Treatment Of Liver Metastases Research Articles

Ephrin A1 Stimulates CCL2 Secretion to Facilitate Pre-metastatic Niche Formation and Promote Gastric Cancer Liver Metastasis.

The liver is a primary target for distal metastasis of gastric cancer (GC). The hepatic pre-metastatic niche (PMN) facilitates crucial communications between primary tumor and liver, thereby playing an essential role in hepatic metastasis. Identification of the molecular mechanisms driving PMN formation in GC could facilitate development of strategies to prevent and treat liver metastasis. Here, we uncovered a role for ephrin A1 (EFNA1) signaling in development of the PMN. EFNA1 overexpression in GC cells significantly increased CCL2 secretion through the Hippo-YAP pathway. Secreted CCL2 activated hepatic stellate cells (HStCs) within the hepatic PMN via the WNT/β-catenin pathway. Inhibition of CCL2 significantly suppressed HStC activation and reduced liver metastasis triggered by EFNA1 signaling in GC cells. Moreover, high CCL2 expression correlated with poor survival in GC patients. Overall, these findings reveal that EFNA1 signaling in GC cells upregulates CCL2, which activates HStCs to engender establishment of a hepatic pre-metastatic niche that supports liver metastasis.

Microwave Ablation of Refractory Oligometastatic Non-Small Cell Lung Cancer in the Liver

Purpose : To evaluate safety and effectiveness of microwave ablation (MWA) in the treatment of liver metastases (LM) secondary to non-small cell lung cancer (NSCLC). Materials and Methods : This retrospective study included patients with NSCLC who underwent MWA of LM from 3/2015 to 7/ 2022. Local tumor progression-free survival (LTPFS) and overall survival (OS) were estimated using competing risk analysis and the Kaplan–Meier method. Post-procedural adverse events were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results : Twenty-three patients with 32 LM were treated in 27 MWA sessions. The dimension of the largest index tumor was 1.96 ± 0.75 cm (mean ± SD). Technical success was 100%. Technical efficacy was achieved in 26/32 tumors (81.3%). Median length of follow-up was 37.7 months (IQR: 20.5-54.5). Median LTPFS was 16.3 months (95% CI: 7.87-44.10). Median OS was 31.7 months (95% CI: 11.1 to 65.8 months). Ablation margin was a significant factor for LTPFS, with tumors ablated without a measurable margin being more likely to progress compared to those with measurable margins (Subdistribution hazard ratios [SHR] 0.008-0.024, p<0.001). Older age (HR:1.18, 95%CI:1.09-1.28, p< 0.001) and presence of synchronous lung metastases (HR:14.73, 95%CI: 1.86-116.95, p = 0.011) were significant predictors of OS. Serious adverse events (CTCAE grade ≥3) within 30 days occurred in 2/27 sessions (7.4%), including pulmonary embolus and severe abdominal pain. Conclusion : Percutaneous MWA is a safe treatment for NSCLC LM, with longer survival seen in younger patients and those without synchronous lung tumors.

The combination of transarterial chemoembolization and microwave ablation is superior to microwave ablation alone for liver metastases from colorectal cancer

ObjectivesThis study aimed to compare the combination therapy of transarterial chemoembolization (TACE) and microwave ablation (MWA) with MWA alone in treating liver metastases from colorectal cancer (LMCRC).Materials and methodsIn this retrospective study, a total of 251 patients with unresectable and not to chemotherapy responding LMCRC were included. Group A consisted of 184 patients (104 male and 80 females; mean age: 64 ± 11.4 years) with 442 metastases who received a combination of TACE and MWA. A total of 67 patients (49 male and 18 females; mean age: 63.2 ± 11.8 years) with 173 metastases patients were included in group B, who received only MWA. Parameters assessed were local tumor progression (LTP), hepatic distant tumor progression (hDTP), hepatic progression-free survival (hPFS), and overall survival (OS).ResultsThe rate of LTP was 4.9% in group A and 4.5% in group B (p-value: 0.062). The rate of hDTP was 71.7% and 83.6% for groups A and B (p-value: 0.81), respectively. The mean hPFS was 13.8 months (95% CI 10.9–16.8) for group A and 8.1 months (95% CI 6.1–10.1) for group B (p-value: 0.03). The median OS time for group A was 30 months (95% CI 26–34), with 1-, 2-, 3-, and 4-year OS rates of 84.2%, 61.1%, 40.8% and 31.3%, respectively. In group B however, the median OS time was 26 months (95% CI 18–34) with 1-, 2-, 3-, and 4-year OS rates of 82.3%, 53.2%, 34.6% and 28.2%, respectively (p-value: 0.67).ConclusionThe combination therapy of TACE and MWA is superior to the monotherapy of MWA for LMCRC, especially regarding hDTP, hPFS and OS.

