Pathology, research and practice最新文献

In early gastric cancer, local recurrence develops after endoscopic resection by field cancerization. Understanding the nature of cancer-prone environments is important to establish effective strategies to prevent recurrence. We hypothesized that the molecular/immune profiles in non-tumor (cancer-prone) tissue differ according to the relative distance from the gastric tumor. For this purpose, we performed whole-exome and transcriptome sequencing of 16 early gastric cancer samples with paired non-tumor mucosa 1 cm (N1) and 3 cm (N3) away from the tumor. The whole exome sequencing revealed mutations in both the tumor and non-tumor mucosa. TTN was the most frequently altered gene in tumors (31 %) and was the second most frequently altered gene in N1 (25 %) samples; however, the mutation rate was significantly lower in N3 (12 %) samples (P = 0.0046). Moreover, the expression levels of TTN mRNA were higher in tumors than in the N1 and N3 samples and were significantly associated with TTN mutations (P = 0.04). TP53 mutations were mainly observed in tumors (50 %) and in 6.3 % of N1, with no mutation detected in N3 samples. Transcriptome sequencing revealed that the expression of the epithelial-mesenchymal transition signature, mesenchymal signature, and proliferation signature was increased in tumors, whereas programmed death-ligand 1 expression was decreased in the non-tumor mucosa. In the tumor, although the numbers of M0/M1 macrophages, neutrophils, and eosinophils increased, plasma cell numbers were markedly decreased compared to non-tumor mucosa. In conclusion, non-tumor mucosa at 1 cm and 3 cm from the tumor harbored different genomic, transcriptomic, and immune cell profiles. The non-tumor mucosa closer to the tumor (1 cm) exhibited similar genomic and transcriptomic features. These findings can offer clinical guidance for acquiring a safe horizontal margin in endoscopic resection for early gastric cancer.

Tumor-infiltrating lymphocytes (TILs) and the tumor microenvironment have become increasingly important in cancer research, and immunotherapy has achieved major breakthroughs in improving patient outcomes. Despite the significant role of the pathologist in identifying, subtyping and reporting TILs, the implementation and assessment of TILs in pathology routine remains vague. To assess the actual use of TILs in routine clinical practice, a formal standardized questionnaire was disseminated on two social media platforms ("X" and LinkedIn) and by email in June 2024. Based on the results, we conducted a literature review on TILs via Medline/Pubmed in the two most scored and reported entities, namely malignant melanoma and colorectal cancer (CRC). 77 participants from 24 different countries around the world, mostly pathologists (n = 63, 82.0 %), completed the survey. More than half of the participants do not assess or report TILs in their daily (clinical) practice, a trend consistent across the countries included in the study. A variety of methods are used to report TILs, ranging from Artificial Intelligence (AI)-based scoring algorithms to quantification by eyeballing. Despite recognizing the importance of TIL assessment in clinical routine, many participants find it time-consuming and express a strong preference for AI-based quantification. Our survey reflects the perspective of mostly early career pathologists who recognize the importance of TILs in cancer but face challenges in implementation. The development of AI tools and consensus guidelines could alleviate these barriers. In addition, increasing the visibility and understanding of the role of pathologists within the medical community remains critical.

Chronic inflammatory conditions, which include respiratory diseases and other ailments, are characterized by persistent inflammation and oxidative stress, and represent a significant health burden, often inadequately managed by current therapies which include conventional inhaled bronchodilators and oral or inhaled corticosteroids in the case of respiratory disorders. The present study explores the potential of Vedicinals®9 Advanced, a polyherbal formulation, to mitigate LPS-induced inflammation and oxidative stress in RAW264.7 mouse macrophages. The cells were pre-treated with Vedicinals®9 Advanced, followed by exposure to LPS to induce an inflammatory response. Key experimental outcomes were assessed, including nitric oxide (NO) and reactive oxygen species (ROS) production, as well as the expression of inflammatory and oxidative stress-related genes and proteins. Vedicinals®9 Advanced significantly reduced LPS-induced NO and ROS production, indicating strong anti-inflammatory and antioxidant properties. Additionally, the formulation downregulated the LPS-upregulated mRNA expression of pro-inflammatory cytokines, such as TNF-α and CXCL1, and oxidative stress markers, including GSTP1 and NQO1. Furthermore, Vedicinals®9 Advanced downregulated the LPS-induced protein expression of the chemokines CCL2 and CCL6, the LPS co-receptor, CD14, and the pro-inflammatory cytokines G-CSF and IL-1β. These findings highlight the potential of Vedicinals®9 Advanced as a therapeutic option for managing CRDs and other inflammatory conditions. The formulation's ability to simultaneously target inflammation and oxidative stress suggests it may offer advantages over existing treatments, with potential for broader application in inflammatory diseases.

