Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.

Cellular and molecular mechanisms of gastrointestinal cancer liver metastases and drug resistance.

Distant metastases and drug resistance account for poor survival of patients with gastrointestinal (GI) malignancies such as gastric cancer, pancreatic cancer, and colorectal cancer. GI cancers most commonly metastasize to the liver, which provides a unique immunosuppressive tumour microenvironment to support the development of a premetastatic niche for tumor cell colonization and metastatic outgrowth. Metastatic tumors often exhibit greater resistance to drugs than primary tumors, posing extra challenges in treatment. The liver metastases and drug resistance of GI cancers are regulated by complex, intertwined, and tumor-dependent cellular and molecular mechanisms that influence tumor cell behavior (e.g. epithelial-to-mesenchymal transition, or EMT), tumor microenvironment (TME) (e.g. the extracellular matrix, cancer-associated fibroblasts, and tumor-infiltrating immune cells), tumor cell-TME interactions (e.g. through cytokines and exosomes), liver microenvironment (e.g. hepatic stellate cells and macrophages), and the route and mechanism of tumor cell dissemination (e.g. circulating tumor cells). This review provides an overview of recent advances in the research on cellular and molecular mechanisms that regulate liver metastases and drug resistance of GI cancers. We also discuss recent advances in the development of mechanism-based therapy for these GI cancers. Targeting these cellular and molecular mechanisms, either alone or in combination, may potentially provide novel approaches to treat metastatic GI malignancies.

Bellmunt risk score as a survival predictor in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: The prognosis of metastatic castration-resistant prostate cancer (mCRPC) is influenced by numerous individual factors. Despite various proposed prognostic models, the clinical application of these remains limited, probably due to complexity. Our study aimed to evaluate the predictive value of the Bellmunt risk score, which is well-known for urothelial carcinoma and easily assessed, in mCRPC patients. METHODS: The Bellmunt risk score was calculated from three risk factors (Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥1, serum hemoglobin <10 g/dL, presence of liver metastases) in 125 patients who received first-line mCRPC treatment between 2005 and 2023. In addition, a modified score was established (one point each for hemoglobin <10 g/dL and the presence of liver metastases added to the ECOG PS). Associations with overall survival (OS) under first- and second-line therapy were tested using Cox regression analyzes, log-rank tests, concordance index (C-index) and time-dependent receiver operating characteristic. RESULTS: There is a significant correlation between the level of the Bellmunt risk score and shorter OS (hazard ratio: 3.23, 95% confidence interval: 2.06-5.05; log-rank p < 0.001; C-index: 0.724). The semi-quantitative modified risk score showed even better prognostic discrimination (log-rank p < 0.001, C-index: 0.764). The score and its dynamics were also predictive in the second-line setting (log-rank p < 0.001 and = 0.01; C-index: 0.742 and 0.595). CONCLUSIONS: The Bellmunt risk score is easy to assess and provides useful prognostic information in mCRPC, and can support physicians in their treatment decisions.

Liver metastases and peritoneal metastases and response to checkpoint inhibitors in metastatic colorectal cancer with microsatellite instability.

BACKGROUND: There have been conflicting reports on the predictive impact of metastatic disease sites on the response to checkpoint inhibitors (CPI) in microsatellite instability (MSI) metastatic colorectal cancers (mCRC). Recent studies have highlighted peritoneal metastases, ascites, and liver metastases as possible indicators of resistance to CPI. METHODS: We performed a detailed analysis of high microsatellite instability (MSI-H) mCRC treated with programmed cell death (PD-1) or PD-1/cytotoxic T-lymphocyte-associated protein 4 CPI in a single center. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and stable disease but with complete pathological response upon resection (SDcPR) were analyzed by the presence of liver metastases, peritoneal metastases, or absence of either. The impact of number and size of liver metastases on clinical outcomes were also interrogated. RESULTS: Thirty-five patients with MSI mCRC were included in the analysis. Patients with peritoneal metastatic disease had lower ORR and shorter PFS compared to patients without liver and peritoneal metastases. Contrary to recent reports, ORR and ORR + SDcPR rates were high in patients with liver metastases, at 58% and 66%, respectively. In the liver metastases category, a better response rate was noted for patients with<5 lesions compared to patients with more than 5 lesions. Patients who responded had a higher median tumor mutation burden than patients with progressive disease. CONCLUSIONS: In MSI mCRC, no single clinical characteristic was sufficient to preclude CPI response. Peritoneal metastatic disease was associated with numerically lower ORR and shorter PFS. In contrast, liver metastases do not predict poor outcome.