Cholesterol synthesis is essential for the growth of liver metastasis-prone colorectal cancer cells.

Metastasis to the liver is a leading cause of death in patients with colorectal cancer. To investigate the characteristics of cancer cells prone to metastasis, we utilized an isogenic model of BALB/c and colon tumor 26 (C26) cells carrying an active KRAS mutation. Liver metastatic (LM) 1 cells were isolated from mice following intrasplenic transplantation of C26 cells. Subsequent injections of LM1 cells generated LM2 cells, and after four cycles, LM4 cells were obtained. Invitro, using a perfusable capillary network system, we found comparable extravasation frequencies between C26 and LM4 cells. Both cell lines showed similar growth rates invitro. However, C26 cells showed higher glucose consumption, whereas LM4 cells incorporated more fluorescent fatty acids (FAs). Biochemical analysis revealed that LM4 cells had higher cholesterol levels than C26 cells. A correlation was observed between fluorescent FAs and cholesterol levels detected using filipin III. LM4 cells utilized FAs as a source for cholesterol synthesis through acetyl-CoA metabolism. In cellular analysis, cholesterol accumulated in punctate regions, and upregulation of NLRP3 and STING proteins, but not mTOR, was observed in LM4 cells. Treatment with a cholesterol synthesis inhibitor (statin) induced LM4 cell death invitro and suppressed LM4 cell growth in the livers of nude mice. These findings indicate that colorectal cancer cells prone to liver metastasis show cholesterol-dependent growth and that statin therapy could help treat liver metastasis in immunocompromised patients.

Unraveling the role of local ablative therapies for patients with metastatic soft tissue sarcoma – A retrospective multicenter study of the Bavarian university hospitals

BackgroundLocal ablative therapies (LAT) are increasingly used in patients with metastatic soft tissue sarcoma (STS), yet evidence-based standards are lacking. This study aimed to assess the impact of LAT on survival of metastatic STS patients and to identify prognostic factors. MethodsIn this retrospective multicenter study, 246 STS patients with metastatic disease who underwent LAT on tumor board recommendation between 2017 and 2021 were analyzed. A mixed effects model was applied to evaluate multiple survival events per patient. ResultsMedian overall survival (OS) after first metastasis was 5.4 years with 1-, 2- and 5-year survival rates of 93.7, 81.7, and 53.1 %, respectively. A treatment-free interval ≥12 months and treatment of liver metastases were positively correlated with progression-free survival (PFS) after LAT (HR = 0.61, p = 0.00032 and HR = 0.52, p = 0.0081, respectively). A treatment-free interval ≥12 months and treatment of metastatic lesions in a single organ site other than lung and liver were positive prognostic factors for OS after first LAT (HR = 0.50, p = 0.028 and HR = 0.40, p = 0.026, respectively) while rare histotypes and LAT other than surgery and radiotherapy were negatively associated with OS after first LAT (HR = 2.56, p = 0.020 and HR = 3.87, p = 0.025). Additional systemic therapy was independently associated with a PFS benefit in patients ≤60 years with ≥4 metastatic lesions (for max. diameter of treated lesions ≤2 cm: HR = 0.32, p = 0.02 and >2 cm: HR = 0.20, p = 0.0011, respectively). ConclusionThis multicenter study conducted at six German university hospitals underlines the value of LAT in metastatic STS. The exceptionally high survival rates are likely to be associated with patient selection and treatment in specialized sarcoma centers.

Ramucirumab in second‑line advanced colorectal cancer therapy: A study on therapeutic outcomes and hepatic sinusoidal platelet aggregation.

