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Introduction: Pancreatic ductal adenocarcinoma (PDAC) represents the complexity of interaction between cancer and cells of the tumor microenvironment (TME). Immune cells affect tumor cell behavior, thus driving cancer progression. Cancer-associated fibroblasts (CAFs) are responsible of the desmoplastic and fibrotic reaction by regulating deposition and remodeling of extracellular matrix (ECM). As tumor-promoting cells abundant in PDAC ECM, CAFs represent promising targets for novel anticancer interventions. However, relevant clinical trials are hampered by the lack of specific markers and elusive differences among CAF subtypes. Indeed, while single-cell transcriptomic analyses have provided important information on the cellular constituents of PDACs and related molecular pathways, studies based on the identification of protein markers in tissues aimed at identifying CAF subtypes and new molecular targets result incomplete. Methods: Herein, we applied multiplexed Imaging Mass Cytometry (IMC) at single-cell resolution on 8 human PDAC tissues to depict the PDAC composing cells, and profiling immune cells, endothelial cells (ECs), as well as endocrine cells and tumor cells. Results: We focused on CAFs by characterizing up to 19 clusters distinguished by phenotype, spatiality, and interaction with immune and tumor cells. We report evidence that specific subtypes of CAFs (CAFs 10 and 11) predominantly are enriched at the tumor-stroma interface and closely associated with tumor cells. CAFs expressing different combinations of FAP, podoplanin and cadherin-11, were associated with a higher level of CA19-9. Moreover, we identified specific subsets of FAP+ and podoplanin+/cadherin-11+ CAFs enriched in patients with negative prognosis. Discussion: The present study provides new general insights into the complexity of the PDAC microenvironment by defining phenotypic heterogeneities and spatial distributions of CAFs, thus suggesting different functions of their subtypes in the PDAC microenvironment. [ABSTRACT FROM AUTHOR]

Objective: To develop and externally validate an updated artificial intelligence (AI) prediction system for stratifying the risk of lymph node metastasis (LNM) in T2 colorectal cancer (CRC). Background: Recent technical advances allow complete local excision of T2 CRC, traditionally treated with surgical resection. Yet, the widespread adoption of this approach is hampered by the inability to stratify the risk of LNM. Methods: Data from patients with pT2 CRC undergoing surgical resection between April 2000 and May 2022 at one Japanese and one Italian center were analyzed. Primary goal was AI system development for accurate LNM prediction. Predictors encompassed 7 variables: age, sex, tumor size, tumor location, lymphovascular invasion, histologic differentiation, and carcinoembryonic antigen level. The tool's discriminating power was assessed through area under the curve, sensitivity, and specificity. Results: Out of 735 initial patients, 692 were eligible. Training and validation cohorts comprised of 492 and 200 patients, respectively. The AI model displayed an area under the curve of 0.75 in the combined validation data set. Sensitivity for LNM prediction was 97.8%, and specificity was 15.6%. The positive and the negative predictive value were 25.7% and 96%, respectively. The false negative rate was 2.2%, and the false positive was 84.4%. Conclusions: Our AI model, based on easily accessible clinical and pathologic variables, moderately predicts LNM in T2 CRC. However, the risk of false negative needs to be considered. The training of the model including more patients across western and eastern centers -- differentiating between colon and rectal cancers -- may improve its performance and accuracy. [ABSTRACT FROM AUTHOR]

Simple Summary: Early-onset rectal cancer (EORC) patients are more likely to undergo neoadjuvant therapies due to the advanced stage of cancer at diagnosis. The response to therapies in this group of patients is still unknown. The aim of this study was to explore the effect of age of onset on the pathological response to neoadjuvant therapies in locally advanced RC patients. A higher rate of incomplete response was reported in EORC patients and early age of onset presented as a risk factor for a worse response in a multivariable analysis. The results of this study call for a different multimodal strategy in EORC patients. The incidence of rectal cancer (RC) is increasing in the