Search Results (213)

Background: Gastrointestinal neuroectodermal tumour (GNET), also known as clear cell sarcoma (CCS) of the gastrointestinal tract, is a rare neural crest-derived malignancy characterized by EWSR1-ATF1 or EWSR1-CREB1 fusions. Due to its rarity, there is limited evidence and no established guidelines for standard management. GNET is aggressive, with high rates of local recurrence, metastasis, and mortality. Case Presentation: We report the case of a 46-year-old woman with a family history of gastrointestinal cancers who was diagnosed in 2020 with an intestinal GNET. She underwent a segmental enterectomy as the first step of multimodal therapy. After three years of follow-up, she developed hepatic and peritoneal metastases. In November 2023, she began combined therapy with the anti-VEGF tyrosine kinase inhibitor cabozantinib and the immune checkpoint inhibitor nivolumab. The patient has maintained stable disease for 18 months with good tolerance and no adverse events. Molecular analysis of the tumour, which showed an EWSR1-CREB1 fusion, supported the selection of targeted therapy and immunotherapy as the preferred treatment approach. Conclusions: Immunotherapy and targeted therapy show promise for GNET/CCS treatment, but clinical standards are lacking, and evidence comes primarily from case reports. Additional data are needed to determine the best sequence and combination of therapies for this very rare disease. Full article

Uterine adenosarcoma with sarcomatous overgrowth (ASSO) is an exceptionally rare and aggressive subtype of uterine sarcomas, characterized by high mitotic activity, deep myometrial invasion, and an elevated risk of recurrence and metastasis. We report the case of a 79-year-old institutionalized woman with a history of hypertension, type 2 diabetes, chronic hepatitis B, and mild Alzheimer’s disease. During routine hepatic ultrasound surveillance, an incidental 26 mm endometrial lesion was detected. Initial diagnostic hysteroscopy revealed a benign endometrial polyp. However, due to the patient’s institutionalization and absence of gynecologic symptoms, no specialized follow-up was conducted. Four years later, she presented with profuse postmenopausal bleeding. Imaging revealed a markedly enlarged uterus with a 12–13 cm heterogeneous endometrial mass containing cystic and hemorrhagic areas, demonstrating diffusion restriction and significant contrast enhancement on MRI, with no radiologically suspicious lymphadenopathy. Hysteroscopy demonstrated a giant polyp with a broad implantation base; histology suggested sarcomatous transformation. Definitive diagnosis after total hysterectomy with bilateral salpingo-oophorectomy confirmed high-grade ASSO with homologous sarcomatoid overgrowth, consistent with endometrial stromal sarcoma. This case illustrates the progressive malignant transformation of an initially benign-appearing lesion in a patient with significant comorbidities and limited follow-up. It underscores the importance of clinical vigilance, regular monitoring, and interdisciplinary coordination in the evaluation of uterine enlargement in asymptomatic postmenopausal women. Full article

Lactylation, a recently identified post-translational modification (PTM) triggered by excessive lactate accumulation, has emerged as a crucial regulator linking metabolic reprogramming to pathological processes in liver diseases. In hepatic contexts, aberrant lactylation contributes to a range of pathological processes, including inflammation, dysregulation of lipid metabolism, angiogenesis, and fibrosis. Importantly, lactylation has been shown to impact tumor growth, metastasis, and therapy resistance by modulating oncogene expression, metabolic adaptation, stemness, angiogenesis, and altering the tumor microenvironment (TME). This review synthesizes current knowledge on the biochemical mechanisms of lactylation, encompassing both enzymatic and non-enzymatic pathways, and its roles in specific liver diseases. From a therapeutic perspective, targeting lactate availability and transport, as well as the enzymes regulating lactylation, has demonstrated promise in preclinical models. Additionally, combinatorial approaches and natural compounds have shown efficacy in disrupting lactylation-driven pathways, providing insights into future research directions for hepatic diseases. Although the emerging role of lactylation is gaining attention, its spatiotemporal dynamics and potential for clinical translation are not yet well comprehended. This review aims to synthesize the multifaceted roles of lactylation, thereby bridging mechanistic insights with actionable therapeutic strategies for liver diseases. Full article

