INTRODUCTION:Mature (MT) and immature teratomas (ITs) contain diverse histological components; however, their tissue-level spatial organization remains poorly understood. This proof-of-concept study aimed to develop a reproducible digital pathology workflow for quantifying the spatial distances among histological components of ovarian teratomas. METHODS:Four representative mature teratoma sections and three ITs with neural elements were analyzed. Whole-slide images of hematoxylin and eosin-stained sections were manually annotated, and each morphologically recognizable component was represented by a centroid using a Python-based image analysis method. Pairwise centroid-based distances were calculated using brute-force and nearest-distance approaches, followed by an exploratory statistical analysis. RESULTS:Anatomically related tissue pairs, including bronchial epithelium-bronchial gland and epidermis-hair follicle, showed relatively short centroid-based distances, suggesting that the workflow can capture the expected tissue-level architectural relationships. Additional associations, such as bronchial gland-bone proximity, were also observed but should be interpreted as hypothesis-generating findings. No consistent spatial proximity was observed between the immature and mature components. CONCLUSION:These findings support the technical feasibility of the proposed workflow for the exploratory tissue-level spatial analysis of teratomas, while emphasizing that spatial associations do not directly demonstrate biological interactions, developmental induction, or lineage relationships.
Introduction: Clear cell renal cell carcinoma (ccRCC) exhibits substantial heterogeneity within its tumor microenvironment, contributing to variable clinical outcomes. The prognostic significance and molecular characteristics of cancer-associated fibroblasts in ccRCC remain poorly defined. Methods: We analyzed 736 ccRCC cases (203 institutional and 533 TCGA) to identify histologically distinct activated cancer-associated fibroblasts (aCAFs; oval to mildly elongated immature fibroblasts occupying >5% of stroma) on H&E-stained slides. Clinicopathological correlations, immunohistochemical immune profiling, transcriptomic analyses, and machine learning-based survival modelling were performed; for the latter, 17 neoadjuvant-treated cases were excluded from the TCGA cohort, yielding an analytic cohort of 516 cases. Results: aCAFs were identified in 12.3% and 12.9% of institutional and TCGA cohorts, respectively, and were significantly associated with advanced tumor stage, higher histologic grade, sarcomatoid features, and poor disease-specific survival, remaining an independent prognostic factor on multivariate analysis. aCAF-positive tumors exhibited reduced tumor-infiltrating lymphocytes and CD4+ T-cell infiltration, enhanced TGF-β signaling, and molecular enrichment in FGFR2 and complement regulation pathways. In machine learning-based survival models, aCAFs ranked among the top five prognostic predictors, and their inclusion improved predictive accuracy with DSS AUC of 0.874 versus 0.858. In silico drug screening identified ponatinib and HG6-64-1 as candidate therapeutic agents for tumors with high fibroblast activation protein-α expression. Conclusion: Morphologically defined aCAFs represent a histologically recognizable and clinically meaningful stromal component associated with immunosuppression and adverse prognosis in ccRCC, with potential utility for routine diagnostic application and therapeutic targeting.
Background: The subependymal giant cell astrocytoma (SEGA) predominantly occurs in patients with tuberous sclerosis. Here, we present an unusual aggressive transformation of SEGA-imitating fibrous meningioma in a child carrying a germline CHEK2 mutation Methods: This case study was conducted at a tertiary pediatric oncology center in accordance with current diagnostic and therapeutic standards. Tumor classification followed WHO CNS5 criteria and was complemented by genome-wide DNA methylation profiling. Comprehensive molecular workup included germline and somatic whole-exome sequencing, copy-number analysis, and RNA-sequencing; Results: An 8.5-year-old girl presented with an intraventricular tumor initially diagnosed as SEGA based on imaging and partial resection histology. Treatment with an mTOR inhibitor led to four years of stability before rapid progression and death due to postoperative brain edema. Re-examination of both specimens revealed transformation into an aggressive anaplastic meningioma, while the initial lesion was reclassified as fibrous meningioma. Whole-exome and microarray analyses excluded germline TSC1/TSC2 defects but identified a pathogenic germline CHEK2 variant (c.1466del, p.Asn489ThrfsTer23). Somatic alterations involving NF1, and TP53 were found in the primary tumor. Conclusions: Constitutional CHEK2 mutations combined with somatic NF1 defect may have promoted the malignant progression of SEGA-imitating fibrous meningioma and its favorable initial response to mTOR inhibitors.
