs) plays a vital role in cancer staging and prognostication. However, as soon as a LN is classed as metastasis-free, no further investigation will be performed and thus, potentially clinically relevant information detectable in tumor-free LNs is currently not captured. Objective: To systematically study and critically assess methods for the analysis of digitized histological LN images described in published research. Methods: A systematic search was conducted in several public databases up to December 2023 using relevant search terms. Studies using brightfield light microscopy images of hematoxylin and eosin or immunohistochemically stained LN tissue sections aiming to detect and/or segment LNs, their compartments or metastatic tumor using artificial intelligence (AI) were included. Dataset, AI methodology, cancer type, and study objective were compared between articles. Results: A total of 7201 articles were collected and 73 articles remained for detailed analyses after article screening. Of the remaining articles, 86% aimed at LN metastasis identification, 8% aimed at LN compartment segmentation, and remaining focused on LN contouring. Furthermore, 78% of articles used patch classification and 22% used pixel segmentation models for analyses. Five out of six studies (83%) of metastasis-free LNs were performed on publicly unavailable datasets, making quantitative article comparison impossible. Conclusions: Multi-scale models mimicking multiple microscopy zooms show promise for computational LN analysis. Large-scale datasets are needed to establish the clinical relevance of analyzing metastasis-free LN in detail. Further research is needed to identify clinically interpretable metrics for LN compartment characterization.

The clinical importance of the host anti-tumour reaction patterns in regional tumour draining lymph nodes in patients with locally advanced resectable gastric cancer: a systematic review and meta-analysis.

BACKGROUND: The status of regional tumour draining lymph nodes (LN) is crucial for prognostic evaluation in gastric cancer (GaC) patients. Changes in lymph node microarchitecture, such as follicular hyperplasia (FH), sinus histiocytosis (SH), or paracortical hyperplasia (PH), may be triggered by the anti-tumour immune response. However, the prognostic value of these changes in GaC patients is unclear. METHODS: A systematic search in multiple databases was conducted to identify studies on the prognostic value of microarchitecture changes in regional tumour-negative and tumour-positive LNs measured on histopathological slides. Since the number of GaC publications was very limited, the search was subsequently expanded to include junctional and oesophageal cancer (OeC). RESULTS: A total of 28 articles (17 gastric cancer, 11 oesophageal cancer) met the inclusion criteria, analyzing 26,503 lymph nodes from 3711 GaC and 1912 OeC patients. The studies described eight different types of lymph node microarchitecture changes, categorized into three patterns: hyperplasia (SH, FH, PH), cell-specific infiltration (dendritic cells, T cells, neutrophils, macrophages), and differential gene expression. Meta-analysis of five GaC studies showed a positive association between SH in tumour-negative lymph nodes and better 5-year overall survival. Pooled risk ratios for all LNs showed increased 5-year overall survival for the presence of SH and PH. CONCLUSIONS: This systematic review suggests that sinus histiocytosis and paracortical hyperplasia in regional tumour-negative lymph nodes may provide additional prognostic information for gastric and oesophageal cancer patients. Further studies are needed to better understand the lymph node reaction patterns and explore their impact of chemotherapy treatment and immunotherapy efficacy.

3D Cell Culture-Based Global miRNA Expression Analysis Reveals miR-142-5p as a Theranostic Biomarker of Rectal Cancer Following Neoadjuvant Long-Course Treatment.

Altered expression of miRNAs in tumor tissue encourages the translation of this specific molecular pattern into clinical practice. However, the establishment of a selective biomarker signature for many tumor types remains an inextricable challenge. For this purpose, a preclinical experimental design, which could maintain a fast and sensitive discovery of potential biomarkers, is in demand. The present study suggests that the approach of 3D cell cultures as a preclinical cancer model that is characterized to mimic a natural tumor environment maintained in solid tumors could successfully be employed for the biomarker discovery and validation. Subsequently, in this study, we investigated an environment-dependent miRNA expression changes in colorectal adenocarcinoma DLD1 and HT29 cell lines using next-generation sequencing (NGS) technology. We detected a subset of 16 miRNAs differentially expressed in both cell lines cultivated in multicellular spheroids compared to expression levels in cells grown in 2D. Furthermore, results of in silico miRNA target analysis showed that miRNAs, which were differentially expressed in both cell lines grown in MCS, are involved in the regulation of molecular mechanisms implicated in cell adhesion, cell-ECM interaction, and gap junction pathways. In addition, integrins and platelet-derived growth factor receptors were determined to be the most significant target genes of deregulated miRNAs, which was concordant with the environment-dependent gene expression changes validated by RT-qPCR. Our results revealed that 3D microenvironment-dependent deregulation of miRNA expression in CRC cells potentially triggers essential molecular mechanisms predominantly including the regulation of cell adhesion, cell-cell, and cell-ECM interactions important in CRC initiation and development. Finally, we demonstrated increased levels of selected miR-142-5p in rectum tumor tissue samples after neoadjuvant long course treatment compared to miR-142-5p expression levels in tumor biopsy samples collected before the therapy. Remarkably, the elevation of miR-142-5p expression remained in tumor samples compared to adjacent normal rectum tissue as well. Therefore, the current study provides valuable insights into the molecular miRNA machinery of CRC and proposes a potential miRNA signature for the assessment of CRC in further clinical research.