population aged ≤ 49 (early-onset RC-EORC). EORC patients are more likely to present with locally advanced disease at diagnosis than late-onset RC (LORC; aged ≥ 50) patients. As a consequence, more EORC patients undergo neoadjuvant therapies. The response to treatment in EORC patients is still unknown. This study aims to explore the effect of age of onset on the pathological response to neoadjuvant therapies in sporadic locally advanced RC (LARC) patients. Based on an institutional prospectively maintained database, LARC patients undergoing neoadjuvant therapies and radical surgery between January 2010 and December 2022 were allocated to the EORC and LORC groups. The primary endpoint was the rate of incomplete response (Dworak 0–2). A total of 326 LORC and 79 EORC patients were included. Pre-neoadjuvant tumor features were comparable. A significantly higher rate of incomplete response was observed in EORC patients (49% vs. 35%; p = 0.028). From multivariable analysis, early age of onset, smoking and extramural invasion presented as independent risk factors for a worse response. This study demonstrates that an early age of onset is related to a worse response and calls for different multimodal strategies in this group of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The Cancer Genome Atlas (TCGA) and more recent genome profiling recently revealed major intrinsic molecular subtypes in urothelial carcinoma (UC). Here we propose a fast and standardized immunophenotypical classification score (Piescore) that may discriminate between luminal, basal, or neu-like UC as a surrogate of molecular profile, and we describe, for the first time, an intratumoral phenotypical switch in tissue protein expression, from non-muscle to muscle-invasive progression. Our data show that a change from a luminal to a neu-like phenotype could worsen overall survival compared with a transition to a basal phenotype. In recent years, immunohistochemical protein expression was studied as a surrogate to the molecular classification of bladder cancer, although no tissue biomarkers are available for clinical use to predict survival or the response to neoadjuvant chemotherapy (CT) in UC, as the literature produced conflicting results. This retrospective study included TURB specimens harboring foci of HG pT2 muscle-invasive bladder carcinoma (MIBC) from 251 patients who subsequently underwent radical cystectomy. We performed immunohistochemical analysis on tumor samples, for relevant gene-expression-based markers for basal type (CD44, CK5/6) and luminal type (CK20 and pPARγ). Piescore, investigated in both non-muscle-invasive (NMI) and muscle-invasive (MI) components of the tumor, divided basal and luminal UC-types when at least three of the four markers were consistent with a specific phenotype, mixed types if one/two luminal and basal markers were present simultaneously, and neu-like types when all four markers investigated were negative. Eighteen selected cases were also investigated with RT-PCR to validate, and to increase the specificity of, the immunohistochemical results. We observe an immunophenotypical difference in the NMI and MI components in 96/251 UC patients (38.25%): half of tumors (44/96 cases) have a transition to basal, 36.46% (35/96 cases) to neu-like, 12.5% (12/96 cases) to mixed, and 5.2% (5/96 cases) to luminal phenotypes. Mixed tumors in the NMI component are more likely to change phenotype than other groups, particularly compared with basal tumors, which demonstrate greater stability (only 8/96 cases, p < 0.00001). The transition of luminal tumors to basal display a better OS compared with the transition toward neu-like tumors (p = 0.027). Overall, the phenotypical switch does not affect lymphovascular invasion, pT, DFS, or OS compared with non-switched cases. In the MI component, the presence of CD44 expression, irrespective of score-related phenotype, shows a protective effect in papillary-type UC (OS p = 0.008, HR 0.453, PFS p = 0.07, HR 0.599), and in UC naïve for CT (p = 0.0479). Piescore immunophenotyping reveals an intratumoral phenotypical transition between the NMI and MI components of the same tumor. The molecular change is a common event in the mixed and luminal categories, but not in basal tumors, which show better phenotypical stability. This phenomenon could partially explain the sensitivity of a subset of luminal UC to chemotherapy: good responders could be "non-real" luminal UC, which acquire nasal markers, such as CD44. [ABSTRACT FROM AUTHOR]