Francesco Corcione

Chronic inflammation and immune remodeling are key features of colorectal cancer (CRC) development and progression, particularly because of the high level of microbiome presence. Among inflammatory mediators, CCL2 has been implicated in the recruitment of monocytes and tumor-associated macrophages, supporting its potential role as a marker of CRC-associated inflammatory remodeling. Therefore, we evaluated nine circulating inflammatory mediators, including CCL2, to assess their potential diagnostic value in patients with CRC. The study included 96 individuals, comprising 52 CRC patients and 44 healthy controls. Plasma cytokine levels were measured using the ProteinSimple Ella microfluidic immunoassay platform, and analyses were also stratified according to sex and BMI category (BMI < 25 vs. ≥25 kg/m²). Patients with CRC had significantly higher levels of CCL2 and IL-6 than healthy controls (p-value < 0.001), regardless of gender or overweight or obesity, confirming a chronic pro-tumor inflammatory profile. Among all markers, CCL2 showed strong exploratory diagnostic performance with an AUC of 0.918, 90.4% sensitivity, and 90.9% specificity (cut-off 436.5 pg/mL). This study highlights the central role of CCL2 as a candidate marker of systemic chronic inflammation associated with colorectal cancer.

Colorectal cancer is the third leading cause of death from neoplasia worldwide. Thanks to new screening programs, we are now seeing an increase in Early Onset of ColoRectal Cancer (EOCRC) in patients below the age of 50. Herein, we report a clinical case of a woman affected by EOCRC. This case illustrates the importance of genetic predisposition testing also in tumor patients. Indeed, for our patient, we used a combined approach of multiple molecular and cellular biology technologies that revealed the presence of an interesting novel variant in the SMARCA4 gene. The latter gene is implicated in damage repair processes and related, if mutated, to the onset of various tumor types. In addition, we stabilized Patient-Derived Organoids from the tumor tissue of the same patient and the result confirmed the presence of this novel pathogenic variant that has never been found before even in early onset cancer. In conclusion, with this clinical case, we want to underscore the importance of including patients even those below the age of 50 years in appropriate screening programs which should also include genetic tests for predisposition to early onset cancers.

Colorectal cancer is one of the most lethal cancers because of late diagnosis and challenges in the selection of therapy options. The histopathological diagnosis of colon adenocarcinoma is hindered by poor reproducibility and a lack of standard examination protocols required for appropriate treatment decisions. In the current study, using state-of-the-art approaches on benchmark datasets, we analyzed different architectures and ensembling strategies to develop the most efficient network combinations to improve binary and ternary classification. We propose an innovative two-stage pipeline approach to diagnose colon adenocarcinoma grading from histological images in a similar manner to a pathologist. The glandular regions were first segmented by a transformer architecture with subsequent classification using a convolutional neural network (CNN) ensemble, which markedly improved the learning efficiency and shortened the learning time. Moreover, we prepared and published a dataset for clinical validation of the developed artificial neural network, which suggested the discovery of novel histological phenotypic alterations in adenocarcinoma sections that could have prognostic value. Therefore, AI could markedly improve the reproducibility, efficiency, and accuracy of colon cancer diagnosis, which are required for precision medicine to personalize the treatment of cancer patients.

ERK1/2 phosphorylation is frequently downregulated in the early phase of colon tumorigenesis with subsequent activation of ERK5. In the current work, we studied the advantages of ERK1/2 downregulation for tumor growth by dissecting the individual functions of ERK1 and ERK2. The patient sample data demonstrated decreased ERK1/2 phosphorylation in the early phase of tumorigenesis followed by increased phosphorylation in late-stage colon adenocarcinomas with intratumoral invasion or metastasis. In vitro results indicated that SOD3-mediated coordination of small GTPase RAS regulatory genes inhibited RAS-ERK1/2 signaling. In vitro and in vivo studies suggested that ERK2 has a more prominent role in chemotactic invasion, collective migration, and cell proliferation than ERK1. Of note, simultaneous ERK1 and ERK2 expression inhibited collective cell migration and proliferation but tended to promote invasion, suggesting that ERK1 controls ERK2 function. According to the present data, phosphorylated ERK1/2 at the early phase of colon adenocarcinoma limits tumor mass expansion, whereas reactivation of the kinases at the later phase of colon carcinogenesis is associated with the initiation of metastasis. Additionally, our results suggest that ERK1 is a regulatory kinase that coordinates ERK2-promoted chemotactic invasion, collective migration, and cell proliferation. Our findings indicate that ROS, especially H₂O₂, are associated with the regulation of ERK1/2 phosphorylation in colon cancer by either increasing or decreasing kinase activity. These data suggest that ERK2 has a growth-promoting role and ERK1 has a regulatory role in colon tumorigenesis, which could lead to new avenues in the development of cancer therapy.