Survival benefit of adjuvant chemotherapy based on molecular residual disease detection in resected colorectal liver metastases: subgroup analysis from CIRCULATE-Japan GALAXY.

BACKGROUND: The prognostic role of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection and its utility for postsurgical risk stratification has been reported in colorectal cancer. In this study, we explored the use of ctDNA-based MRD detection in patients with colorectal liver metastases (CLM), for whom the survival benefit of adjuvant chemotherapy (ACT) after surgical resection remains unclear. METHODS: Patients with CLM without extrahepatic disease from the GALAXY study (UMIN000039205) were included. The disease-free survival (DFS) benefit of ACT was evaluated in MRD-positive and -negative groups after adjusting for age, gender, number, and size of liver metastases, RAS status, and previous history of oxaliplatin for primary cancer. ctDNA was detected using a personalized, tumor-informed 16-plex polymerase chain reaction-next-generation sequencing (mPCR-NGS) assay. ctDNA-based MRD status was evaluated 2-10 weeks after curative surgery, before the start of ACT. RESULTS: Among 6061 patients registered in GALAXY, 190 surgically resected CLM patients without any preoperative chemotherapy were included with a median follow-up of 24 months (1-48 months). ctDNA positivity in the MRD window was 32.1% (61/190). ACT was administered to 25.1% (48/190) of patients. In the MRD-positive group, 24-month DFS was higher for patients treated with ACT [33.3% versus not reached, adjusted hazard ratio (HR): 0.07, P < 0.0001]; whereas no benefit of ACT was seen in the MRD-negative group (24-month DFS: 72.3% versus 62.2%, adjusted HR: 0.68, P = 0.371). Multivariate analysis showed that the size of liver metastases (HR: 3.94, P = 0.031) was prognostic of DFS in the MRD-positive group. In the MRD-negative group, however, none of the clinicopathological factors were prognostic of DFS. CONCLUSIONS: Our data suggest that ACT may offer notable clinical benefits in MRD-positive patients with CLM. MRD status-based risk stratification could be potentially incorporated in future clinical trials for CLM.

FASN promotes anoikis resistance in colorectal liver metastases through the ERK1/2 pathway.

PURPOSE: Colorectal cancer (CRC) is recognized as the third most common form of malignancy, with the liver frequently serving as the main site for metastasis. Anoikis resistance (AR) is critical in colorectal cancer liver metastases (CRLM). Fatty acid synthase (FASN), essential in lipid synthesis, mediates AR in many cancers. The present research examines the function of FASN in ERK1/2-mediated AR in CRLM and evaluates its therapeutic potential. METHODS: We performed scratch and migration experiment to evaluate the migration capacity of the LoVo cells. Flow cytometry was employed to identify cell apoptosis. The levels of FASN, p-ERK1/2, and proteins related to apoptosis was analyzed by Western blot. The mRNA level of FASN was determined by q-PCR after FASN silencing. In addition, we used an intrasplenic liver metastasis model of nude to assess the effect of FASN on CRLM. RESULTS: In vitro experiments showed that after FASN silencing, the cell apoptosis rate was increased, migration capability was notably decreased, the expression of p-ERK1/2, the proteins related to anti-apoptotic were significantly decreased, and the proteins related to apoptosis were significantly increased. In vivo experiments showed that AR significantly increased the number of liver metastatic foci, whereas FASN silencing significantly inhibited CRLM. CONCLUSION: These results suggest that FASN silencing suppressed AR through the ERK 1/2 pathway, which in turn suppressed CRLM.

