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The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep-learning algorithms for whole-slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver-metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting preclinical and clinical research perspectives., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the "canonical" Hh pathway, in which ligand binding to the receptor PTCH1 initiates a signaling cascade that culminates in the activation of the GLI transcription factors, is mainly organized in a paracrine manner, both in the healthy colon and in CRC. Such canonical Hh signals largely act as tumor suppressors. In addition, stromal Hh signaling has complex immunomodulatory effects in the intestine with a potential impact on carcinogenesis. In contrast, non-canonical Hh activation may have tumor-promoting roles in a subset of CRC tumor cells. In this review, we attempt to summarize the current knowledge of the Hh pathway in CRC, with a focus on the tumor-suppressive role of canonical Hh signaling in the stroma. Despite discouraging results from clinical trials using Hh inhibitors in CRC and other solid cancers, we argue that a more granular understanding of Hh signaling might allow the exploitation of this key morphogenic pathway for cancer therapy in the future., Competing Interests: The authors declare no conflict of interest. The funders had no role in the writing of the manuscript, or in the decision to publish the results.

Objectives: The objective of this study was to evaluate the spatial relationship between colorectal cancer (CRC) mortality and ambulatory surgery center (ASC) density in Pennsylvania's 67 counties., Study Design: This was an ecological study., Methods: Age-adjusted CRC mortality rates were linked to ASC densities per 1,000 people. The data set was analyzed using global, local, and regional Moran's I, to test for randomness in CRC mortality and ASC density., Results: CRC mortality rates (median: 15.30 per 100,000 of the US 2000 standard million population) exhibited hot spots in rural Pennsylvania counties. ASC densities (median: 0.35 providers/km 2 per 1,000 people) showed hot spots in urban southeastern Pennsylvania and cold spots in northern Pennsylvania., Conclusions: CRC mortality rates tended to cluster in rural northern Pennsylvania counties; ASC density tended to cluster in urban southeastern counties, indicating a spatial disparity between needed and provided healthcare resources. There is a need for public health and health system changes to increase the availability of CRC services to rural communities., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)