ERK1/2 phosphorylation is frequently downregulated in the early phase of colon tumorigenesis with subsequent activation of ERK5. In the current work, we studied the advantage of ERK1/2 downregulation for tumor growth by dissecting the individual functions of ERK1 and ERK2. The patient sample data demonstrated decreased ERK1/2 phosphorylation in the early phase of tumorigenesis followed by upregulation of the phosphorylation in late-stage colon adenocarcinomas with intratumoral invasion or metastasis. In vitro results indicated SOD3-mediated coordination of small GTPase RAS regulatory genes in the inhibition of RAS-ERK1/2 signaling. In vitro and in vivo studies suggested that ERK2 has a more prominent role in chemotactic invasion, collective migration, and cell proliferation than ERK1. Noteworthily, simultaneous ERK1 and ERK2 expression inhibited collective cell migration and proliferation but tended to promote invasion, therefore suggesting that ERK1 controls ERK2 function. According to the present data, phosphorylated ERK1/2 at the early phase of colon adenocarcinoma limits tumor mass expansion, whereas reactivation of the kinases at the later phase of colon carcinogenesis is associated with the initiation of metastasis. Additionally, our results suggest that ERK1 is a regulatory kinase, which coordinates ERK2-promoted chemotactic invasion, collective migration, and cell proliferation. Our findings indicate that ROS, especially H2O2, are associated with the regulation of ERK1/2 phosphorylation in colon cancer either increasing or decreasing the kinase activity. The data suggesting a growth-promoting role for ERK2 and a regulatory role for ERK1 could result in new avenues in the developmental strategies for cancer therapy.

The recurrence rate in patients who undergo surgery for abdominal wall hernias (AWHs) is high. AWHs have been hypothesized to be a disease of the extracellular matrix, which is supported by evidence showing a high incidence of AWHs in patients with connective tissue disorders. This study aimed to investigate the most recent literature studies describing the levels of several matrix metalloproteinases (MMPs) in the blood and fascia, with the objective of better clarifying the pathogenetic role of matrix metalloproteinases (MMPs) and their inhibitors in inguinal hernias (IHs). A systematic literature search was conducted using the PubMed, Scopus, and Web of Science electronic databases to identify eligible studies. The identified studies were included in the analysis, and a qualitative synthesis of the results is provided to describe the most recent findings. Seventeen studies were included. An association between MMP-2 and direct IHs has also been demonstrated. MMP-1, MMP-2, MMP-9, MMP-12, and MMP-13 levels were increased in both the serum and fascia of patients with IHs. The analysis of inhibitors showed an increase in tissue inhibitors of metalloproteinases (TIMPs), specifically TIMP-1 in IHs, particularly in direct hernias, and a reduction in TIMP-2 in the biopsy samples of the transversalis fascia. In contrast, a reduction in TIMP-1 and an increase in TIMP-2 levels have been reported only in the serum of patients with IHs. Metalloproteinases play a crucial role in the pathogenesis of IHs. The analysis of other molecules, such as TIMPs or their correlation with specific genes, is enhancing our understanding of the pathophysiology of IHs. However, more prospective studies, including comprehensive clinical and laboratory data collection, are required to confirm the relationship between the studied biomarkers and the risk of IHs.

Reoperation for recurrent papillary thyroid cancer (RPTC) is much more complex than primary surgery is, with a higher rate of complications. We describe, for the first time, the use of the Orbeye™ surgical microscope/exoscope for the treatment of RPTC with lymphadenectomy. This system offers 4K, three-dimensional magnified and illuminated imaging without the need for eyepieces. Magnification of the field of view facilitates a more precise dissection, preserving the anatomical structure. Currently, the Orbeye™ is regularly used in neurosurgery; however, its potential in conventional open surgery has not yet been fully exploited. Owing to its magnification capacity, the Orbeye™ exoscope is a valuable tool to help surgeons identify and preserve the integrity of the recurrent laryngeal nerves and parathyroids during thyroid surgery.