To predict the therapeutic response of systemic therapy, comprehensive analyses of the tumor microenvironment in papillary renal cell carcinoma (pRCC) have been conducted previously using immunohistochemistry and RNA sequencing. This study aimed to evaluate the correlation between hematoxylin and eosin-based histological immunophenotypes and gene signatures employed in several clinical trials predicting responsiveness to immune checkpoint inhibitors and tyrosine kinase inhibitors, using data from the Cancer Genome Atlas (TCGA)-KIRP cohort (n = 254). Herein, we evaluated tumor-associated immune cells (TAICs) using three methodologies previously reported in clear cell RCC: a 3-tier immunophenotype (desert, excluded, and inflamed) based on the spatial distribution of TAICs; a 4-tier immunophenotype (cold, immune-low, excluded, and hot) considering both the location and degree of TAICs; and an inflammation score (score 0, 1, and 2) focusing only on the degree of TAICs. Furthermore, we compared the predictive ability of the three immunophenotypes. The histological immunophenotype in pRCC exhibited a correlation with adverse clinicopathological factors (including higher stage, WHO/ISUP grade, and the presence of sarcomatoid/rhabdoid changes), gene signatures related to angiogenesis, Teff, myeloid cells, JAVELIN Renal 101 Immuno, and immune checkpoints, as well as a poorer prognosis. Among the three methodologies, the 4-tier immunophenotype demonstrated the strongest correlation with gene signatures. In conclusion, the 4-tier immunophenotype may yield potential predictive biomarkers for pRCC and guide treatment decisions.

Background: Advanced-stage tube-ovarian cancers (TOC) and uterine cancers (UC) significantly contribute to cancer mortality. While surgery achieves clinical remission in most cases, recurrence often necessitates systemic therapy. Recent molecular phenotype studies have advanced targeted therapies. We employed whole genome sequencing (WGS) to investigate biomarkers in gynecologic malignancies.

Design: Ninety-one tumor samples (45 TOC, 46 UC) were analyzed for germline mutations, somatic driver mutations, rearrangements, genome-wide signatures, and molecular phenotypes. A WGS-based high-confidence classifier for homologous recombination deficiency (HRD) was applied. Genomic profiles were correlated with clinical outcomes.

Results: The HRD phenotype was identified in serous carcinoma components, with 50 % of HRD cases showing BRCA1/2 wildtype (33 %) or variants of unknown significance (17 %). HRD correlated with better overall survival in tubo-ovarian serous carcinoma and was linked to responses to platinum therapy and PARP inhibitors. Endometrioid carcinomas showed no HRD phenotype despite BRCA1/2 variants. CDK12-type genomic instability (10 %) occurred in cases with CDK12 rearrangements, and CCNE1 gain (8 %) was observed in CCNE1-amplified cases, independent of copy number. In endometrioid carcinoma, mismatch repair (MMR) deficiency single base substitution signatures, particularly SBS44, contributed to high tumor mutation burden (TMB). Ultra-high TMB was found in two cases with pathogenic POLE and POLQ mutations, exhibiting multiple SBS signatures, including MMR deficiency.

Conclusion: Comprehensive genomic profiling of advanced-stage TOC and UC via WGS reveals key biomarkers and therapeutic targets, enhancing diagnostic accuracy and advancing personalized medicine in gynecological cancers.

Background: Patients with clear cell renal cell carcinoma (ccRCC) metastases face poor prognoses, even with adjuvant therapies. Tumor-infiltrating T-cells and macrophages are critical in targeting tumor cells within the renal microenvironment. Beyond VHL mutations, loss-of-function mutations in SWI/SNF complex genes, including PBRM1, BAP1, ARID1A, SETD2, SMARCA4 (BRG1), and SMARCA2 (BRM), have been implicated in ccRCC progression.

Design: A tissue microarray of 160 ccRCC cases was analyzed via immunohistochemistry (IHC) for SWI/SNF protein expression and CD4 + /CD8 + T-cell infiltration. Clinical and pathologic features were obtained through electronic medical records. Statistical analyses included one-way ANOVA, two-way ANOVA, Pearson's chi-square and t-tests.

Results: Loss of SWI/SNF protein expression was observed in PBRM1 (31 %), ARID1A (51 %), SETD2 (14 %), BRG1 (15 %), BRM (38 %), and BAP1 (40 %). T-cell counts varied significantly with stage: CD4 + counts peaked at Stage 3, while CD8 + counts increased through Stage 4 (p < 0.001). Loss of PBRM1 was more frequent in advanced stages (29.4 %, p < 0.001), while BRM and BRG1 losses were more common in earlier stages (p < 0.001, p = 0.006). ARID1A and BRM losses correlated with reduced CD8 + counts (p = 0.016, p = 0.032) and stage-specific CD4 + variations (p < 0.001, p = 0.042).

