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Fee Klupp,1 Christina Giese,1 Niels Halama,2 Clemens Franz,1 Felix Lasitschka,3,4 Arne Warth,3 Thomas Schmidt,1 Matthias Kloor,5 Alexis Ulrich,1 Martin Schneider1 1Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany; 2National Center for Tumor Diseases, Medical Oncology and Internal Medicine VI, Tissue Imaging and Analysis Center, Bioquant, University of Heidelberg, Heidelberg 69120, Germany; 3Institute of Pathology, University of Heidelberg, Heidelberg 69120, Germany; 4Tissue Bank of the National Center for Tumor Diseases, Heidelberg 69120, Germany; 5Department of Applied Tumor Biology, German Cancer Research Center, Heidelberg 69120, Germany Purpose: Smurf2 is a member of the homologous to E6-AP carboxyl terminus family of E3 ubiquitin ligases. Changes in their expression pattern are known to contribute to tumorigenesis. Smurf2 plays a decisive role in cell differentiation, proliferation, and migration and exhibits a dual role in cancer – functioning as both oncogene and tumor suppressor. Dysregulation of Smurf2 in different cancer types has been described, besides colorectal cancer (CRC). We therefore examined the expression and oncogenic potential of Smurf2 in human CRC patients.Materials and methods: Expression levels of Smurf2 were analyzed via qRT-PCR in CRC specimens and healthy mucosa from 98 patients who had undergone surgery due to CRC. Spatial expression of Smurf2 was additionally studied by immunohistochemistry. siRNA-mediated knockdown of Smurf2 was applied for migration and invasion assays in DLD-1 and SW-480 cells.Results: Smurf2 was significantly overexpressed in CRC tissue compared to corresponding healthy colon mucosa. Smurf2 expression levels differed significantly between microsatellite instable (MSI) and microsatellite stable (MSS) CRC. In patients suffering from MSS CRC, high tumoral expression of Smurf2 was significantly associated with impaired overall survival. Consistently, in vitro analysis revealed that knockdown of Smurf2 reduced the invasive and migratory potential of MSS CRC cells.Conclusion: Smurf2 expression is upregulated in CRC specimens and affects survival dependent on patients’ MSI status. Moreover, Smurf2 supports cancer cell migration and invasion, collectively suggesting an oncogenic function in CRC. Keywords: Smurf2, colorectal cancer, MSS status, prognosis, biomarker

Background: Tumour-associated stroma has a critical role in tumour proliferation. Our aim was to determine a specific protein expression profile of stromal angiogenic cytokines and matrix metalloproteinases (MMPs) to identify potential biomarkers or new therapy targets.Methods: Frozen tissue of primary colorectal cancer (n=25), liver (n=25) and lung metastases (n=23) was laser-microdissected to obtain tumour epithelial cells and adjacent tumour-associated stroma. Protein expression of nine angiogenic cytokines and eight MMPs was analysed using a multiplex-based protein assay.Results: We found a differential expression of several MMPs and angiogenic cytokines in tumour cells compared with adjacent tumour stroma. Cluster analysis displayed a tumour-site-dependent stromal expression of MMPs and angiogenic cytokines. Univariate analysis identified stromal MMP-2 and MMP-3 in primary colorectal cancer, stromal MMP-1, -2, -3 and Angiopoietin-2 in lung metastases and stromal MMP-12 and VEGF in liver metastases as prognostic markers (P>0.05, respectively). Furthermore, stroma-derived Angiopoietin-2 proved to be an independent prognostic marker in colorectal lung metastases.Conclusion: Expression of MMPs and angiogenic cytokines in tumour cells and adjacent tumour stroma is dependent on the tumour site. Stroma-derived MMPs and angiogenic cytokines may be useful prognostic biomarkers. These data can be helpful to identify new agents for a targeted therapy in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Leiomyomatosis peritonealis disseminata (LPD) is defined as the occurrence of multiple tumorous intraabdominal lesions, which are myomatous nodules. LPD is a rare disease with only about 100 cases reported. The usual course of LPD is benign with the majority of the patients being premenopausal females. Only two cases involving men have been reported, no syndrome or familial occurrence of LPD has been described. Case presentation We describe a Caucasian-American family in which six members (three men) are diagnosed with Leiomyomatosis peritonealis disseminata (LPD) and three deceased family members most likely had LPD (based on the autopsy reports). Furthermore we describe the association of LPD with Raynaud's syndrome and Prurigo nodularis. Conclusion Familial clustering of Leiomyomatosis peritonealis disseminata (LPD) has not been reported so far. The etiology of LPD is unknown and no mode of inheritance is known. We discuss possible modes of inheritance in the presented case, taking into account the possibility of a genetic syndrome. Given the similarity to other genetic syndromes with leiomyomatosis and skin alterations, we describe possible similar genetic pathomechanisms.

