Liver first approach is one of the possible strategies for synchronous CRLM. Less attention is generally reserved to colorectal resection after hepatic surgery. Aim of the study is to investigate the influence of liver resection on primary tumor surgery. In the present monocentric cohort study, patients operated onlaparoscopic CR resection after open or laparoscopic liver surgery are compared (propensity score matching analysis 1:3) with laparoscopically operated non metastatic CR patients in period 2015-2023. Primary endpoint: 30 day morbidity; secondary endpoints: conversion, reintervention and 90 days mortality rate, surgery duration. Forty liver-first and 642 control patients are matched; 40 and 120 patients respectively are compared after matching. Morbidity rate 32.5% and 37.5% (p = 0.568); CCI 100 >20.9 4/40 and 21/120 (p = 0.257); conversion rate 7.5% and 10% (p = 0.638); reintervention 3/40 and 13/120 (p = 0.761); mortality 0/40 and 1/120; surgery duration 288 and 279 min (p = 0.650). No difference in hospital stay (6.5 and 7 days in liver first and control group respectively). Liver-first approach does not worsten intraoperative and post-operative short term outcomes of primary tumor resection.

Perioperative chemotherapy is frequently used for resectable colorectal liver metastases (CRLM), despite persistent uncertainty regarding the extent of its survival benefit. This perspective revisits the evidence supporting this practice and asks whether upfront liver-directed treatment should be more strongly considered in selected patients. A central paradox underpins this debate: although adjuvant chemotherapy improves OS in stage III colon cancer, randomized trials in resectable CRLM have consistently failed to demonstrate an OS advantage for perioperative or adjuvant systemic therapy. Instead, chemotherapy primarily appears to delay recurrence while exposing patients to potential harms. These harms include treatment-related hepatic injury, increased perioperative morbidity, and, in some cases, progression during induction therapy that may preclude curative resection. Several explanations may account for this discrepancy, including clonal selection of resistant disease, the influence of the hepatic metastatic microenvironment, and the availability of salvage local therapy at recurrence. Nevertheless, systemic therapy remains relevant in selected patients with technically or biologically complex disease, such as those requiring staged liver surgery, downsizing for resectability, or treatment sequencing in synchronous primary and liver disease. Additionally, thermal ablation is emerging as a valid early liver-directed option for carefully selected small-volume metastases. Looking forward, circulating tumor DNA and other molecular tools may better identify the subgroup most likely to benefit from perioperative treatment. Treatment sequencing in resectable CRLM should therefore be guided by anatomy, tumour biology, and emerging molecular markers of residual risk, with systemic therapy used selectively rather than as a universal default.

Objective: To analyze the clinicopathological characteristics, treatment, and prognosis of SMARCA4-deficient tumors of digestive system origin, and to deepen the understanding of this tumor subtype. Methods: A retrospective analysis was conducted on 18 patients diagnosed with SMARCA4-deficient tumors of digestive system origin at Tianjin Medical University Cancer Institute and Hospital from January 1, 2021 to December 31, 2024. Their clinicopathological features, treatments, and prognoses were summarized. Immunohistochemical staining was used to detect BRG1. Using solid tumor data from the MSK-CHORD cohort (25 040 samples from 24 950 patients) and the MSK-IMPACT cohort (54 331 samples from 48 179 patients) in the public database cBioPortal, survival analysis and gene mutation profiling were performed focusing on SMARCA4 gene alterations. Results: The 18 SMARCA4-deficient tumors included 10 gastric cancers, 4 gallbladder/bile duct cancers, 2 liver cancers, and 2 colorectal cancers. The mean age of the patients was 62.8 years; there were 14 males and 4 females. Seven patients were initially diagnosed with advanced-stage disease, of whom 5 had metastases to ≥2 distant organs. Based on cytomorphology and immunohistochemistry (IHC) results, 8 cases were classified as undifferentiated carcinoma, 2 as poorly differentiated carcinoma, 5 as poorly differentiated adenocarcinoma, 1 as neuroendocrine carcinoma and 2 as undifferentiated sarcomas. Among the 18 patients, 16 had a Ki-67 index>50%, and high expression levels were observed for INI1 (14/14) and Syn (12/15). Regarding survival, 5 patients had an overall survival (OS) of <6 months, including 3 with stage Ⅱ/Ⅲ disease. Six patients had an OS exceeding 1 year; among them, 4 underwent radical surgery (2 patients with gastric cancer received perioperative immunotherapy combined with chemotherapy), and 2 patients initially diagnosed with advanced-stage disease received immunotherapy combined with chemotherapy, achieving an OS exceeding 17 months and are currently still on maintenance therapy. Database analysis results showed that the frequency of SMARCA4 gene mutations in solid tumors was 5%. Patients without SMARCA4 mutations had better OS than those with SMARCA4 mutations (MSK-CHORD cohort: 50.43 vs 33.24 months, HR=0.743, P<0.001; MSK-IMPACT cohort: 44.05 vs 35.60 months, HR=0.816, P<0.001). Conclusions: SMARCA4-deficient tumors of digestive system origin are poorly differentiated, may present as undifferentiated carcinoma, and some cases show differentiation tendencies toward adenocarcinoma or neuroendocrine carcinoma. These tumors are highly aggressive with poor prognosis. The limited sample size shows a polarized trend in survival data.