Background: Tracking differential growth of secondary liver metastases is important for early detection of progression but remains challenging due to variable tumor growth rates. We aimed to automate accurate, consistent, and efficient longitudinal monitoring. Methods: We developed an automatic 3D segmentation and tracking algorithm to quantify differential growth, tested on contrast-enhanced MRI follow-ups of patients with neuroendocrine liver metastases (NELMs). The output was integrated into a decision support tool to distinguish between progressive disease, stable disease, and partial/complete response. A user study involving an expert group of seven expert radiologists evaluated its impact. Group comparisons used the Friedman test with post hoc analyses. Results: Our algorithm detected 991 metastases in 30 patients: 13% new, 30% progressive, 18% stable, and 18% regressive; the remainder were either too small to measure (15%) or merged with another metastasis in the follow-up assessment (6%). Diagnostic accuracy improved with additional information on hepatic tumor load and differential growth, albeit not significantly (p = 0.72). The diagnosis time increased (p < 0.001). All radiologists found the method useful and expressed a desire to integrate it in existing diagnostic tools. Conclusions: We automated segmentation and quantification of individual NELMs, enabling comprehensive longitudinal analysis of differential tumor growth with the potential to enhance clinical decision-making. Full article

Colorectal cancer (CRC) is a leading global malignancy with a poor prognosis in advanced stages. Early and accurate diagnosis remains challenging due to the overlapping of clinical manifestations between early-stage CRC and inflammatory bowel diseases. Although dynamic contrast-enhanced MRI (DCE-MRI) is a critical imaging modality for the diagnosis of CRC and colorectal cancer liver metastasis (CRLM), conventional gadolinium-based contrast agents (GBCAs) have the limitations of rapid clearance and potential toxicity risks. In this study, we report a gadolinium-free T1-weighted nanocontrast agent based on Fe(III)-coordinated poly(α-amino acid)s (Fe@POS) nanomicelles. Fe@POS nanomicelles exhibit a high longitudinal relaxivity (r₁ = 5.56 mM⁻¹s⁻¹) and prolonged blood circulation time with selective CRC tumor accumulation via enhanced permeability and retention (EPR) effect. In vivo MRI studies revealed long-period MRI of CRC. In CRLM lesions, normal hepatic tissue demonstrates greater Fe@POS uptake compared to tumor tissue, which enables clear delineation of tumor margins on MRI. Histological and biochemical analysis confirmed the biocompatibility of Fe@POS nanomicelles, with no acute toxicity observed, highlighting their potential as alternatives to GBCAs for clinical diagnostic applications. Full article

Surgery is one of the most effective treatment methods for liver metastases developing from primary colorectal cancer (CRC). Despite the widespread application of surgical approaches, recurrence rates remain substantial. Although chemotherapy is frequently employed, the supporting evidence for its efficacy in this context remains inconclusive. In the present study, we aimed to identify potential predictors of post-metastasectomy recurrence by analyzing clinical, pathological, and molecular features of both primary colorectal tumors and their corresponding hepatic metastases. Specifically, we evaluated the expression of epithelial–mesenchymal transition (EMT) markers, cancer stem cell (CSC) markers, and selected oncogenic mRNAs (RAS, mTOR, and CMYC) in tissue samples from 84 patients. RAS and CMYC are well-known proto-oncogenes involved in cell proliferation and survival, while mTOR functions as a central regulator of cell growth and metabolism. Following liver metastasectomy, intra-hepatic recurrence was observed in 40.5% of the cases. Among the molecular markers analyzed, the EMT transcription factor SNAIL—which plays a critical role in cancer cell invasion and metastasis—and mTOR exhibited significantly elevated expression in metastatic lesions from patients who experienced recurrence. While SNAIL expression did not show a clear association with the time to recurrence, increased mTOR expression in metastatic liver tissue was significantly associated with both shorter recurrence-free survival and diminished overall survival (p < 0.001). Results showed that mTOR expression levels could be a clinically relevant predictive indicator of remnant liver recurrence. In patients with liver metastases, the use of mTOR inhibitors may be considered after hepatic metastasectomy. Full article