Therapy based on chimeric antigen receptor–engineered invariant natural killer T (iNKT) cells (CAR-NKT cells) is an innovative cellular immunotherapy strategy that offers advantages over conventional CAR-T cell therapy in the treatment of solid tumors. This article reviews the research progress and current application of CAR-NKT cells in solid tumors. Current studies have shown that CAR-NKT cells can efficiently recognize tumor-associated antigens, infiltrate the tumor microenvironment, and exert anti-tumor effects through direct killing and cytokine secretion. Compared with CAR-T therapy, CAR-NKT therapy exhibits stronger anti-tumor potency and a reduced incidence of graft-versus-host disease. Furthermore, CAR-NKT cells can enhance anti-tumor immunity by regulating dendritic cells, NK cells, and CD8⁺ T cells. Early clinical trials for neuroblastoma and preclinical trials for other solid tumors have shown good safety and preliminary efficacy, and therapies have great potential for clinical translation. However, this therapy still faces challenges such as optimizing antigen selection, insufficient in vivo expansion and persistence, tumor heterogeneity, and immune suppression barriers. Future directions include advancing cytokine engineering and combination therapies. Collectively, CAR-NKT cells provide new ideas and new means to break through the difficulties in treating solid tumors and hold the promise of becoming the next generation of cellular immunotherapy.
Introduction: High inter- and intraobserver variability is acknowledged in Negative for Intraepithelial Lesion or Malignancy (NILM), Atypical Squamous Cells of Undetermined Significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) diagnostic categories in cervical cytology. As digital cytology (DC) has emerged, whole-slide images (WSI) have been compared to conventional light microscopy (LM) to evaluate its feasibility in routine practice. Methods: Six cytopathologists evaluated 20 liquid-based cervical samples diagnosed as ASC-US, LSIL or NILM with known hrHPV status, both by conventional LM and WSI, equalling 240 evaluations. Interobserver agreement was measured using Fleiss’s Kappa, Kendall´s coefficient and interclass correlation (ICC). Results: Most of the samples (93.75%) were assigned to the same original range of categories: NILM 5 (25%), ASC-US 10 (50%) and LSIL 5 (25%). WSI versus LM interobserver agreement varied with Fleiss’s Kappa (0.324 versus 0.319), Kendall’s W (0.670 versus 0.572) and ICC (0.585 versus 0.414). Interobserver agreement for the ASC-US category was higher in Kendall’s W (0.435 for WSI versus 0.329 for LM) and in ICC (0.394 versus 0.118). Fleiss’s kappa showed lower interobserver agreement for ASC-US in WSI than LM (0.000 versus 0.039). Conclusion: This study illustrated that despite overall better agreement in WSI, ASC-US results were less favourable in WSI than LM, according to Fleiss’s kappa test, but not other tests.
Introduction: Herein, we present the first documented case of a solitary fibrous tumor (SFT) arising within thyroid follicular nodular disease and discuss its histogenesis. Case Presentation: A man in his 60s presented with a left thyroid nodule. Histologically, the nodule was composed of spindle cells and thyroid follicles. The spindle cells were positive for CD34 and STAT6, negative for PAX8 and cytokeratin, and harbored a NAB2::STAT6 fusion, confirming the diagnosis of SFT. No extrathyroidal SFT was identified, and the Demicco model classified the tumor as low risk. Conclusion: This report suggests that SFT may arise de novo within the stromal component of thyroid follicular nodular disease. This underscores the need to consider SFT in the differential diagnosis of spindle cell lesions occurring within thyroid nodules.