Colorectal cancer (CRC) liver metastases are the leading cause of CRC-related mortality, yet the genetic and epigenetic drivers underlying this process remain poorly understood. Here, we established a pro-metastatic CRC organoid library through serial orthotopic transplantation of liver metastasis-derived organoids. Integrative RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses identified a pro-metastatic signature characterized by multilineage plasticity, including fetal-like and basal-like/squamous transcriptional programs. Motif and transcription factor activity analyses identified GATA6 as a key regulator of these epigenetic alterations. GATA6 expression is downregulated in liver metastases, and its genetic ablation enhances liver metastasis with minimal effects on primary tumor growth. Mechanistically, GATA6 loss triggers pro-metastatic transcriptional programs, including fetal-like and basal-like/squamous states, accompanied by LGR5- cell generation. This reprogramming is mediated by the direct repression of HNF4A and increased H3K27ac and occurs independently of SOX17. Together, these findings identify GATA6 loss as a central regulator of multilineage plasticity that drives liver metastasis in CRC.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancerrelated mortality worldwide. Liver transplantation (LT) is a curative option for selected patients; however, recurrence remains the major determinant of post-transplant survival. Most recurrences occur within the first five years, while ultra-late events are exceptionally rare. We describe a 66-year-old male with cirrhosis due to hereditary hemochromatosis and a solitary 4-cm HCC within the Milan criteria, who underwent cadaveric orthotopic LT after bridging therapy with a single session of transarterial chemoembolization. Explant pathology confirmed HCC without microvascular invasion. The postoperative course was uneventful, and the patient remained disease-free for thirteen years. He then presented with rapidly progressive bilateral paraparesis. Magnetic resonance imaging revealed a 30-mm intradural extramedullary lesion at T6 causing severe spinal cord compression. Neurosurgical resection was performed, and histopathology with immunohistochemistry (HepPar-1 positive) confirmed metastatic HCC. This is, to our knowledge, the first reported case of spinal cord metastasis from HCC occurring thirteen years after LT. Conventional tumor markers, including alpha-fetoprotein, remained within normal limits, underscoring the limitations of current surveillance protocols. The exceptionally prolonged disease-free interval and atypical metastatic site challenge the prevailing paradigm that follow-up can be safely limited to the early post-transplant years. Ultra-late recurrence of HCC after LT, though rare, is clinically relevant and may manifest in unusual sites. This case highlights the need for risk-stratified, individualized, and potentially extended surveillance strategies to optimize long-term outcomes in LT recipients.

Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide, with a poor survival rate at the metastatic stage. Here, we identify CD109-a negative regulator of TGFβ signaling-as a key driver of stemness and drug resistance through modulation of Wnt signaling in advanced CRC. CD109 expression strongly correlates with TGFβ levels in patient tumors and is enriched in the aggressive CRIS-B subtype, where it associates with poor clinical outcome. CD109 silencing reduced STAT3 phosphorylation and cell proliferation, without affecting migration or invasion. Moreover, global expression analysis revealed downregulation of various hallmarks of cancer stemness (i.e. LGR5 expression), together with increased TGFβ signaling and cellular senescence. Mechanistically, CD109 interacts with LRRC8A, a subunit of the volume-regulated anion channel (VRAC), which associates with AKAP12 to activate PKCα and promote STAT3 phosphorylation. This CD109/LRRC8A/AKAP12/PKCα axis sustains Wnt signaling, stemness, and drug resistance. Consistently, co-expression of CD109/LRRC8A/AKAP12 correlates with poor prognosis in CRC patients. Genetic or pharmacological disruption of this CD109/LRRC8A/AKAP12/PKCα axis impaired STAT3 signaling, reduced LGR5 expression and Wnt signaling, and sensitized cells to chemotherapy. In vivo, CD109 or LRRC8A knockdown significantly impaired liver homing and metastatic colonization in mouse models, showing stronger effects in Swiss nude mice than in highly immunodeficient NSG mice. Collectively, these findings support CD109 as a central regulator for STAT3-driven stemness and chemoresistance in advanced CRC, via the LRRC8A/AKAP12/PKCα axis, and highlight its potential value as a therapeutic target in metastatic disease.