Generation and assessment of cytokine-induced killer cells for the treatment of colorectal cancer liver metastases.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Cytokine-induced killer (CIK) cells are an adoptive immunotherapy reported to have strong anti-tumour activity across a range of cancers. They are a heterogeneous mix of lymphoid cells generated by culturing human peripheral blood mononuclear cells with cytokines and monoclonal antibodies in vitro. In this study, we investigated the yield and function of CIK cells generated from patients with CRC liver metastases. We first showed that CIK cells generated in serum free medium X-VIVO 15 were comparable to those from RPMI medium with 10% FBS in terms of the number and percentages of the main subsets of cells in the CIK culture, and the intracellular levels of granzyme B and perforin, and the pro-inflammatory cytokines IL-2, IFN-γ and TNF-α. The CIK cells were cytotoxic to CRC cell lines grown in 2D cultures or as spheroids, and against autologous patient-derived tumour organoids. Donor attributes such as age, sex, or prior chemotherapy exposure had no significant impact on CIK cell numbers or function. These results suggest that functional CIK cells can be generated from patients with CRC liver metastatic disease, and support further investigations into the therapeutic application of autologous CIK cells in the management of patients with CRC liver metastases.

Viscoelastic properties of colorectal liver metastases reflect tumour cell viability.

BACKGROUND: Colorectal cancer is the third most common tumour entity in the world and up to 50% of the patients develop liver metastases (CRLM) within five years. To improve and personalize therapeutic strategies, new diagnostic tools are urgently needed. For instance, biomechanical tumour properties measured by magnetic resonance elastography (MRE) could be implemented as such a diagnostic tool. We postulate that ex vivo MRE combined with histological and radiological evaluation of CRLM could provide biomechanics-based diagnostic markers for cell viability in tumours. METHODS: 34 CRLM specimens from patients who had undergone hepatic resection were studied using ex vivo MRE in a frequency range from 500 Hz to 5300 Hz with increments of 400 Hz. Single frequency evaluation of shear wave speed and wave penetration rate as proxies for stiffness and viscosity was performed, along with rheological model fitting based on the spring-pot model and powerlaw exponent α, ranging between 0 (complete solid behaviour) and 1 (complete fluid behaviour). For histological analysis, samples were stained with H&E and categorized according to the degree of regression. Quantitative histologic analysis was performed to analyse nucleus size, aspect ratio, and density. Radiological response was assessed according to RECIST-criteria. RESULTS: Five samples showed major response to chemotherapy, six samples partial response and 23 samples no response. For higher frequencies (> 2100 Hz), shear wave speed correlated significantly with the degree of regression (p ≤ 0.05) indicating stiffer properties with less viable tumour cells. Correspondingly, rheological analysis of α revealed more elastic-solid tissue properties at low cell viability and major response (α = 0.43 IQR 0.36, 0.47) than at higher cell viability and no response (α = 0.51 IQR 0.48, 0.55; p = 0.03). Quantitative histological analysis showed a decreased nuclear area and density as well as a higher nuclear aspect ratio in patients with major response to treatment compared to patients with no response (all p < 0.05). DISCUSSION: Our results suggest that MRE could be useful in the characterization of biomechanical property changes associated with cell viability in CRLM. In the future, MRE could be applied in clinical diagnosis to support individually tailored therapy plans for patients with CRLM.

Metastatic Colorectal Cancer Treated with Combined Liver Resection, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Predictive Factors for Early Recurrence.

BACKGROUND: Selection of colorectal cancer patients with concomitant peritoneal (PM) and liver metastases (LM) for radical treatment with cytoreductive surgery (CRS), including liver resection and hyperthermic intraperitoneal chemotherapy (HIPEC), needs improvement. This retrospective, monocentric study was designed to evaluate the predictive factors for early recurrence, disease-free survival (DFS), and overall survival (OS) in such patients treated in a referral center. METHODS: Consecutive colorectal cancer patients with concomitant LM and PM treated with curative intent with perioperative systemic chemotherapy, simultaneous complete CRS, liver resection, and HIPEC in 2011-2022 were included. Clinical, radiological (before and after preoperative chemotherapy), surgical, and pathological data were investigated, along with long-term oncologic outcomes. A multivariate analysis was performed to identify predictive factors associated with early recurrence (diagnosed <6 months after surgery), DFS, and OS. RESULTS: Of more than 61 patients included, 31 (47.1%) had pT4 and 27 (40.9%) had pN2 primary tumors. Before preoperative chemotherapy, the median number of LM was 2 (1-4). The median surgical PCI (peritoneal carcinomatosis index) was 3 (5-8.5). The median DFS and OS were 8.15 (95% confidence interval [CI] 5.5-10.1) and 34.1 months (95% CI 28.1-53.5), respectively. In multivariate analysis, pT4 (odds ratio [OR] = 4.14 [1.2-16.78], p = 0.032]) and pN2 (OR = 3.7 [1.08-13.86], p = 0.042) status were independently associated with an early recurrence, whereas retroperitoneal lymph node metastasis (hazard ratio [HR] = 39 [8.67-175.44], p < 0.001) was independently associated with poor OS. CONCLUSIONS: In colorectal cancer patients with concomitant PM and LM, an advanced primary tumor (pT4 and/or pN2) was associated with a higher risk of early recurrence following a radical multimodal treatment, whereas RLN metastases was strongly detrimental for OS.