INTRODUCTION:Fumarate hydratase-deficient renal cell carcinoma (FHd RCC) is a rare, aggressive subtype of kidney cancer associated with hereditary leiomyomatosis and renal cell carcinoma syndrome. METHODS:We retrospectively analyzed 12 FHd RCC cases from Hungarian patients, assessing clinical, histopathological, immunohistochemical, and molecular features. RESULTS:The median age at diagnosis was 48.5 years, with a male-to-female ratio of 1.6:1. Most patients presented symptomatically and in an advanced stage; ten underwent surgery, and seven had metastatic disease at diagnosis. Tumors were unifocal, unilateral, and high-grade, displaying heterogeneous architectural patterns, often with eosinophilic cytoplasm and prominent viral inclusion-like nucleoli. Fumarate hydratase (FH) expression was lost in all but 1 tumor, while aberrant nuclear and cytoplasmic 2SC positivity was observed in all cases. CK7 was consistently negative, whereas AMACR and PAX8 were positive in all tested tumors. GATA3 expression was focal in 2 tumors. PD-L1 positivity was detected in 4 tumors, including 1 with high tumor mutational burden. Pathogenic FH mutations were confirmed in nine cases, including three germline alterations. Systemic therapy was administered in 7 patients, with variable responses. CONCLUSION:Our findings highlight the pronounced morphological heterogeneity of FHd RCC and the critical role of combined FH and 2SC immunohistochemistry for accurate diagnosis. FHd RCC should be recognized as a distinct, highly malignant renal neoplasm, warranting comprehensive histological, immunohistochemical, and genetic assessment, along with genetic counseling to identify potential hereditary background.
BACKGROUND:Lactate levels are significantly elevated in the tissues of patients with inflammatory bowel disease (IBD) and colorectal cancer (CRC). In IBD, lactate promotes anti-inflammatory repair by inducing M2 macrophage polarization, whereas abnormal lactate levels in the CRC tumor microenvironment contribute to tumor initiation and progression through acidification, immune reprogramming, and activation of pro-angiogenic pathways. Akkermansia muciniphila (Akk) exhibits a distinct preference for lactate as a nutritional substrate, and its abundance increases significantly in the murine gut following lactate administration. As an important intestinal symbiont, Akk shows potential in the prevention and treatment of both IBD and CRC. KEY MESSAGES:We hypothesize that targeting lactate metabolism and leveraging the active components of Akk may provide novel strategies for the prevention and therapy of IBD and CRC. SUMMARY:This review aims to summarize the relationship among lactate, Akk, and inflammation-associated CRC, thereby offering new perspectives and approaches for the clinical management of CRC.
INTRODUCTION:Pancreatic cancer is known for its poor prognosis, characterized by early systemic dissemination and locally aggressive behavior. Podoplanin (PDPN) is a mucin-type transmembrane glycoprotein physiologically expressed in various tissues. In certain malignancies, overexpression of PDPN has been linked to enhanced tumor invasiveness, metastatic potential, and unfavorable clinical outcomes. In this study, we evaluated stromal PDPN expression in a cohort of patients diagnosed with pancreatic carcinoma and investigated its immunohistochemical profile in relation to patient survival. METHODS:This retrospective study included 103 cases of pancreatic ductal adenocarcinoma (PDAC). Histological grade, perineural invasion, pathological tumor stage, lymph node status, and lymphovascular invasion were evaluated. Immunohistochemical expression of PDPN was evaluated as a percentage by calculating the proportion of PDPN-positive (of any staining intensity) tumor stroma relative to the total tumor stromal area. RESULTS:Among 103 cases of PDAC, the median value of immunohistochemical expression of PDPN in tumor stroma was 20%. Complete absence of PDPN expression was observed in 7 patients (6.8%). The survival analysis indicated that higher stromal PDPN expression was associated with shorter overall survival (log-rank p = 0.0129). High PDPN expression in cancer-associated fibroblasts showed a borderline association with overall survival in multivariable Cox regression analysis (hazard ratio: 1.52, 95% confidence interval: 1.00-2.32, p = 0.05). CONCLUSION:PDPN expression may serve as a prognostic biomarker in PDAC and could contribute to future therapeutic stratification.
