KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2.

Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm abnormalities and embryonic lethality. Employing RNA-seq and CUT&Tag analyses on trophoblast stem cells (TSCs), we further discover that KAT8 regulates the transcriptional activation of the trophoblast stemness marker, CDX2, via acetylating H4K16. Remarkably, CDX2 overexpression partially rescues the defects arising from Kat8 knockout. Moreover, increasing H4K16ac via using deacetylase SIRT1 inhibitor, EX527, restores CDX2 levels and promoted placental development. Clinical analysis shows reduced KAT8, CDX2 and H4K16ac expression are associated with recurrent pregnancy loss (RPL). Trophoblast organoids derived from these patients exhibit impaired TSC self-renewal and growth, which are significantly ameliorated with EX527 treatment. These findings suggest the therapeutic potential of targeting the KAT8-H4K16ac-CDX2 axis for mitigating RPL, shedding light on early gestational abnormalities.

[Primary mucinous gland lesions of fallopian tube: a clinicopathological analysis of fourteen cases].

Objective: To investigate the clinical and pathological characteristics of primary mucinous gland lesions of the fallopian tubes. Methods: The clinical data, pathomorphological characteristics and immunophenotype of 14 cases of primary mucinous gland lesions of the fallopian tube diagnosed at Obstetrics and Gynecology Hospital of Fudan University from 2015 to 2023 were analyzed retrospectively. In addition, a comprehensive review of relevant literature was conducted. Results: The age of 14 patients ranged from 53 to 83 years, with an average of 65 years. Among them, 13 cases exhibited unilateral involvement while one case showed bilateral presentation. Nine cases were mucinous metaplasia of the fallopian tube, four cases were invasive mucinous adenocarcinoma and one case was mucinous carcinoma in situ. Morphologically, mucinous metaplasia of the fallopian tube was focal, with or without inflammation. The cells of mucinous adenocarcinoma or mucinous carcinoma in situ exhibited characteristics indicative of gastrointestinal differentiation. Immunohistochemical analysis revealed diffuse positive expression of CK7, and negative expression of SATB2. CDX2 demonstrated positive staining in two cases. One case exhibited diffuse and strongly positive mutant expression of p53, whereas the remaining cases displayed wild-type expression. MUC6 showed diffuse or focally positive staining in mucinous gland lesions characterized by gastric differentiation. Some cases of mucinous adenocarcinoma of fallopian tube were subject to AB-PAS staining, resulting in red to purple cytoplasmic staining. Conclusions: Primary mucinous lesions of the fallopian tube are exceedingly uncommon. All cases of mucinous adenocarcinoma of fallopian tubes in this study exhibit the morphology and immunohistochemical characteristics of gastrointestinal differentiation. Mucinous metaplasia of the fallopian tube is a benign lesion of incidental finding, which is closely related to inflammation or gastric differentiation. Mucinous lesions of cervix, ovary and digestive tract are excluded in all patients, confirming the independent existence of mucinous lesions within fallopian tubes.

Molecular Deciphering of Colorectal Cancer: Exploring Molecular Classifications and Analyzing the Interplay among Molecular Biomarkers MMR/MSI, KRAS, NRAS, BRAF and CDX2 - A Comprehensive Literature Review.

Background: Colorectal cancer (CRC) exhibits molecular and morphological diversity, involving genetic, epigenetic alterations, and disruptions in signaling pathways. This necessitates a comprehensive review synthesizing recent advancements in molecular mechanisms, established biomarkers, as well as emerging ones like CDX2 for enhanced CRC assessment. Material and Methods: This review analyzes the last decade's literature and current guidelines to study CRC's molecular intricacies. It extends the analysis beyond traditional biomarkers to include emerging ones like CDX2, examining their interaction with carcinogenic mechanisms and molecular pathways, alongside reviewing current testing methodologies. Results: A multi-biomarker strategy, incorporating both traditional and emerging biomarkers like CDX2, is crucial for optimizing CRC management. This strategy elucidates the complex interaction between biomarkers and the tumor's molecular pathways, significantly influencing prognostic evaluations, therapeutic decision-making, and paving the way for personalized medicine in CRC. Conclusions: This review proposes CDX2 as an emerging prognostic biomarker and emphasizes the necessity of thorough molecular profiling for individualized treatment strategies. By enhancing CRC treatment approaches and prognostic evaluation, this effort marks a step forward in precision oncology, leveraging an enriched understanding of tumor behavior.