Laparoscopic Portal Vein Ligation and Embolization During First-Stage Hepatectomy for Initially Unresectable Colorectal Liver Metastases.

BACKGROUND: Two-stage hepatectomy (TSH) is the only treatment for the patients with multiple bilobar colorectal liver metastases (CRMs) who are not candidates for one-step hepatectomy because of insufficient future remnant liver volume and/or impaired liver function.1-5 Although laparoscopic approaches have been introduced for TSH,6-8 the postoperative morbidity and mortality remains high because of the technical difficulties during second-stage hepatectomy.9,10 The authors present a video of laparoscopic TSH with portal vein (PV) ligation and embolization, which minimizes adhesions and PV thrombosis risk in the remnant liver, thereby facilitating second-stage hepatectomy. METHODS: Three patients with initially unresectable bilateral CRMs received a median of chemotherapy 12 cycles, followed by conversion TSH. After right PV ligation, laproscopic PV embolization was performed by injection of 100% ethanol into the hepatic side of the right PV using a 23-gauge winged needle. After PV embolization, a spray adhesion barrier (AdSpray, Terumo, Tokyo, Japan)11 was applied. RESULTS: During the first stage of hepatectomy, two patients underwent simultaneous laparoscopic colorectal resection (left hemicolectomy and high anterior resection). In the initial hepatectomy, two patients underwent two limited hepatectomies each, and one patient underwent six hepatectomies in the left lobe. After hepatectomy, all the patients underwent right PV embolization. During the second stage, two patients underwent open extended right hepatectomy (right adrenalectomy was performed because of adrenal invasion in one patient), and one patient underwent laparoscopic extended right hepatectomy. No postoperative complications occurred in the six surgeries. CONCLUSIONS: Laparoscopic TSH with PV embolization is recommended for safe completion of the second hepatectomy.

Locoregional therapies combined with immune checkpoint inhibitors for liver metastases.

Immune checkpoint inhibitors (ICIs) have achieved remarkable success in clinical research and practice. Notably, liver metastasis is not sensitive to ICIs. Liver locoregional therapies can cause irreversible damage to tumor cells and release tumor antigens, thereby providing a rationale for immunotherapy treatments in liver metastasis. The combination therapy of ICIs with locoregional therapies is a promising option for patients with liver metastasis. Preclinical studies have demonstrated that combining ICIs with locoregional therapies produces a significantly synergistic anti-tumor effect. However, the current evidence for the efficacy of ICIs combined with locoregional therapies remains insufficient. Therefore, we review the literature on the mechanisms of locoregional therapies in treating liver metastasis and the clinical research progress of their combination with ICIs.

Dose-effect relationships in neuroendocrine tumour liver metastases treated with [166Ho]-radioembolization.