The present study investigated the role of ramucirumab (RAM) in treating liver metastases (LMs) as a second-line or salvage treatment in patients with advanced CRC. Of the 36 patients, 21 (58%) received RAM plus folinic acid, fluorouracil and irinotecan (FOLFIRI) as second-line treatment, whereas 15 (42%) received it in a salvage setting. The median overall survival time was 23 months [95% confidence interval (CI), 12-34 months] for those in the second-line treatment group and 8 months (95% CI, 5-19 months) for those in the salvage treatment group. Of the 36 patients, 14 (39%) underwent surgical resection of LMs during chemotherapy. A total of 6 patients underwent surgical resection for LMs for the first time during second-line RAM plus FOLFIRI (RAM-LM); of the remaining 8 patients, 6 underwent resection of LMs during first-line bevacizumab (BEV)-based chemotherapy (BEV-LM). Immunohistochemical analysis of CD42b showed that the platelet aggregation score (CD42b score), which ranges from 0 (absence of deposition) to 3 (presence of linear deposition), tended to decrease with the increasing duration of treatment with both RAM and BEV. Although there was no significant difference in the mean duration of anti-VEGF antibody treatment between the BEV-LM and RAM-LM groups, the median CD42b score was higher in the RAM-LM group (median CD42b score, 3; range, 0-3) compared with that in the BEV-LM group (median CD42b score, 1; range, 0-3; P=0.01), suggesting that RAM induces a different degree of platelet aggregation in liver sinusoids compared to BEV.

HDR brachytherapy versus robotic-based and linac-based stereotactic ablative body radiotherapy in the treatment of liver metastases – A dosimetric comparison study of three radioablative techniques

PurposeThe aim of our study was to compare dosimetric aspects of three radioablation modalities – direct high-dose-rate brachytherapy (HDR-BT) and virtually planned stereotactic body radiation therapy performed on CyberKnife (SBRTck) and Elekta Versa HD LINAC (SBRTe) applied in patients with liver metastases. Material and methodsWe selected 30 patients with liver metastases, who received liver interstitial HDR-BT and virtually prepared plans for SBRTck and SBRTe. In all the cases, the prescribed dose was a single fraction of 25 Gy. Treatment delivery time, doses delivered to PTV and organs at risk, as well as conformity indices, were calculated and compared. ResultsThe longest median treatment delivery time was observed in SBRTck in contrast to HDR-BT and SBRTe which were significantly shorter and comparable. HDR-BT plans achieved better coverage of PTV (except for D98%) in contrast to SBRT modalities. Between both SBRT modalities, SBRTck plans resulted in better dose coverage in Dmean, D50%, and D90% values compared to SBRTe without difference in D98%. The SBRTe was the most advantageous considering the PCI and R100%. SBRTck plans achieved the best HI, while R50% value was comparable between SBRTe and SBRTck. The lowest median doses delivered to uninvolved liver volume (V5Gy, V9.1Gy) were achieved with HDR-BT, while the difference between SBRT modalities was insignificant. SBRT plans were better regarding more favourable dose distribution in the duodenum and right kidney, while HDR-BT achieved lower doses in the stomach, heart, great vessels, ribs, skin and spinal cord. There were no significant differences in bowel and biliary tract dose distribution between all selected modalities. ConclusionsHDR-BT resulted in more favourable dose distribution within PTVs and lower doses in organs at risk, which suggests that this treatment modality could be regarded as an alternative to other local ablative therapies in carefully selected patients’ with liver malignancies. Future studies should further address the issue of comparing treatment modalities in different liver locations and clinical scenarios.

Isolated liver chemoperfusion in a patient with mesenteric leiomyosarcoma and liver metastasis

Background. Treatment for inoperable secondary liver cancer remains challenging especially in patients with colorectal cancer. Traditional systemic drug therapy is often ineffective, and the use of transarterial chemoembolization is limited due to the systemic toxicity of some drugs. Combining high efficacy and low systemic toxicity, isolated chemoperfusion is a promising treatment option for patients with liver metastasis. Case report. A patient with mesentery leiomyosarcoma underwent several surgeries and chemotherapy courses, but liver metastases continued to grow. Isolated liver chemoperfusion with melphalan was performed after resection of liver segment and mobilization of liver vessels. To reduce the tumor volume and prevent complications, atypical liver resection was also performed. Conclusion. Isolated liver chemoperfusion for the treatment of liver cancer remains a subject of debate and is not included in the standards for treatment of primary and metastatic liver tumors. This technique was shown to be safe and promising in treating liver metastasis from leiomyosarcoma. However, further research is required to assess the role of this procedure in overall survival.