Pathological and immunohistochemical analysis of gastric mucosa after one anastomosis gastric bypass surgery.

BACKGROUND: One anastomosis gastric bypass (OAGB) is now the third most common bariatric surgery worldwide. This procedure is garnering increasing attention, but its complication of bile reflux and the associated risk of gastric carcinogenesis remains controversial. OBJECTIVE: The study aims to assess the impact of bile reflux on the gastric mucosa by comparing pathological and immunohistochemical results of gastric mucosa before and 2 years after OAGB surgery. METHODS: This retrospective study analyzed gastric lesions observed in gastroscopy before and after OAGB surgery. Pathological examinations were conducted on mucosal samples from proximal, middle and distal part of stomach, with a particular focus on the expression of Ki-67, P53, and CDX2 in immunohistochemistry. Ki-67 indicates cellular proliferation, P53 is a tumor suppressor protein, and CDX2 is a marker for intestinal differentiation. RESULTS: A total of 16 patients completed the follow-up. Regarding gastritis, presurgery nonerosive gastritis was found in two cases (12.5%), and postsurgery in six cases (37.5%). Erosive gastritis increased from one case (6.2%) presurgery to three cases (18.7%) postsurgery, totaling an increase from three to nine cases (p = .028). Bile reflux in the stomach increased from one case (6.2%) presurgery to three cases (18.7%) postsurgery. Most lesions in the proximal, middle, and distal part of stomach were relatively mild, with normal tissue states being predominant. Mild inflammation was found in all three areas, whereas moderate inflammation, intestinal metaplasia, and glandular atrophy were less common. No cases of severe inflammation were noted. The expression of gastric biomarkers CDX-2, Ki67, and P53 showed no significant statistical variation in different areas. CONCLUSION: Bile reflux does occur after OAGB, but its incidence is not high. Based on the immunohistochemical and pathological results of the gastric mucosa 2 years post-OAGB, there seems to be no significant causal relationship between OAGB and oncogenic inflammation around the gastric tube.

Individual transcription factors modulate both the micromovement of chromatin and its long-range structure.

The control of eukaryotic gene expression is intimately connected to highly dynamic chromatin structures. Gene regulation relies on activator and repressor transcription factors (TFs) that induce local chromatin opening and closing. However, it is unclear how nucleus-wide chromatin organization responds dynamically to the activity of specific TFs. Here, we examined how two TFs with opposite effects on local chromatin accessibility modulate chromatin dynamics nucleus-wide. We combine high-resolution diffusion mapping and dense flow reconstruction and correlation in living cells to obtain an imaging-based, nanometer-scale analysis of local diffusion processes and long-range coordinated movements of both chromatin and TFs. We show that the expression of either an individual transcriptional activator (CDX2) or repressor (SIX6) with large numbers of binding sites increases chromatin mobility nucleus-wide, yet they induce opposite coherent chromatin motions at the micron scale. Hi-C analysis of higher-order chromatin structures shows that induction of the pioneer factor CDX2 leads both to changes in local chromatin interactions and the distribution of A and B compartments, thus relating the micromovement of chromatin with changes in compartmental structures. Given that inhibition of transcription initiation and elongation by RNA Pol II has a partial impact on the global chromatin dynamics induced by CDX2, we suggest that CDX2 overexpression alters chromatin structure dynamics both dependently and independently of transcription. Our biophysical analysis shows that sequence-specific TFs can influence chromatin structure on multiple architectural levels, arguing that local chromatin changes brought by TFs alter long-range chromatin mobility and its organization.