PURPOSE: Aim of this study was to investigate a dose-response relationship, dose-toxicity relationship, progression free survival (PFS) and overall survival (OS) in neuroendocrine tumour liver metastases (NELM) treated with holmium-166-microspheres radioembolization ([166Ho]-radioembolization). MATERIALS AND METHODS: Single center, retrospective study included patients with NELM that received [166Ho]-radioembolization with post-treatment SPECT/CT and CECT or MRI imaging for 3 months follow-up. Post-treatment SPECT/CT was used to calculate tumour (Dt) and whole liver healthy tissue (Dh) absorbed dose. Clinical and laboratory toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 5 at baseline and three-months follow-up. Response was determined according to RECIST 1.1. The tumour and healthy doses was correlated to lesion-based objective response and patient-based toxicity. Kaplan Meier analyses were performed for progression free survival (PFS) and overall survival (OS). RESULTS: Twenty-seven treatments in 25 patients were included, with a total of 114 tumours. Median follow-up was 14 months (3 - 82 months). Mean Dt in non-responders was 68 Gy versus 118 Gy in responders, p = 0.01. ROC analysis determined 86 Gy to have the highest sensitivity and specificity, resp. 83% and 81%. Achieving a Dt of ≥ 120 Gy provided the highest likelihood of response (90%) for obtaining response. Sixteen patients had grade 1-2 clinical toxicity and only one patient grade 3. No clear healthy liver dose-toxicity relationship was found. The median PFS was 15 months (95% CI [10.2;19.8]) and median OS was not reached. CONCLUSION: This study confirms the safety and efficacy of [166Ho]-radioembolization in NELM in a real-world setting. A clear dose-response relationship was demonstrated and future studies should aim at a Dt of ≥ 120 Gy, being predictive of response. No dose-toxicity relationship could be established.

Prognostic factors associated with early recurrence following liver resection for colorectal liver metastases: a systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is the 3rd most common malignancy with the liver being the most common site of metastases. The recurrence rate of colorectal liver metastases (CRLM) after liver resection (LR) is notably high, with an estimated 40% of patients experiencing recurrence within 6 months. In this context, we conducted a meta-analysis to synthesize and evaluate the reliability of evidence pertaining to prognostic factors associated with early recurrence (ER) in CRLM following LR. METHODS: Systematic searches were conducted from the inception of databases to July 14, 2023, to identify studies reporting prognostic factors associated with ER. The Quality in Prognostic Factor Studies (QUIPS) tool was employed to assess risk-of-bias for included studies. Meta-analysis was then performed on these prognostic factors, summarized by forest plots. The grading of evidence was based on sample size, heterogeneity, and Egger's P value. RESULTS: The study included 24 investigations, comprising 12705 individuals, during an accrual period that extended from 2007 to 2023. In the evaluation of risk-of-bias, 22 studies were rated as low/moderate risk, while two studies were excluded because of high risk. Most of the studies used a postoperative interval of 6 months to define ER, with 30.2% (95% confidence interval [CI], 24.1-36.4%) of the patients experiencing ER following LR. 21 studies were pooled for meta-analysis. High-quality evidence showed that poor differentiation of CRC, larger and bilobar-distributed liver metastases, major hepatectomy, positive surgical margins, and postoperative complications were associated with an elevated risk of ER. Additionally, moderate-quality evidence suggested that elevated levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA199), lymph node metastases (LNM) of CRC, and a higher number of liver metastases were risk factors for ER. CONCLUSION: This review has the potential to enhance the efficacy of surveillance strategies, refine prognostic assessments, and guide judicious treatment decisions for CRLM patients with high risk of ER. Additionally, it is essential to undertake well-designed prospective investigations to examine additional prognostic factors and develop salvage therapeutic approaches for ER of CRLM.

Troponin Elevation in Patients Undergoing Percutaneous Hepatic Perfusion for Metastatic Uveal Melanoma.