BACKGROUND:The final step of the Human immunodeficiency virus type 1 (HIV-1) replication cycle, virion budding and scission from the host cell membrane, is executed not by a viral enzyme but by the hijacked host endosomal sorting complexes required for transport (ESCRT) machinery. SUMMARY:This review synthesizes current knowledge on how HIV-1 Gag polyprotein recruits and coordinates the ESCRT pathway. We detail the critical roles of the PTAP and YPXnL late-domain motifs in engaging Tsg101 (ESCRT-I) and ALIX adaptors, which nucleate the assembly of constrictive ESCRT-III polymers and the VPS4 ATPase to catalyze membrane fission. We examine the plasticity of these recruitment pathways, the regulatory influence of ubiquitination, and how cell-type-specific factors impact budding efficiency. Furthermore, we assess emerging connections between ESCRT function, viral pathogenesis, and therapeutic opportunities. KEY MESSAGES:The ESCRT-dependent budding of HIV-1 is a robust yet vulnerable process, characterized by redundant entry points converging on an essential core scission engine. This mechanistic understanding reveals critical virus-host interfaces that present promising targets for novel antiviral strategies aimed at disrupting this late stage of the viral life cycle.
INTRODUCTION:FAT1 is mutated in many types of cancer. The objective of this study was to analyze the diagnostic role of FAT1 protein in cancers affecting the serosal cavities. METHODS:FAT1 protein expression by immunohistochemistry was analyzed in 256 effusions (139 peritoneal, 116 pleural, 1 pericardial), consisting of 96 tubo-ovarian carcinomas, 56 breast carcinomas, 44 mesotheliomas, 28 uterine corpus and cervical carcinomas, 15 lung carcinomas, 13 gastrointestinal carcinomas, and 4 cancers of other origin. RESULTS:FAT1 expression was most common in gastrointestinal carcinomas (12/13; 92%), followed by lung (9/15; 60%), breast (31/56; 55%), and uterine cervical (4/8; 50%) carcinomas, with infrequent expression in other tumors, including tubo-ovarian carcinomas (5/96; 5%). Mesotheliomas were uniformly negative. Staining of a limited series of surgical specimens showed comparable results for patient-matched breast carcinomas (29/41; 71%), whereas tubo-ovarian carcinomas were more frequently positive (16/57; 28%), though often focally, compared to effusions. Eight epithelioid mesotheliomas were negative (0/8; 0%). Survival analysis for 42 breast carcinoma patients with effusion for whom clinical data were available showed no association with overall (p = 0.398) or disease-free (p = 0.255) survival. CONCLUSION:FAT1 is commonly expressed in carcinomas of gastrointestinal, lung, or breast origin but is rarely expressed in tubo-ovarian carcinoma effusions and is absent in mesothelioma. Whether this difference is of use in the diagnostic setting remains to be established.
BACKGROUND:Therapy based on chimeric antigen receptor-engineered invariant natural killer T cells (chimeric antigen receptor natural killer T [CAR-NKT] cells) is an innovative cellular immunotherapy strategy that offers advantages over conventional CAR-T cell therapy in the treatment of solid tumors. SUMMARY:This article reviewed the research progress and current application of CAR-NKT cells in solid tumors. Current studies have shown that CAR-NKT cells can efficiently recognize tumor-associated antigens, infiltrate the tumor microenvironment, and exert antitumor effects through direct killing and cytokine secretion. Compared with CAR-T therapy, CAR-NKT therapy exhibits stronger antitumor potency and a reduced incidence of graft-versus-host disease. Furthermore, CAR-NKT cells can enhance antitumor immunity by regulating dendritic cells, NK cells, and CD8+ T cells. Early clinical trials for neuroblastoma and preclinical trials for other solid tumors have shown good safety and preliminary efficacy, and therapies have great potential for clinical translation. KEY MESSAGES:However, this therapy still faces challenges such as optimizing antigen selection, insufficient in vivo expansion and persistence, tumor heterogeneity, and immune suppression barriers. Future directions include advancing cytokine engineering and combination therapies. Collectively, CAR-NKT cells provide new ideas and new means to break through the difficulties in treating solid tumors and hold the promise of becoming the next generation of cellular immunotherapy.