Chromatin landscape instructs precise transcription factor regulome during embryonic lineage specification.

Embryos, originating from fertilized eggs, undergo continuous cell division and differentiation, accompanied by dramatic changes in transcription, translation, and metabolism. Chromatin regulators, including transcription factors (TFs), play indispensable roles in regulating these processes. Recently, the trophoblast regulator TFAP2C was identified as crucial in initiating early cell fate decisions. However, Tfap2c transcripts persist in both the inner cell mass and trophectoderm of blastocysts, prompting inquiry into Tfap2c's function in post-lineage establishment. In this study, we delineate the dynamics of TFAP2C during the mouse peri-implantation stage and elucidate its collaboration with the key lineage regulators CDX2 and NANOG. Importantly, we propose that de novo formation of H3K9me3 in the extraembryonic ectoderm during implantation antagonizes TFAP2C binding to crucial developmental genes, thereby maintaining its lineage identity. Together, these results highlight the plasticity of the chromatin environment in designating the genomic binding of highly adaptable lineage-specific TFs and regulating embryonic cell fates.

Concomitant expression patterns of CDX2 and SATB2 as prognostic factors in stage III colorectal cancers.

CDX2 and SATB2 are often used as biomarkers for identification of colorectal origin in primary or metastatic adenocarcinomas. Loss of CDX2 or SATB2 expression has been associated with poor prognosis in patients with colorectal cancer (CRC). However, little is known regarding clinicopathological features, including prognosis, of CRCs with concomitant loss of CDX2 and SATB2. A total of 431 stage III CRCs were analyzed for their expression status in CDX2 and SATB2 using tissue microarray-based immunohistochemistry and expression status was correlated with clinicopathological variables, molecular alterations, and survival. CDX2-negative (CDX2-) CRCs and SATB2-negative (SATB2-) CRCs were found in 8.1 % and 17.2 % of CRCs, respectively, whereas both CDX2-negative and SATB2-negative (CDX2-/SATB2-) CRCs comprised 3.2 % of the CRCs. On survival analysis, neither CDX2-/SATB2+ nor CDX2+/SABT2- CRCs but CDX2-/SATB2- CRCs were associated with poor prognosis. CDX2-/SATB2- CRCs showed significant associations with tumor subsite of right colon, poor differentiation, decreased expression of CK20, aberrant expression of CK7, CIMP-high, MSI-high, and BRAF mutation. In summary, our results suggest that concomitant loss of CDX2 and SATB2 is a prognostic biomarker but isolated loss of CDX2 or SATB2 is not a prognostic biomarker for stage III CRCs.

CDX2 dose-dependently influences the gene regulatory network underlying human extraembryonic mesoderm development.

Loss of Cdx2 in vivo leads to stunted development of the allantois, an extraembryonic mesoderm-derived structure critical for nutrient delivery and waste removal in the early embryo. Here, we investigate how CDX2 dose-dependently influences the gene regulatory network underlying extraembryonic mesoderm development. By engineering human induced pluripotent stem cells (hiPSCs) consisting of wild-type (WT), heterozygous (CDX2-Het), and homozygous null CDX2 (CDX2-KO) genotypes, differentiating these cells in a 2D gastruloid model, and subjecting these cells to single-nucleus RNA and ATAC sequencing, we identify several pathways that are dose-dependently regulated by CDX2 including VEGF and non-canonical WNT. snATAC-seq reveals that CDX2-Het cells retain a WT-like chromatin accessibility profile, suggesting accessibility alone is not sufficient to drive this variability in gene expression. Because the loss of CDX2 or TBXT phenocopy one another in vivo, we compared differentially expressed genes in our CDX2-KO to those from TBXT-KO hiPSCs differentiated in an analogous experiment. This comparison identifies several communally misregulated genes that are critical for cytoskeletal integrity and tissue permeability. Together, these results clarify how CDX2 dose-dependently regulates gene expression in the extraembryonic mesoderm and reveal pathways that may underlie the defects in vascular development and allantoic elongation seen in vivo.