BACKGROUND: Percutaneous Hepatic Perfusion (PHP) is a liver directed regional therapy recently FDA approved for metastatic uveal melanoma to the liver involving percutaneous isolation of liver, saturation of the entire liver with high-dose chemotherapy and filtration extracorporeally though in line filters and veno-venous bypass. The procedure is associated with hemodynamic shifts requiring hemodynamic support and blood product resuscitation due to coagulopathy. OBJECTIVE: To assess the cardiac safety and subsequent clinically significant sequalae of this therapy. METHODS: Consecutive PHP procedures done at our center between 2010-2022 were assessed retrospectively. Cardiac risk factors, post procedural cardiac enzymes, electrocardiograms, and transthoracic echocardiograms along with 90-day cardiac outcomes were reviewed. All data were reviewed by cardio-oncologists at our institution. RESULTS: Of 37 patients reviewed, mean age was 63 years and 57% were women. 132 procedures were performed with an average of 3.57 procedures per patient. 68.6% of patients had elevated troponin during at least 1 procedure. No patients were found to have acute coronary syndrome, heart failure, unstable arrhythmias, or cardiac death. No patients had notable echocardiographic changes. 10.8% of patients with positive troponin had asymptomatic transient electrocardiographic changes not meeting criteria for myocardial infarction. One patient had non-sustained ventricular tachycardiac intra-operatively which did not recur subsequently. Three patients died from non-cardiac causes within 90-days. There was no oncology treatment interruption, even in those with troponin elevation. In multivariable analysis, a history of hyperlipidemia was a predictor of postoperative troponin elevation. (P = .042). CONCLUSION: Percutaneous Hepatic Perfusion is safe and associated with a transient, asymptomatic troponin elevation peri-operatively without major adverse cardiac events at 90 days. The observed troponin elevation is likely secondary to coronary demand-supply mismatch related to procedural hemodynamic shifts, hypotension, and anemia.

Percutaneous hepatic perfusion using melphalan in patients with uveal melanoma and liver metastases carries no significant cardiac adverse events.

Safety and efficacy of percutaneous arterial port Implantation for Hepatic Arterial Infusion Chemotherapy.

OBJECTIVES: Approximately 40% of patients with colorectal cancer will develop liver metastases. Hepatic arterial infusion chemotherapy (HAIC) represents a valuable treatment option, with curative, palliative, or adjuvant intent. The aim of our study was to describe technical considerations, safety, and oncological outcomes of patients receiving HAIC. MATERIALS AND METHODS: All patients who underwent percutaneous hepatic arterial port placement in our institution between 2004 and 2021 were included in this retrospective analysis. Demographic, anatomical and technical data were collected. Tumor response was assessed using RECIST 1.1. Kaplan-Meier estimates were used for overall survival (OS) and hepatic progression-free survival (PFS). Adverse events (AEs) were graded using the Clavien-Dindo classification. RESULTS: A total of 360 patients (median age, 58.6 years [interquartile range (IQR): 49.5-65.4]; 208 men [57.8%]) were included. Percutaneous hepatic arterial port placement was successful in 87.9% of cases, resulting in 379 port placements (431 attempts). Overall, 394 HAIC courses were delivered, mostly oxaliplatin-based (94.7%), with a median of 6 cycles per course (IQR: 3-8). AEs (all grades) were observed in 42.0% of ports (grade IIIb-V: 1.1%). Most port dysfunctions could be resolved, resulting in a 73.1% rate of HAIC resumption, without impact on OS. Median OS was 22 months (IQR: 18-24), and median hepatic PFS was 11 months (IQR: 9.5-13). Tumor downstaging allowed surgery in 35.6% of patients, with significantly longer median OS than non-operated patients (39 months [IQR: 33-79] versus 14 months [IQR: 12-16], p < 0.001). CONCLUSION: This retrospective cohort study demonstrates the feasibility, safety, and efficacy of percutaneous hepatic arterial port placement with an impact on survival for selected patients. CLINICAL RELEVANCE STATEMENT: Percutaneous hepatic arterial port placement is feasible, safe and effective with an impact on the survival of selected patients. KEY POINTS: Hepatic arterial infusion chemotherapy provides promising tumor response and overall survival, especially in cases of resection/ablation. Total complication rate of hepatic arterial infusion chemotherapy port use is high, but serious complications are rare. Port revision is often necessary but allows the resumption of hepatic arterial infusion chemotherapy without affecting overall survival.

Establishing the clinical relevance of grade A post-hepatectomy liver failure.