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, remains a global health challenge with limited therapeutic options and high mortality rates. Despite advances in understanding its molecular pathogenesis, the role of metabolic reprogramming in HCC progression and therapy resistance demands further exploration. Nicotinamide N-methyltransferase (NNMT), a metabolic enzyme central to NAD⁺ and methionine cycles, has emerged as a critical regulator of tumorigenesis across cancers. However, its tissue-specific mechanisms in HCC—particularly in the context of viral hepatitis and methionine cycle dependency—remain understudied. This review systematically synthesizes current evidence on NNMT’s dual role in HCC: (1) driving NAD⁺ depletion and homocysteine (Hcy) accumulation via metabolic dysregulation, (2) promoting malignant phenotypes (proliferation, invasion, metastasis, and drug resistance), and (3) serving as a prognostic biomarker and therapeutic target. We highlight how NNMT intersects with epigenetic modifications, immune evasion, and metabolic vulnerabilities unique to HCC. Additionally, we critically evaluate NNMT inhibitors, RNA-based therapies, and non-pharmacological strategies (e.g., exercise) as novel interventions. By bridging gaps between NNMT’s molecular mechanisms and clinical relevance, this review provides a roadmap for advancing NNMT-targeted therapies and underscores the urgency of addressing challenges in biomarker validation, inhibitor specificity, and translational efficacy. Our work positions NNMT not only as a metabolic linchpin in HCC but also as a promising candidate for precision oncology. Full article

Background: Patients with jejunoileal neuroendocrine tumors (JINETs) can live for many years despite liver metastases. Evidence suggests that tumor heterogeneity is prognostically important, hence the selection of Ki67 hotspots for tumor grading. According to the stepwise metastasis model, clonal hotspots should predominate in the metastases. However, an alternative view holds that the polyclonality of metastases is consistent with origin from genetically heterogeneous clusters of disseminated cells. The shortcomings of Ki67 grading are also being recognized, thus renewing the search for other prognostic parameters. Methods: A 20-year retrospective study that paired JINETs and hepatic metastases was conducted by analyzing them for various parameters. Results: There were 43 patients (mean follow-up of 7.234 years); 14 were dead due to the disease, 22 were alive with the disease, and 7 were alive with no evidence of the disease. Most JI NETs (22/30) were grade 1, eight were grade 2, and none were grade 3. Tumor grades for both the primaries and liver metastases were not prognostic (p-values = 0.1260 and 0.2566, respectively). Seventeen of the 41 JI NETs showed mesenteric fibrogenesis (MF), and 18 had EMVI, with a high level of agreement between these parameters (92.68%) (kappa value 0.85), and both were strongly associated with poor outcomes. Conclusions: JINETs and their liver metastases tend to have low proliferation rates. However, an important mechanism in the metastatic cascade appears to be mesenteric fibrogenesis. It encases vessels, which enhances extramural vascular invasion, thereby conveying clusters of tumor cells to the liver. This supports the polyclonal nature of tumor progression rather than origin from hotspot aberrant clones. Full article

Background/Objectives: Composite hemangioendothelioma (CHE) is a rare vascular endothelial tumor with borderline malignancy. This study presents a case of CHE and an updated systematic review of previously reported cases, providing insights into recurrence patterns and survival outcomes. Methods: A comprehensive electronic search was conducted across PubMed, Scopus, the Cochrane Library, and Web of Science up to 31 December 2024, to identify eligible case reports. Kaplan–Meier curves were used to estimate event-free survival. Results: We report a 61-year-old man with a splenic lesion associated with weight loss and abdominal pain persisting for 1 year. Intraoperative findings revealed an enlarged spleen and multiple hepatic deposits. Splenectomy and liver biopsy revealed a well-demarcated, nodular tumor measuring 160 × 145 × 100 mm, with histological and immunohistochemical findings consistent with CHE, complicated by hepatic metastasis. Of 405 potentially eligible studies, 59 were included in the review, covering cases from 2000 to 2024, with a peak in 2020 and 2023. The median age of patients was 42 years, with the most common tumor sites being the lower extremities (30.48%), followed by the face, head, and neck (20.95%), and upper extremities (18.1%). Surgical intervention was the most common treatment (60.95%). Recurrence-free survival was observed in 42.86% of cases, while 15.24% experienced recurrence with or without metastasis. Two patients (1.90%) died from the disease. The median recurrence-free survival was 48 months (95% CI: 7.3–88.7). Conclusions: CHE exhibits significant morphological variation and can mimic other vascular tumors. Accurate diagnosis is crucial for proper prognosis and avoiding overtreatment due to misdiagnosis as more aggressive neoplasms. Patients with high-risk CHE should undergo closer surveillance to ensure timely detection of progression. Full article