Combined Use of Helicobacter pylori Genotyping and CDX2 Expression as a Predictor of Malignant Potential in Gastric Intestinal Metaplasia.

OBJECTIVE: Gastrointestinal metaplasia (GIM) has a close relationship with gastric cancer (GC), but it is unclear how to judge which GIM could develop into GC. This study aimed to assess the role of CDX2 and its association with Helicobacter pylori (H.pylori) genotypes in GIM. METHODS: CagA and vacA genes were identified via PCR in 466 H. pylori-positive gastric tissues, including gastritis (n=104), GIM diagnosed endoscopically (GIM-1; n=82), gastric cancer (GC; n=173), and paired adjacent GIM tumors resected surgically (GIM-2; n=107). GIM was subclassified per the HID- AB pH2.5-PAS as follows: type I (n=23), type II (n=43), and type III (n=16) in GIM-1; type I (n=8), type II (n=40), and type III (n=59) in GIM-2. CDX2 expression was evaluated immunohistochemically. RESULTS: In GIM-1, the infection rate of vacAm2 (55.8%) and vacAs1m2 (53.5%) was higher in subtype II than in others (P<0.05), while that of vacAm1 (49.2%) and vacAs1m1 (33.9%) was higher in subtype III than in others. The cagA+ rate was higher in subtypes I (75.0%) and III (64.4%) than in subtype II (40.0%; P<0.05) respectively. CDX2 was upregulated in subtype I than in subtypes II and III in GIM-1 and GIM-2. In GIM-2 and GC, CDX2 was downregulated in vacAm1, vacAs1m1, and cagA+ (P<0.05). The predominant genotype was vacAs1m2 in subtype II of GIM-1, CDX2 expression remaining unaltered; however, the predominant genotype was cagA+ vacAs1m1 in subtypes II and III of GIM-2, negatively correlated with CDX2 expression. CONCLUSION: These GIM subtypes (cagA+ vacAs1m1 H. pylori-positive GIM with negative CDX2 expression) resemble GC and should be evaluated similar to cancerous GIM.

Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.

Cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAFV600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program concurrently is tumor suppressive, and Cdx2 loss sufficiently creates permissive state for BRAFV600E-driven transformation. Human proximal colon cancers with CDX2 downregulation showed similar transcriptional program as in mouse proximal organoids with Cdx2 loss. Developmental transcription factors, such as CDX2, are thus critical in maintaining tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor development.

CDX2 alleviates hypoxia-induced apoptosis and oxidative stress in spermatogenic cells through suppression of reactive oxygen species-mediated Wnt/ß-catenin pathway.

Hypoxia-induced apoptosis and oxidative stress in spermatogenic cells are considered to be important factors leading to male infertility. It was reported that CDX2 expression was downregulated in hypoxia-stimulated spermatogenic cells. However, the effects of CDX2 on hypoxia-induced apoptosis and oxidative stress in spermatogenic cells are still unknown. This study aimed to explore the roles of CDX2 in hypoxia-induced injury of spermatogenic cells, as well as its mechanism of action. Spermatogenic cells were cultured under 1% oxygen for 48 h to established hypoxia damage model. Reactive oxygen species (ROS) generation was determined using 2',7'-dichlorofluorescein diacetate assay. Apoptosis was assessed using flow cytometry. Enzyme-linked immunosorbent assay was used to evaluate oxidative stress markers, including malondialdehyde (MDA) content and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidases (GSH-Px). Protein levels were detected using western blotting. Hypoxia exposure induced increase in ROS generation, apoptosis rate, and oxidative stress in spermatogenic cells. ROS scavenger inhibited hypoxia-induced apoptosis, oxidative stress, and Wnt/ß-catenin pathway activation. Hypoxia exposure induced CDX2 downregulation. CDX2 overexpression suppressed hypoxia-induced ROS generation, apoptosis rate, oxidative stress, and Wnt/ß-catenin pathway activation. Moreover, CDX2 knockdown restores the inhibitory effects of si-ß-catenin or NAC on hypoxia-induced activation of the Wnt/ß-catenin pathway, apoptosis, and oxidative stress. In conclusion, our study suggests that CDX2 overexpression alleviates hypoxia-induced apoptosis and oxidative stress by suppression of ROS-mediated Wnt/ß-catenin pathway in spermatogenic cells.