INTRODUCTION: The International Study Group of Liver Surgery's criteria stratifies post-hepatectomy liver failure (PHLF) into grades A, B, and C. The clinical significance of these grades has not been fully established. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) hepatectomy-targeted database was analyzed. Outcomes between patients without PHLF, with grade A PHLF, and grade B or C PHLF were compared. Univariate and multivariable logistic regression were performed. RESULTS: Six thousand two hundred seventy-four adults undergoing elective major hepatectomy were included in the analysis. The incidence of grade A PHLF was 4.3% and grade B or C was 5.3%. Mortality was similar between patients without PHLF (1.2%) and with grade A PHLF (1.1%), but higher in those with grades B or C PHLF (25.4%). Overall morbidities rates were 19.3%, 41.7%, and 72.8% in patients without PHLF, with grade A PHLF, and with grade B or C PHLF, respectively (p < 0.001). Grade A PHLF was associated with increased morbidity (grade A: odds ratios [OR] 2.7 [95% CI: 2.0-3.5]), unplanned reoperation (grade A: OR 3.4 [95% CI: 2.2-5.1]), nonoperative intervention (grade A: OR 2.6 [95% CI: 1.9-3.6]), length of stay (grade A: OR 3.1 [95% CI: 2.3-4.1]), and readmission (grade A: OR 1.8 [95% CI: 1.3-2.5]) compared to patients without PHLF. CONCLUSIONS: Although mortality was similar between patients without PHLF and with grade A PHLF, other postoperative outcomes were notably inferior. Grade A PHLF is a clinically distinct entity with relevant associated postoperative morbidity.

Development and external validation of MRI-based RAS mutation status prediction model for liver metastases of colorectal cancer.

BACKGROUND: The mutation status of rat sarcoma viral oncogene homolog (RAS) has prognostic significance and serves as a key predictive biomarker for the effectiveness of antiepidermal growth factor receptor (EGFR) therapy. However, there remains a lack of effective models for predicting RAS mutation status in colorectal liver metastases (CRLMs). This study aimed to construct and validate a diagnostic model for predicting RAS mutation status among patients undergoing hepatic resection for CRLMs. METHODS: A diagnostic multivariate prediction model was developed and validated in patients with CRLMs who had undergone hepatectomy between 2014 and 2020. Patients from Institution A were assigned to the model development group (i.e., Development Cohort), while patients from Institutions B and C were assigned to the external validation groups (i.e., Validation Cohort_1 and Validation Cohort_2). The presence of CRLMs was determined by examination of surgical specimens. RAS mutation status was determined by genetic testing. The final predictors, identified by a group of oncologists and radiologists, included several key clinical, demographic, and radiographic characteristics derived from magnetic resonance images. Multiple imputation was performed to estimate the values of missing non-outcome data. A penalized logistic regression model using the adaptive least absolute shrinkage and selection operator penalty was implemented to select appropriate variables for the development of the model. A single nomogram was constructed from the model. The performance of the prediction model, discrimination, and calibration were estimated and reported by the area under the receiver operating characteristic curve (AUC) and calibration plots. Internal validation with a bootstrapping procedure and external validation of the nomogram were assessed. Finally, decision curve analyses were used to characterize the clinical outcomes of the Development and Validation Cohorts. RESULTS: A total of 173 patients were enrolled in this study between January 2014 and May 2020. Of the 173 patients, 117 patients from Institution A were assigned to the Model Development group, while 56 patients (33 from Institution B and 23 from Institution C) were assigned to the Model Validation groups. Forty-six (39.3%) patients harbored RAS mutations in the Development Cohort compared to 14 (42.4%) in Validation Cohort_1 and 8 (34.8%) in Validation Cohort_2. The final model contained the following predictor variables: time of occurrence of CRLMs, location of primary lesion, type of intratumoral necrosis, and early enhancement of liver parenchyma. The diagnostic model based on clinical and MRI data demonstrated satisfactory predictive performance in distinguishing between mutated and wild-type RAS, with AUCs of 0.742 (95% confidence interval [CI]: 0.651─0.834), 0.741 (95% CI: 0.649─0.836), 0.703 (95% CI: 0.514─0.892), and 0.708 (95% CI: 0.452─0.964) in the Development Cohort, bootstrapping internal validation, external Validation Cohort_1 and Validation Cohort_2, respectively. The Hosmer-Lemeshow goodness-of-fit values for the Development Cohort, Validation Cohort_1 and Validation Cohort_2 were 2.868 (p = 0.942), 4.616 (p = 0.465), and 6.297 (p = 0.391), respectively. CONCLUSIONS: Integrating clinical, demographic, and radiographic modalities with a magnetic resonance imaging-based approach may accurately predict the RAS mutation status of CRLMs, thereby aiding in triage and possibly reducing the time taken to perform diagnostic and life-saving procedures. Our diagnostic multivariate prediction model may serve as a foundation for prognostic stratification and therapeutic decision-making.