Background: Microsatellite instability (MSI) status and tumour-infiltrating lymphocytes (TIL) are established prognostic factors in colorectal cancer. Previous studies evaluating the combination of TIL and MSI status identified distinct colorectal cancer subtypes with unique prognostic associations. However, these studies were often limited by sample size, particularly for MSI-high (MSI-H) tumours, and there is no comprehensive summary of the available evidence. We aimed to review the literature to compare the survival outcomes associated with the subtypes derived from the integrated MSI-TIL classification in patients with colorectal cancer., Methods: In this systematic review and network meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Library without language restrictions, for articles published between Jan 1, 1990, and March 13, 2024. Patient cohorts comparing different combinations of TIL (high or low) and MSI status (MSI or microsatellite stable [MSS]) in patients with surgically resected colorectal cancer were included. Studies were excluded if they focused on neoadjuvant therapy or on other immune markers such as B cells or macrophages. Methodological quality assessment was done with the Newcastle-Ottawa scale; data appraisal and extraction was done independently by two reviewers. Summary estimates were extracted from published reports. The primary outcomes were overall survival, disease-free survival, and cancer-specific survival. A frequentist network meta-analysis was done to compare hazard ratios (HRs) and 95% CI for each outcome. The MSI-TIL subgroups were prognostically ranked based on P-score, bias, magnitude, and precision of associations with each outcome. The protocol is registered with PROSPERO (CRD42023461108)., Findings: Of 302 studies initially identified, 21 studies (comprising 14 028 patients) were included in the systematic review and 19 (13 029 patients) in the meta-analysis. Nine studies were identified with a low risk of bias and the remaining ten had a moderate risk of bias. The MSI-TIL-high (MSI-TIL-H) subtype exhibited longer overall survival (HR 0·45, 95% CI 0·34-0·61; I 2 =77·7%), disease-free survival (0·43, 0·32-0·58; I 2 =61·6%), and cancer-specific survival (0·53, 0·43-0·66; I 2 =0%), followed by the MSS-TIL-H subtype for overall survival (HR 0·53, 0·41-0·69; I 2 =77·7%), disease-free survival (0·52, 0·41-0·64; I 2 =61·6%), and cancer-specific survival (0·55, 0·47-0·64; I 2 =0%) than did patients with MSS-TIL-low tumours (MSS-TIL-L). Patients with the MSI-TIL-L subtype had similar overall survival (0·88, 0·66-1·18; I 2 =77·7%) and disease-free survival (0·93, 0·69-1·26; I 2 =61·6%), but a modestly longer cancer-specific survival (0·72, 0·57-0·90; I 2 =0%) than did the MSS-TIL-L subtype. Results from the direct and indirect evidence were strongly congruous., Interpretation: The findings from this network meta-analysis suggest that better survival was only observed among patients with TIL-H colorectal cancer, regardless of MSI or MSS status. The integrated MSI-TIL classification should be further explored as a predictive tool for clinical decision-making in early-stage colorectal cancer., Funding: German Research Council (HO 5117/2-2)., Competing Interests: Declaration of interests MH received third-party funding by German Research Council (HO 5117/2-2). The other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Chemokines orchestrate many aspects of tumorigenic processes such as angiogenesis, apoptosis and metastatic spread, and related receptors are expressed on tumor cells as well as on inflammatory cells (e.g., tumor-infiltrating T cells, TILs) in the tumor microenvironment. Expressional changes of chemokines and their receptors in solid cancers are common and well known, especially in affecting colorectal cancer patient outcomes. Therefore, the aim of this current systematic review and meta-analysis was to classify chemokines as a prognostic biomarker in colorectal cancer patients. A systematic literature search was conducted in PubMed, CENTRAL and Web of Science. Information on the chemokine expression of 25 