INTRODUCTION:The corded and hyalinized variant of endometrioid adenocarcinoma (CHEC) is a biphasic tumor composed of cords of epithelioid and/or spindle cells (CoES) within hyalinized or chondroid stroma, which is often misdiagnosed as carcinosarcoma. CHEC predominantly occurs in younger women, and it has a favorable clinical outcome. Thus, many patients wish to preserve their fertility and undergo conservative treatment. This study investigated a selective loss of progesterone receptor (PR) in the CoES component and reported clinical, histopathological, and immunohistochemical features of CHEC. METHODS:A total 6 patients with CHEC between 2004 and 2021 were searched. We performed immunohistochemistry for estrogen receptor (ER), PR, β-catenin, E-cadherin, cytokeratin, p53, and Ki-67. RESULTS:The patients were 21-40 years old. All of the tumors were FIGO grade 1 endometrioid adenocarcinoma (EAC) intermingled with CoES component. Notably, PR expression was completely lost in the CoES component in contrast to the EAC component, with a significantly different expression pattern of cytokeratin, ER, β-catenin, and E-cadherin from the areas of typical EAC. Four of the 6 patients initially received exogenous progestin treatment, and two of them ultimately had a hysterectomy after progestin treatment. All 4 patients treated with progestin had persistent tumors at the last follow-up curettage or hysterectomy. CONCLUSION:Considering the usual high rate of complete remission with progestin treatment in patients with EAC, the high rate of persistent tumors in our case series suggests that CHEC may be intrinsically resistant to progestin treatment due to the lack of expression of PR in the CoES component.
BACKGROUND:Renal cell carcinoma (RCC) is a heterogeneous disease, with the last World Health Organization (WHO) classification introducing several novel entities, among which the molecularly defined RCCs. This growing complexity highlights the need for integration of morphology, immunohistochemistry (IHC) and molecular techniques, ensuring accurate classification and reducing the "RCC not otherwise specified (NOS) category." SUMMARY:Molecular assays such as next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) are increasingly necessary for diagnosing molecularly defined RCCs. IHC remains fundamental for diagnosing both "old" and newly defined RCCs, representing a surrogate for molecular alterations such as fumarate-hydratase and succinate-dehydrogenase deficiency, anaplastic lymphoma kinase rearrangements, SMARCB1 loss, and TFE3 rearrangements. However, entities like ELOC-mutated RCC require molecular testing for diagnosis. Liquid biopsy offers a further diagnostic tool. Circulating microRNAs can support diagnosis, classification, and monitoring. Furthermore, circulating tumor DNA (ctDNA) methylation analyses and circulating tumor cells (CTCs) offer promising and minimally invasive tools for stratification, though their clinical use is still evolving. KEY MESSAGES:A precise diagnosis integrating histopathology, IHC, and molecular testing is critical for guiding management, identifying hereditary syndromes, and implementing personalized tumor biology-based therapies. With evolving molecular diagnostic and circulating biomarkers, careful clinical integration is needed to optimize outcomes and treatment.