Irreversible Electroporation in Treating Colorectal Liver Metastases in Proximity to Critical Structures.

PURPOSE: To evaluate the safety, efficacy and oncological outcomes of irreversible electroporation (IRE) of unresectable colorectal liver metastases (CRLM) close to critical structures. MATERIALS AND METHODS: This is a single center, IRB approved, retrospective analysis of patients who underwent percutaneous, CT-guided IRE of CRLM. Between August 2018 and October 2023, 26 patients had 46 tumors treated with percutaneous IRE in 30 ablation sessions. Primary endpoints were tumor response and local progression-free survival (LPFS) analyzed using Kaplan-Meier survival curves. Secondary endpoints were overall survival (OS), and distant progression-free survival (DPFS) using Kaplan-Meier survival curves, adverse events rated according to Common Terminology Criteria for Adverse Events, and length of hospital stay. RESULTS: All tumors were close to critical structures, including portal and hepatic veins, inferior vena cava, bile ducts and the gallbladder. All patients received preprocedural systemic therapy (median ten cycles). Median length of hospital stay was one night. Adverse events occurred in seven out of 30 (23%) procedures, with four grade 1 and two grade 2 adverse events, including pleural effusions (n=2), ileus (n=1), small hematoma (n=1) and pneumothorax (n=2) requiring chest tube placements. Following IRE, 1- and 2-year LTPFS was 55.0% and 51.3%. Median DPFS was 3.5 months, with 1- and 2-year DPFS of 23.3% and 9.7%. Six patients died during follow-up (23.1%), with a median OS of 40.4 months. The 1- and 2-year OS were 90.9% and 83.9%. CONCLUSION: IRE is a safe and viable option in the treatment of unresectable CRLM in locations close to critical structures.

Recurrence-risk stratification using the Beppu score and selection of perioperative chemotherapy for colorectal liver metastases.

The annual postoperative disease-free survival for colorectal liver metastases can be easily estimated by weighting six preoperative clinical parameters (Beppu score). We identified three recurrence-risk stratification groups: the low (≤6 points), moderate (7-10 points), and high-risk (≥11 points). For low-, moderate-, and high-risk patients, hepatectomy alone, hepatectomy with adjuvant chemotherapy, and hepatectomy with preoperative chemotherapy are recommended, respectively. The Beppu score enables the decision on the necessity and timing of perioperative chemotherapy.

Advancements in the Management of Synchronous Colorectal Liver Metastases: A Comprehensive Review of Surgical, Systemic, and Local Treatment Modalities.

PURPOSE OF REVIEW: This review addresses the current landscape of colorectal cancer (CRC) with a focus on liver metastases, the third most common cancer globally. It explores recent findings in treatment strategies, emphasizing the dynamic interplay between surgery, systemic chemotherapy, and local therapies for synchronous colorectal liver metastases (CRLMs). RECENT FINDINGS: Highlighting the role of advanced imaging, the review underscores the significance of contrast-enhanced MRI in surgical planning for CRLMs. Surgical resection remains a primary choice for resectable cases, with considerations for oncologic scoring systems and tumor biology. Perioperative systemic chemotherapy plays a pivotal role, especially in conversion therapy for initially unresectable CRLMs. The review also explores various local therapies, including radiofrequency ablation, microwave ablation, stereotactic body radiotherapy, hepatic arterial infusional chemotherapy, selective internal radiation therapy, and transarterial chemoembolization for unresectable cases. A comprehensive approach, integrating surgery, systemic chemotherapy, and local therapies, is crucial for managing synchronous CRLMs. Surgical resection and perioperative chemotherapy are key players, guided by considerations of tumor biology and scoring systems. For unresectable cases, local therapies offer viable alternatives, emphasizing the need for tailored treatments. Multidisciplinary collaboration among medical oncologists, surgeons, and radiologists is essential. Ongoing research will refine treatment approaches, while emerging technologies hold promise for further advancements in managing colorectal liver metastases.