Clinical impact of ampulla of Vater cancer subtype classification based on immunohistochemical staining.

BACKGROUND: The histological subtype is an important prognostic factor for ampulla of Vater (AoV) cancer. This study proposes a classification system for the histological subtyping of AoV cancer based on immunohistochemical (IHC) staining and its prognostic significance. METHODS: Seventy-five AoV cancers were analyzed for cytokeratin 7 (CK7), CK20, and causal-type homeobox transcription factor 2 (CDX2) expression by IHC staining. We differentiated the subtypes (INT, intestinal; PB, pancreatobiliary; MIX, mixed; NOS, not otherwise specified) into classification I: CK7/CK20, classification II: CK7/CK20 or CDX2, classification III: CK7/CDX2 and examined their associations with clinicopathological factors. RESULTS: Classifications I, II, and III subtypes were INT (7, 10, and 10 cases), PB (43, 37, and 38 cases), MIX (13, 19, and 18 cases), and NOS (12, 9, and 9 cases). Significant differences in disease-free survival among the subtypes were observed in classifications II and III using CDX2; the PB and NOS subtype exhibited shorter survival time compared with INT subtype. In classification III, an association was revealed between advanced T/N stage, poor differentiation, lymphovascular invasion (LVI), the PB and NOS subtypes, and recurrence risk. In classification III, the subtypes differed significantly in T/N stage and LVI. Patients with the PB subtype had advanced T and N stages and a higher incidence of LVI. CONCLUSIONS: Classification using CDX2 revealed subtypes with distinct prognostic significance. Combining CK7 and CDX2 or adding CDX2 to CK7/CK20 is useful for distinguishing subtypes, predicting disease outcomes, and impacting the clinical management of patients with AoV cancer.

TEAD4 regulates KRT8 and YAP in preimplantation embryos in mice but not in cattle.

In brief: Lineage specification plays a vital role in preimplantation development. TEAD4 is an essential transcription factor for trophectoderm lineage specification in mice but not in cattle. Abstract: Tead4, a critical transcription factor expressed during preimplantation development, is essential for the expression of trophectoderm-specific genes in mice. However, the functional mechanism of TEAD4 in mouse preimplantation development and its conservation across mammals remain unclear. Here, we report that Tead4 is a crucial transcription factor necessary for blastocyst formation in mice. Disruption of Tead4 through base editing results in developmental arrest at the morula stage. Additionally, RNA-seq analysis reveals dysregulation of 670 genes in Tead4 knockout embryos. As anticipated, Tead4 knockout led to a decrease in trophectoderm genes Cdx2 and Gata3. Intriguingly, we observed a reduction in Krt8, suggesting that Tead4 influences the integrity of the trophectoderm epithelium in mice. More importantly, we noted a dramatic decrease in nuclear Yap in outside cells for Tead4-deficient morula, indicating that Tead4 directly regulates Hippo signaling. In contrast, bovine embryos with TEAD4 depletion could still develop to blastocysts with normal expression of CDX2, GATA3, and SOX2, albeit with a decrease in total cell number and ICM cell number. In conclusion, we propose that Tead4 regulates mouse blastocyst formation via Krt8 and Yap, both of which are critical regulators of mouse preimplantation development.

Loss of SATB2 and CDX2 expression is associated with DNA mismatch repair protein deficiency and BRAF mutation in colorectal cancer.