chemokines in colorectal cancer tissue and survival data of the patients were investigated. The hazard ratio of overall survival and disease-free survival with chemokine expression was examined. The risk of bias was analyzed using Quality in Prognosis Studies. Random effects meta-analysis was performed to determine the impact on overall respectively disease survival. For this purpose, the pooled hazard ratios (HR) and their 95% confidence intervals (CI) were used for calculation. Twenty-five chemokines were included, and the search revealed 5556 publications. A total of thirty-one publications were included in this systematic review and meta-analysis. Overexpression of chemokine receptor CXCR4 was associated with both a significantly reduced overall survival (HR = 2.70, 95%-CI: 1.57 to 4.66, p = 0.0003) as well as disease-free survival (HR = 2.68, 95%-CI: 1.41 to 5.08, p = 0.0026). All other chemokines showed either heterogeneous results or few studies were available. The overall risk of bias for CXCR4 was rated low. At the current level of evidence, this study demonstrates that CXCR4 overexpression in patients with colorectal cancer is associated with a significantly diminished overall as well as disease-free survival. Summed up, this systematic review and meta-analysis reveals CXCR4 as a promising prognostic biomarker. Nevertheless, more evidence is needed to evaluate CXCR4 and its antagonists serving as new therapeutic targets.

Objective: To examine coping strategies in relation to student experience of food insecurity during the transitionary period from high school to college., Participants: Freshmen undergraduates ( n  = 231) enrolled in one of two public universities during December of 2021, living in traditional student housing., Methods: Participants were emailed a link to a USDA 6-item food insecurity and coping strategies survey to investigate if students' degree of food insecurity correlates to coping strategies used. Questions were answered about experiences as a high school senior and college freshman. Data was analyzed with group comparison tests., Results: Food insecurity rates approximately doubled from students' high school experience to college. Students with lower food security during both their high school and college experience were significantly more likely to practice coping strategies., Conclusion: Improving education on utilization of available resources may help students obtain adequate nutrition, decreasing their need to rely on coping strategies.

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background/aim: Systemic treatment for metastatic colorectal cancer (CRC) includes chemotherapy in combination with a targeted antibody. Novel targeted therapies and immunotherapies are introduced for specific molecular subgroups. Prognostic relevant determinants are still under investigation., Patients and Methods: Systemic therapies of an unselected patient cohort with metastatic CRC were retrospectively analyzed. Treatment outcome was evaluated according to time-to-next-treatment (TTNT) and frequency of conversion surgery and compared between subgroups stratified by primary tumor side, molecular profile, sex and age, and metastases sites., Results: More than 50% of patients with locally advanced or metastatic CRC underwent secondary resection after first-line systemic therapy. Rectum carcinoma had the best prognosis under anti-EGFR-antibody treatment. Female patients had a worse prognosis than male patients in late disease stage. Young patients demonstrated poor response to systemic therapy, but a high rate of conversion surgeries. Conversely, elderly patients benefited from systemic therapy but underwent surgery less frequently. Liver and lung metastases had a worse prognosis than other metastases sites, whereas lung metastases were more likely to be resected than liver metastases in early disease stage., Conclusion: Patient age, sex, primary tumor localization, and metastatic sites are prognostic factors that could guide future treatment decisions for the therapy of metastatic CRC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)