Conclusion: Loss of PBRM1, SMARCA2/BRM, and SMARCA4/BRG1 expression is significantly associated with ccRCC progression, with PBRM1 loss prevalent in advanced stages and SMARCA2/BRM and SMARCA4/BRG1 in earlier stages. ARID1A and SMARCA2/BRM losses correlate with reduced CD8 + counts and stage-specific CD4 + infiltration, highlighting their potential as biomarkers for disease progression and immunotherapeutic response.

PCBP1 is a multifunctional adaptor protein, whose function as an iron chaperone and epigenetic regulator of several chemical messengers involved in ferroptosis has garnered much attention. Herein, this review, several attempts have been made to simplify our understanding of the complex roles of PCBP1. The review begins by elucidating the relevance of PCBP1 in key events governing ferroptosis. We expeditiously shed light on some of the important mechanisms that have critical implications for the ferroptosis landscape. For instance, senescence, EMT, hypoxia, and regulation of the cell cycle and immune checkpoints, among others, have been demonstrated to influence ferroptosis sensitivity to varying degrees. Thus, this review entails a conscious attempt to carefully examine the relevance of PCBP1 in such potential mechanisms. Furthermore, we investigated the therapeutic relevance of PCBP1 in tumor biology and autoimmunity, while underscoring the contrasting perspective of ferroptosis targeting across the disease spectrum. Finally, we debate the different strategies that can be exploited to target PCBP1 in promoting or inhibiting ferroptosis.

Gynecologic cancer, a prevalent and debilitating disease affecting women worldwide, is characterized by the uncontrolled proliferation of cells in the reproductive organs. The complex etiology of gynecologic cancer encompasses multiple subtypes, including cervical, ovarian, uterine, vaginal, and vulvar cancers. Despite optimal treatment strategies, which typically involve cytoreductive surgery and platinum-based chemotherapy, gynecologic cancer frequently exhibits recalcitrant relapse and poor prognosis. Recent studies have underscored the significance of the tumor microenvironment in ovarian carcinogenesis, particularly with regards to the discovery of aberrant genomic, transcriptomic, and proteomic profiles. Within this context, cancer-associated fibroblasts (CAFs) emerge as a crucial component of the stromal cell population, playing a pivotal role in oncogenesis and cancer progression. CAF-derived exosomes, small extracellular vesicles capable of conveying biological information between cells, have been implicated in a range of tumor-related processes, including tumorigenesis, cell proliferation, metastasis, drug resistance, and immune responses. Furthermore, aberrant expression of CAF-derived exosomal noncoding RNAs and proteins has been found to strongly correlate with clinical and pathological characteristics of gynecologic cancer patients. Our review provides a novel perspective on the role of CAF-derived exosomes in gynecologic cancer, highlighting their potential as diagnostic biomarkers and therapeutic targets.

Colorectal cancer (CRC) is a prevalent malignancy worldwide, driven by complex molecular mechanisms. This study aims to elucidate the role of lncRNAs within TGF-β pathway, a crucial signaling pathway in CRC progression, focusing specifically on their interaction with the SPP1 gene. We employed a multi-faceted approach, starting with comprehensive in silico analyses to identify candidate lncRNAs potentially involved in TGF-β pathway regulation. These candidates were further validated through experimental RT-qPCR assays, comparing lncRNA expression profiles in CRC tissues to adjacent normal samples. Our findings revealed novel lncRNA candidates with significant associations with SPP1 in CRC, highlighting their potential regulatory roles in the TGF-β pathway. This integrative study underscores the importance of combining computational predictions with laboratory experimentation to uncover complex regulatory networks in cancer, providing insights into new therapeutic targets and diagnostic biomarkers for CRC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with complex etiological factors and a diverse genetic landscape. Among the critical genetic mutations in HCC, the AT-rich interaction domain 1 A (ARID1A) gene, a key component of the SWI/SNF chromatin remodeling complex, stands out due to its significant role in both tumor suppression and oncogenesis. This review comprehensively examines the molecular and pathological impacts of ARID1A mutations in HCC. ARID1A mutations, which occur in approximately 7.9 % of HCC cases, predominantly involve truncating mutations leading to loss of function. These mutations are associated with various aggressive cancer features, including larger tumor size, higher rates of metastasis, and poor prognosis. The dual role of ARID1A in HCC is context-dependent, acting as a tumor suppressor by regulating cell cycle control, DNA damage repair, and gene expression, while also displaying oncogenic properties in specific contexts by promoting early tumorigenesis through oxidative stress pathways. Understanding the molecular mechanisms of ARID1A, including its interactions with key cellular pathways such as PI3K/AKT/mTOR, β-catenin, and PD-L1, provides insights into its complex role in HCC pathogenesis. Furthermore, ARID1A's impact on cancer stem cell maintenance, metabolic reprogramming, and immune evasion underscores its potential as a therapeutic target. This review highlights the need for context-specific therapeutic strategies targeting ARID1A, which could lead to more effective treatments for HCC, addressing both its tumor-suppressive and oncogenic activities.