Introduction: The subependymal giant cell astrocytoma (SEGA) predominantly occurs in patients with tuberous sclerosis. Here, we present an unusual aggressive transformation of SEGA-imitating fibrous meningioma in a child carrying a germline CHEK2 mutation. Methods: This case study was conducted at a tertiary pediatric oncology center in accordance with current diagnostic and therapeutic standards. Tumor classification followed WHO CNS5 criteria and was complemented by genome-wide DNA methylation profiling. Comprehensive molecular workup included germline and somatic whole exome sequencing, copy number analysis, and RNA sequencing. Results: An 8.5-year-old girl presented with an intraventricular tumor initially diagnosed as SEGA based on imaging and partial resection histology. Treatment with an mTOR inhibitor led to 4 years of stability before rapid progression and death due to postoperative brain edema. Re-examination of both specimens revealed transformation into an aggressive anaplastic meningioma, while the initial lesion was reclassified as fibrous meningioma. Whole exome and microarray analyses excluded germline TSC1/TSC2 defects but identified a pathogenic germline CHEK2 variant (c.1466del, p.Asn489ThrfsTer23). Somatic alterations involving NF1 and TP53 were found in the primary tumor. Conclusions: Constitutional CHEK2 mutations combined with somatic NF1 defect may have promoted the malignant progression of SEGA-imitating fibrous meningioma and its favorable initial response to mTOR inhibitors.
Background: In cancers, key prognostic determinants such as clinical stage and mutational load are well recognized. However, mucinous adenocarcinomas (MACs) display distinct biological behavior, as a large proportion of their tumor volume consists of extracellular mucin, predominantly the MUC2 protein, rather than neoplastic cells. MUC2 provides a protective barrier for cancer cells against external factors, including chemotherapeutic agents and cytotoxic lymphocytes, while its anti-inflammatory and tumor-suppressive properties paradoxically support tumor persistence and immune evasion. Summary: Excessive mucin secretion and its viscoelastic properties facilitate rapid local expansion and dissemination into adjacent tissues. These effects are particularly significant in organs that open into body cavities, such as the colon and appendix, whereas they are less pronounced in confined organs such as the breast. In ductal organs, overexpression of MUC2 may promote early invasion through pressure-induced disruption of ductal structures. Key Messages: Consequently, in MACs, tumor location and organ architecture, alongside clinical stage and mutational profile, are critical determinants of biological behavior. Accurate differential diagnosis and therapeutic approaches should address both organ-specific pathways and MUC2-related mechanisms, including its structural, anti-inflammatory, and tumor-suppressive functions. MUC2-targeted therapies may thus represent a promising adjunct to conventional, organ-based treatment strategies.
INTRODUCTION:High inter- and intraobserver variability is acknowledged in negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US), and low-grade squamous intraepithelial lesion (LSIL) diagnostic categories in cervical cytology. As digital cytology has emerged, whole-slide images (WSIs) have been compared to conventional light microscopy (LM) to evaluate its feasibility in routine practice. METHODS:Six cytopathologists evaluated 20 liquid-based cervical samples diagnosed as ASC-US, LSIL, or NILM with known hrHPV status, both by conventional LM and WSI, equalling 240 evaluations. Interobserver agreement was measured using Fleiss's kappa, Kendall´s coefficient and interclass correlation (ICC). RESULTS:Most of the samples (93.75%) were assigned to the same original range of categories: NILM 5 (25%), ASC-US 10 (50%), and LSIL 5 (25%). WSI versus LM interobserver agreement varied with Fleiss's kappa (0.324 versus 0.319), Kendall's W (0.670 versus 0.572), and ICC (0.585 versus 0.414). Interobserver agreement for the ASC-US category was higher in Kendall's W (0.435 for WSI versus 0.329 for LM) and in ICC (0.394 versus 0.118). Fleiss's kappa showed lower interobserver agreement for ASC-US in WSI than LM (0.000 versus 0.039). CONCLUSION:This study illustrated that despite overall better agreement in WSI, ASC-US results were less favourable in WSI than LM, according to Fleiss's kappa test, but not other tests.