The relationship between the expression of the SATB2 and CDX2 proteins and common molecular changes and clinical prognosis in colorectal cancer (CRC) still needs further clarification. We collected 1180 cases of CRC and explored the association between the expression of SATB2 and CDX2 and clinicopathological characteristics, molecular alterations, and overall survival of CRC using whole-slide immunohistochemistry. Our results showed that negative expression of SATB2 and CDX2 was more common in MMR-protein-deficient CRC than in MMR-protein-proficient CRC (15.8% vs. 6.0%, P = 0.001; 14.5% vs. 4.0%, P = 0.000, respectively). Negative expression of SATB2 and CDX2 was more common in BRAF-mutant CRC than in BRAF wild-type CRC (17.2% vs. 6.1%, P = 0.003; 13.8% vs. 4. 2%; P = 0.004, respectively). There was no relationship between SATB2 and/or CDX2 negative expression and KRAS, NRAS, and PIK3CA mutations. The lack of expression of SATB2 and CDX2 was associated with poor histopathological features of CRC. In multivariate analysis, negative expression of SATB2 (P = 0.030), negative expression of CDX2 (P = 0.043) and late clinical stage (P = 0.000) were associated with decreased overall survival of CRC. In conclusion, the lack of SATB2 and CDX2 expression in CRC was associated with MMR protein deficiency and BRAF mutation, but not with KRAS, NRAS and PIK3CA mutation. SATB2 and CDX2 are prognostic biomarkers in patients with CRC.

The CDX2 G allele and the FoKI F allele of the VDR gene are more prevalent and related to changes in vitamin D levels in patients with psoriasis vulgaris: A pilot study.

BACKGROUND AND AIMS: Psoriasis is a chronic, non-contagious autoimmune condition marked by dry, itchy,erythematous and scaly plaques. From modest, localized plaques to total body coverage, the severity of psoriasis varies. Plaque, guttate, inverted, pustular, and erythrodermic psoriasis are the five primary kinds. About 90% of cases are of plaque psoriasis, commonly known as psoriasis vulgaris. Study aims to determine the impact of an rs2228570 (FokI) variant and an rs11568820 (CDX2) variant on serum vitamin D levels (SVD) in patients with psoriasis, and the correlation between the two variants and disease severity. METHODS: A case-control study consisting of 95 psoriasis vulgaris patients and 84 healthy controls. The clinical investigation, molecular genetics analysis, and biochemical analysis were done for both groups. RESULTS: SVD levels were significantly decreased in psoriasis patients group. FokI genotypes analysis, we found no significant variance between groups. CDX2 G/G genotype is more prevalent in patients than controls. Moderate psoriasis vulgaris patients with CDX2 G/G genotypes have higher SVD levels than CDX2 G/A, and CDX2 A/A p = 0.003. CONCLUSION: The study found a difference in vitamin D levels between patients and healthy subjects, as well as a difference in vitamin D levels with different FoKI and CDX2 genotypes.

A Case of Biphenotypic Adnexal Carcinoma With Bowenoid and Basaloid Features: Focus on the Expression of SOX9 and Wnt Signaling Pathway Molecules, Including CDX2.

ABSTRACT: An 87-year-old woman presented with a pedunculated nodule of 1.2 × 1.2 × 0.6 cm on her left cheek. Microscopic examination of the lesion revealed bowenoid and rosette-like basaloid components, resembling Bowen disease and neuroendocrine carcinoma, respectively. Immunohistochemically, both components were positive for Wnt signaling pathway molecules-nuclear/cytoplasmic beta-catenin, lymphoid enhancer binding factor 1 (LEF1), and caudal type homeobox 2 (CDX2)-and the adnexal marker SRY-box transcription factor 9 (SOX9). Unlike neuroendocrine tumors and basal cell carcinomas, the basaloid component in the present case was negative for chromogranin A, INSM1, synaptophysin, and p40. Previously reported cases of similar CDX2-positive lesions were diagnosed as squamous cell carcinoma with enteric adenocarcinomatous differentiation and basaloid cutaneous carcinoma with a primitive cytomorphology. However, the lesion in the present case was simultaneously positive for SOX9, indicating adnexal differentiation. In particular, the expression of multiple Wnt signaling pathway molecules indicates follicular differentiation despite the absence of morphological follicular features, such as shadow cells. Moreover, shared immunopositivity for SOX9, CDX2, nuclear/cytoplasmic beta-catenin, and LEF1 by both bowenoid and basaloid components indicated that the bowenoid component did not represent Bowen disease but a part of the adnexal tumor, and that the basaloid component was not a tumor-to-tumor metastasis. After complete excision, no recurrence has been observed for 5 months. The findings of the present case expand the histological spectrum of cutaneous adnexal tumors with follicular immunophenotypic differentiation.