Background: Preclinical studies on liposomal interleukin (IL) therapy demonstrate considerable promise in cancer treatment. This review explores the achievements, challenges, and future potential of liposomal IL encapsulation, focusing on preclinical studies. Methods: A structured search was conducted using the PubMed and Web of Science databases with the following search terms and Boolean operators: (“liposomal interleukin” OR “liposome-encapsulated interleukin”) AND (“gene therapy” OR “gene delivery”) AND (“cancer” OR “tumor” OR “oncology”) AND (“pre-clinical studies” OR “animal models” OR “in vitro studies”. Results: Liposomal IL-2 formulations are notable for enhancing delivery and retention at tumor sites. Recombinant human interleukin (rhIL-2) adsorbed onto small liposomes (35–50 nm) substantially reduces metastases in murine models. Hepatic metastasis models demonstrate superior efficacy of liposomal IL-2 over free IL-2 by enhancing immune responses, particularly in the liver. Localized delivery strategies, including nebulized liposomal IL-2 in canine pulmonary metastases and intrathoracic administration in murine sarcoma models, reduce systemic toxicity while promoting immune activation and tumor regression. Liposomal IL gene therapy, delivering cytokine genes directly to tumor sites, represents a notable advancement. Combining IL-2 gene therapy with other cytokines, including IL-6 or double-stranded RNA adjuvants, synergistically enhances macrophage and T-cell activation. Liposomal IL-4, IL-6, and IL-21 therapies show potential across various tumor types. Pairing liposomal IL-2 with chemotherapy or immune agents improves remission and survival. Innovative strategies, including PEGylation and ligand-targeted systems, optimize delivery, release, and therapeutic outcomes. Conclusions: Utilizing immune-stimulatory ILs through advanced liposomal delivery and gene therapy establishes a strong foundation for advancing cancer immunotherapy. Full article

Background: Liver cancer, specifically hepatocellular carcinoma (LIHC), ranks as the second most common cause of cancer-related fatalities globally. Moreover, the occurrence rate of LIHC is steadily increasing. A recently identified gene, SPSB2, has been implicated in cell signaling, impacting the development and progression of non-small cell lung cancer. Nevertheless, studies on the role of SPSB2 in the pathogenesis of LIHC are lacking. Methods: Using the TCGA, GTEx, and GEO databases, we obtained differentially expressed genes that affect the prognosis of patients with LIHC. We utilized the Kruskal–Wallis test, along with univariate and multivariate COX regression analyses, to determine the correlation between SPSB2 and patient clinical indicators. Potential biological functions of SPSB2 in LIHC were explored by enrichment analysis, ssGSEA, and Spearman correlation analysis. Finally, LIHC cell lines Huh7 and SMMC-7721 were used to validate the biological function of SPSB2. Results: The results showed LIHC patients with higher SPSB2 expression had a poorer prognosis, and SPSB2 expression was significantly correlated with LIHC patients’ Histologic grade, Pathologic T stage, Prothrombin time, Pathologic stage, BMI, weight, adjacent hepatic tissue inflammation, AFP level, and OS event (p < 0.05). SPSB2 shows notable enrichment in pathways linked to tumorigenesis and the immune system. Moreover, its expression is strongly connected to immune cells and immune checkpoints. Knockdown of SPSB2 expression in Huh7 cells and SMMC-7721 cells inhibits SPSB2’s biological functions, including proliferation, invasion, metastasis, and other phenotypes. Conclusions: SPSB2 plays a crucial role in the development of LIHC. It is related to the immune response and unfavorable outcomes. SPSB2 may function as a clinical biomarker for prognosis. Full article

The liver is the most common site of metastasis of colorectal cancer (CRC), and colorectal liver metastasis is one of the major causes of CRC-related deaths worldwide. The tumor microenvironment, particularly the extracellular matrix (ECM), plays a critical role in CRC metastasis and chemoresistance. Based on findings from clinical and basic research, this review attempts to offer a complete understanding of the role of the ECM in colorectal liver metastasis and to suggest potential ways for therapeutic intervention. First, the ECMs’ role in regulating cancer cell fate is explored. We then discuss the hepatic ECM fingerprint and its influence on the metastatic behavior of CRC cells, highlighting key molecular interactions that promote metastasis. In addition, we examine how changes in the ECM within the metastatic niche contribute to chemoresistance, focusing on ECM remodeling by ECM stiffening and the activation of specific signaling pathways. Understanding these mechanisms is crucial for the development of novel strategies to overcome metastasis and improve outcomes for CRC patients. Full article