Introduction: We recently proposed SARIFA (Stroma AReactive Invasion Front Areas), defined as direct tumour-adipocyte interaction, as an H&E-based histopathologic biomarker in gastrointestinal cancers, particularly gastric cancer (GC) and colorectal cancer (CRC). Despite SARIFA’s well-validated prognostic value, its mechanistic underpinnings remain unclear. We hypothesized that extracellular matrix remodelling, specifically the plasmin/plasminogen activator system, may contribute to SARIFA formation. Methods: To test this, we compared the prognostic value of H&E-based SARIFA status with enzyme-linked immunosorbent assay (ELISA)-based protein levels of the serine proteases urokinase-type plasminogen activator (uPA, encoded by PLAU) and plasminogen activator inhibitor-1 (PAI-1, encoded by SERPINE1) in CRC. We further examined associations between SARIFA status and the plasmin/plasminogen activator system as well as downstream metalloproteinases using both protein (ELISA, immunohistochemistry) and bulk gene expression data (TCGA-COAD/READ and TCGA-STAD), as well as spatial gene expression profiling in CRC (n = 8) and GC (n = 12). Results: Our findings show that high expression of the plasmin/plasminogen activator system and downstream metalloproteinases correlates with SARIFA positivity. Digital spatial profiling revealed PLAU upregulation in tumour cells and PLAUR (encoding uPAR) upregulation in adjacent stromal cells at SARIFAs, suggesting a potential receptor-ligand interaction. Notably, SARIFA-positive tumours showed significantly higher numbers of tumour buds. Conclusion: These results provide new insights into the biological basis of SARIFAs and suggest therapeutic vulnerabilities related to the plasmin/plasminogen activator system.
Introduction: REV7 functions in various biological processes, including the DNA damage response. REV7 expression has been linked to the prognosis and chemoresistance in several human cancers. This study investigated the significance of REV7 in gallbladder adenocarcinoma (GBAC). Methods: REV7 expression was examined immunohistochemically in 77 resected GBAC specimens, and its association with clinicopathological features was analyzed. REV7-depleted GBAC cell lines were established, and the biological effects of REV7 depletion were evaluated. Results: High REV7 expression in GBAC tissues correlated with increased cell proliferation, as assessed by Ki-67 labeling indices (p < 0.001), and was associated with a trend toward shorter overall survival (p = 0.070) and significantly shorter post-progression survival (p = 0.035). REV7-knockout and REV7-knockdown cell lines derived from NOZ and G415 GBAC cells (NOZ-KO and G415-KD, respectively) showed reduced proliferation and increased sensitivity to cisplatin; however, REV7 depletion did not affect cell migration and invasion. Reintroduction of REV7 into NOZ-KO cells restores chemoresistance. Furthermore, RNA sequencing analysis comparing wild-type NOZ and NOZ-KOs revealed that REV7 inactivation downregulates genes involved in the DNA damage response. Conclusion: REV7 may contribute to tumor progression and chemoresistance in GBAC and may serve as a prognostic biomarker and molecular target for GBAC management.
INTRODUCTION:Cervical cancer, primarily driven by oncogenic HPV16/18, often relapses despite standard treatments. HPV circulating tumor DNA (ctDNA), which reflects tumor-derived genetic material in the bloodstream, has emerged as a promising noninvasive biomarker for monitoring disease progression. METHODS:A prospective study was conducted on 20 patients with HPV16/18-associated cervical cancer. Posttreatment blood samples were collected, and HPV ctDNA levels were measured using droplet digital PCR. The correlation between HPV ctDNA levels and disease progression was examined. RESULTS:HPV ctDNA was detected in 21% (18/85) of samples, with 6% (5/85) showing positivity. Patients without disease progression (n = 15) were HPV ctDNA negative, indicating a false positivity rate of zero. HPV ctDNA concentrations appeared higher in samples collected before or during disease progression, suggesting a potential association with disease status. Patients with positive HPV ctDNA tended to have shorter progression-free survival compared to those with negative ctDNA. CONCLUSIONS:This study suggests that HPV ctDNA may aid in monitoring disease progression in patients with HPV16/18-associated cervical cancer, highlighting the need for further validation.