Histologic subtype-based evaluation of recurrence and survival outcomes in patients with adenocarcinoma of the ampulla of Vater.

Patients with ampulla of Vater adenocarcinoma exhibit diverse outcomes, likely since these malignancies can originate from any of the three converging epithelia at this site. Such variability presents difficulties in clinical decision-making processes and in devising therapeutic approaches. In this study, the potential clinical value of histomolecular phenotypes was determined by integrating histopathological analysis with protein expression (MUC1, CDX2, CK20, and MUC2), in a cohort of 87 patients diagnosed with stage IB to III ampulla of Vater adenocarcinoma who underwent curative surgical resection. Of the 87 patients, 54 were classified as pancreato-biliary (PB) subtype and 33 as intestinal subtype. The median follow-up time for all patients was 32.8 months (95% CI, 25.3-49.2). Patients with a histomolecular PB phenotype (CDX2 negative, MUC1 positive, MUC2 negative, and irrespective of the CK20 results) were associated with poor prognostic outcomes in both disease-free survival (DFS) (HR = 1.81; 95% CI, 1.04-3.17; p = 0.054) and overall survival (OS) (HR = 2.01; 95% CI, 1.11-3.66; p = 0.039) compared to those with histomolecular intestinal carcinomas. Patients with the PB subtype were more likely to have local recurrence alone (11 of 37, 29.7%) compared to those with the intestinal subtype (1 of 15, 6.7%). In the context of systemic disease, a notably greater proportion of patients exhibiting elevated carbohydrate antigen 19-9 levels were observed in the PB subtype compared to the intestinal subtype (p = 0.024). In the cohort of 38 patients who received first-line palliative chemotherapy, a diminished median overall survival (OS) was observed in the PB group compared to the intestinal group (10.3 vs. 28.3 months, HR = 2.47; 95% CI, 1.23-4.95; p = 0.025). By integrating histopathologic and molecular criteria, we can identify distinct and clinically relevant histomolecular phenotypes in adenocarcinomas of the ampulla of Vater, which could have considerable impact on existing therapeutic approaches.

The prognostic potential of CDX2 in colorectal cancer: Harmonizing biology and clinical practice.

Adjuvant chemotherapy following surgical intervention remains the primary treatment option for patients with localized colorectal cancer (CRC). However, a significant proportion of patients will have an unfavorable outcome after current forms of chemotherapy. While reflecting the increasing complexity of CRC, the clinical application of molecular biomarkers provides information that can be utilized to guide therapeutic strategies. Among these, caudal-related homeobox transcription factor 2 (CDX2) emerges as a biomarker of both prognosis and relapse after therapy. CDX2 is a key transcription factor that controls intestinal fate. Although rarely mutated in CRC, loss of CDX2 expression has been reported mostly in right-sided, microsatellite-unstable tumors and is associated with aggressive carcinomas. The pathological assessment of CDX2 by immunohistochemistry can thus identify patients with high-risk CRC, but the evaluation of CDX2 expression remains challenging in a substantial proportion of patients. In this review, we discuss the roles of CDX2 in homeostasis and CRC and the alterations that lead to protein expression loss. Furthermore, we review the clinical significance of CDX2 assessment, with a particular focus on its current use as a biomarker for pathological evaluation and clinical decision-making. Finally, we attempt to clarify the molecular implications of CDX2 deficiency, ultimately providing insights for a more precise evaluation of CDX2 protein expression.