Transforming growth factor-beta (TGF-β) plays a dual role in hepatocellular carcinoma (HCC), acting as a tumor suppressor in early stages by inducing cell cycle arrest and apoptosis, and as a promoter in advanced stages by fostering tumor progression, epithelial–mesenchymal transition (EMT), and metastasis. Understanding TGF-β’s role in HCC progression, particularly its impact on tumor–stroma interactions, is crucial for developing personalized therapies. This study aims to clarify TGF-β function in HCC using patient-derived cell lines and advanced 2D and 3D culture models. Three new cell lines (HLC21, HLC19 tumoral, and HLC19 metastatic) were isolated from HCC patient biopsies, characterizing their phenotypic markers and responses to TGF-β and its inhibitor, galunisertib. HLC21 cells displayed a mixed epithelial–mesenchymal phenotype, responding to TGF-β suppressing growth and undergoing EMT, which were inhibited by galunisertib. Conversely, HLC19 tumoral and metastatic cells exhibited mesenchymal phenotypes and were resistant to both TGF-β suppression and galunisertib effects. In 3D co-cultures with hepatic fibroblasts, TGF-β inhibitory effects were diminished for responsive cell lines, while resistant lines maintained their non-responsiveness. These findings highlight TGF-β’s dual role in HCC and its influence on tumor–stroma crosstalk, offering valuable models for exploring personalized anti-TGF-β therapies based on tumor characteristics. Full article

Background/Objectives: There is increasing evidence that a subset of patients with stage IV pancreatic ductal adenocarcinoma (PDAC) and liver-only metastasis may benefit from surgical resection of both the primary tumor and metastatic lesions. Methods: A meta-analysis and systematic review were conducted in patients with stage IV PDAC and hepatic-only metastasis. A comprehensive literature search (January 2015–June 2023) was performed using PubMed with keywords including “pancreatic cancer”, “oligometastatic”, and “surgery”. Results: Sixteen articles were included in the final review and characterized based on patient selection factors and prognostic indicators. Seven studies reported hazard ratios (HRs) or Kaplan–Meier curves for survival in synchronous resected cohorts versus chemotherapy/palliation alone, which indicated a statistically significant survival benefit in the resection cohorts (pooled HR: 0.41, 95% CI: 0.31–0.53, p < 0.01). Prognostic indicators for synchronous and metachronous resection included lower pre-operative CA19-9, negative margin status of the primary tumor, moderate-to-well-differentiated tumors (grades I–II), and receiving pre-operative chemotherapy. Conclusions: Surgical/ablation selection factors are evolving, with priorities on (1) response to induction chemotherapy, (2) ability to achieve R0 resection, and (3) minimally invasive approaches remaining critical to optimal patient selection. Standardized radiologic and tumor marker evaluation and response to neoadjuvant therapy and optimizing performance status are critical to improved outcomes. Full article

Objectives: Although systemic chemotherapy (SC) is the mainstay for treating unresectable intrahepatic cholangiocarcinoma (ICC), its efficacy is limited and it causes severe systemic side effects. This study focuses on evaluating the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib plus programmed death-1 (PD-1) inhibitors (HLP), compared to SC in combination with lenvatinib plus PD-1 inhibitors (SCLP) for unresectable ICC. Methods: We analyzed patients initially diagnosed with unresectable ICC at our center between March 2021 and December 2023, classifying them into HLP and SCLP groups according to treatment regimen. This study assessed and compared overall survival (OS), progression-free survival (PFS), tumor response, and safety outcomes across the two treatment groups. Results: This study enrolled 53 subjects in total; 25 were treated with HLP and 28 with SCLP. The two groups showed well-matched baseline characteristics. The HLP group reported an extended median OS (12.8 vs. 11.0 months, p = 0.310) and a prolonged median PFS (8.8 vs. 6.4 months, p = 0.043), compared to the SCLP group. The HLP group had a better objective response rate (ORR) (52% vs. 25%, p = 0.043) and disease control rate (DCR) (96% vs. 78.6%, p = 0.104). Based on OS (p = 0.019) and PFS (p = 0.032) results, those without extrahepatic metastasis seemed to benefit more significantly from the HLP regimen than from the SCLP regimen. The HLP group experienced fewer grade 3–4 adverse events (AEs) than the SCLP group. Conclusions: The HLP regimen for unresectable ICC is an effective and safe strategy and is potentially better suited for patients without extrahepatic metastases. Full article