Metastasis is the leading cause of death in breast cancer, yet the mechanisms controlling organotropism are not well defined. Coagulation has emerged as a biologically relevant contributor to metastatic progression, but mechanisms linking pro-thrombotic phenotypes to organ-specific metastasis remain unresolved, significantly hindering the development of novel treatments. Here, a serial transplantation approach was used to enrich for liver organotropism from a spontaneous mouse mammary tumor model with occasional liver and lymph node metastasis. Comparative transcriptomics between the enriched liver and lymph node metastases revealed strong upregulation of coagulation in liver metastases, due in part to loss of repression of FXII with knockout of the E2F5 transcription factor. In vitro clotting assays demonstrated that tumor-derived FXII was sufficient to induce fibrin(ogen) clot formation. Moreover, liver metastatic cells exhibit elevated lipid peroxide levels and impaired lipid droplet formation associated with a pro-coagulant phenotype. Inhibition of coagulation with low molecular weight heparin reduced the presence of circulating tumor cells and suppressed liver metastasis in the mouse model. Human electronic health record data supported the translational relevance of these findings. Together, these data reveal a new mouse model where loss of E2F5 has resulted in tumors with elevated expression of FXII that have a propensity for liver metastasis and illustrates that anti-coagulation dramatically reduces the liver-specific metastasis in breast cancer.

Neuroendocrine carcinomas of the ampulla of Vater are rare but highly aggressive, poorly differentiated neoplasms associated with poor outcomes. This contrasts with ampullary adenocarcinoma, which is generally associated with more favourable survival following curative resection, and with well-differentiated periampullary neuroendocrine tumours, which typically demonstrate more indolent behaviour and better prognosis. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review was conducted across PubMed/MEDLINE, Embase, Scopus, Web of Science, and Google Scholar (from inception to July 2025) to identify reported cases of large-cell neuroendocrine carcinoma (LCNEC) of the ampulla of Vater. Studies reporting extractable patient-level clinicopathological, treatment, and outcome data were included. Data were standardised and synthesised descriptively due to the rarity and heterogeneity of the condition. A total of 22 patient-level cases of LCNEC of the ampulla of Vater were identified from 14 studies. The median age was 70 years (range: 44-84), with a male predominance. Tumours were generally small at presentation (median size approximately 20 mm); however, lymph node metastasis was present in 16 of 20 evaluable patients (80%). All patients underwent pancreaticoduodenectomy or pylorus-preserving pancreaticoduodenectomy. Adjuvant chemotherapy was administered in 12 of 22 patients (55%), most commonly platinum-based regimens. Tumour recurrence occurred in approximately 55-60% of cases, most frequently involving the liver. Median overall survival was approximately 11 months, with eight patients (36%) alive at the last follow-up. LCNEC of the ampulla of Vater is an aggressive malignancy with poor prognosis despite surgical resection. This review highlights a clinically important "size-biology paradox," whereby relatively small tumours demonstrate early metastatic behaviour and adverse outcomes. Tumour biology appears to outweigh conventional staging parameters, underscoring the need for early recognition, accurate histopathological classification, and consideration of systemic therapy. Further multicentre studies are required to optimise management strategies and improve patient outcomes.

Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive malignancy predominantly affecting young male patients, typically originating from the abdomen or pelvis, with a poor prognosis. Since the first description as a distinct clinical entity in 1989, approximately 850 cases have been reported in the literature. All cases share the chromosomal translocation t(11;22)(p13;q12), leading to the formation of the EWSR1-WT1 fusion gene. DSRCT characteristically arises in the abdomen or pelvis and carries a poor prognosis despite multimodal therapy. We report a rare and extensive case of abdominopelvic DSRCT with liver and peritoneal metastases in a 17-year-old Moroccan male, who presented with a progressive abdominal mass, pain, and hepatomegaly. The diagnosis was initially challenging due to the non-specific clinical presentation. The final diagnosis was established through liver biopsy and immunohistochemical analysis. The patient is currently undergoing treatment with a multidrug chemotherapy regimen.

Metastatic pancreatic cancer carries a poor prognosis, with palliative chemotherapy offering limited survival benefit and conversion to resectability considered rare. The present study reports the case of a 60-year-old woman with pancreatic adenocarcinoma and extensive liver metastases treated with palliative FOLFIRINOX, achieving complete radiological disappearance of hepatic disease and sustained control of the primary tumour. After a treatment pause and subsequent reinitiation of chemotherapy for local progression, the liver metastases remained absent. At 32 months post-diagnosis, the patient underwent pancreatic resection with negative margins and remains alive and free from hepatic recurrence 84 months from diagnosis. This case highlights that select patients may achieve long-term survival through individualized, multimodal treatment strategies.

Bile duct tumours are most commonly primary cholangiocarcinomas, and upfront surgical resection is often undertaken with curative intent, as preoperative histological confirmation is not routinely required. Melanoma, an aggressive malignancy of neural crest origin, can metastasize widely, but involvement of the biliary tract is exceedingly rare. Even rarer is primary melanoma of the bile duct. The present report describes a 44-year-old man presenting with obstructive jaundice and a mass in the common bile duct (CBD) presumed to represent cholangiocarcinoma. The patient underwent pancreaticoduodenectomy, but histopathology unexpectedly revealed malignant melanoma. Comprehensive staging and dermatological assessment excluded a cutaneous, mucosal or ocular primary, supporting the diagnosis of primary CBD melanoma. To the best of our knowledge, this represents the 14th reported case. This case highlights that melanoma, although rare, should be considered in the differential diagnosis of biliary obstruction, especially in younger patients, as it mandates a distinct postoperative oncological management pathway.