Abstract PO5-25-01: Treating liver metastases by reversing cell competition between metastatic cancer cells and hepatocytes

Abstract Background: Although breast cancer liver metastases (BCLM) are common events, with 40-50% of patients with metastatic breast cancer developing liver metastases, their development indicates poor prognosis. Patients with BCLM have a 5-year survival rate of 8%. Specific treatments for liver metastases are virtually non-existent, partly because the key events of early liver metastasis formation remain unknown. The liver is a dense organ, and metastatic breast cancer cells (MCC) must clear space among hepatocytes, the primary cell population in the liver, during metastatic formation. Cell competition is a developmentally conserved process that explains how organs or primary tumors form when cells within those tissues have varying fitness and compete with one another. This competition can result in the survival and expansion of one cell population, and the induction of cell death through apoptosis in the other. We hypothesized that MCC use cell competition with hepatocytes to create space and expand within the liver. Objectives: In this study, we tested the hypothesis that MCC use cell competition with hepatocytes to create space and expand within the liver, resulting in hepatocyte apoptosis. Methods: We develop new in-vitro and mouse lineage-traced models to assay cell competition between MCC and hepatocytes, initially using balb/c derived breast cancer (4T1) and hepatocyte (H2.35) cells and syngeneic mouse models of liver metastasis. These models directly capture MCC and hepatocyte interactions, and we can assess modes of cell competition, including apoptosis, through immunostaining. Because prior literature suggests that the developing mammary gland informs both cell competition and metastasis, we next performed a bioinformatics screen to identify potential signals that contribute to cell competition between MCC and hepatocytes. We generated a new single-cell RNA-seq dataset that incorporates information from the developing mammary gland and breast cancer cells. This dataset includes 3264 primary breast cancer cells across 3 models of aggressive breast cancers, encompassing HER2+ and TNBC subtypes, as well as 526 embryonic mammary gland cells. Using this platform, we identify genes enriched in both breast cancer and the developing mammary gland. Next, we validate genes by testing for their high expression in MCC when compared to hepatocytes. Then, we determine the impact of target genes on cell competition in our models. Results/Discussion: Our models demonstrate that MCC use cell competition to create space in the liver by inducing apoptosis in neighboring hepatocytes. MCC induce apoptosis in neighboring hepatocytes through cell competition in in-vitro co-cultures by 11.7-fold compared to MCC apoptosis. Hydrodynamic tail-vein engraftment in NOD-scid-gamma mice livers with MCC also resulted in increased neighboring hepatocyte apoptosis. Using our bioinformatics screen, we identified 5 potential targets that could drive breast cancer metastasis and cell competition. Using our competition models, perturbation of SerpinE2, a protease inhibitor which was one of the top gene targets, successfully modulated competition between MCC and hepatocytes. Knock-out of SerpinE2 in MCC did not affect their viability or growth but resulted in MCC apoptosis adjacent to hepatocyte neighbors by 16.9-fold when compared to wild type conditions. Further, co-culture of MCC that lacked SerpinE2 with hepatocytes resulted in decreased hepatocyte apoptosis by 2.3-fold compared to hepatocytes co-cultured with wild-type (WT) MCC. These findings suggest that hepatocytes cannot outcompete or kill WT MCC, but they can outcompete and kill MCC that lack SerpinE2. Future work focused on the perturbation of SerpinE2 may lead to novel therapies for patients at risk for or with BCLM. Our findings suggest that restoring the competitiveness of the liver parenchyma could be a new treatment modality for treating liver metastases. Citation Format: Katherine Lake, Sakshi Mohta, Clayton Smith, Venkata Repaka, Lily Xu, Kaitlyn Saunders, Vrushali Pandit, Emily Goff, Christine Zhang, Jacob Pena, Christine Hodgdon, Julia Maues, Elizabeth Chen, Isaac Chan. Treating liver metastases by reversing cell competition between metastatic cancer cells and hepatocytes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-25-01.

Abstract A041: Treating liver metastases by reversing cell competition between metastatic cancer cells and hepatocytes

Abstract Background Although breast cancer liver metastases (BCLM) are common events, with 40-50% of patients with metastatic breast cancer developing liver metastases, their development indicates particularly poor prognosis. Targeted treatments for liver metastases are virtually non-existent, partly because the key events of early liver metastasis formation remain unknown. The liver is a dense organ, and metastatic breast cancer cells (MCC) must first clear space among hepatocytes, the primary cell population in the liver, to form. Cell competition is a process that explains how organs or primary tumors form from two populations of competing cells with varied fitness levels. The expansion of one population of cells creates space through the induction of apoptosis in the other. Objectives In this study, we tested the hypothesis that MCC use cell competition with hepatocytes to create space and expand within the liver, resulting in hepatocyte apoptosis. Methods We develop new in-vitro and mouse lineage-traced models to assay cell competition between MCC and hepatocytes. These models directly capture MCC and hepatocyte interactions and we can assess modes of cell competition, including apoptosis, through immunostaining. Because prior literature suggests that the developing mammary gland informs both cell competition and metastasis, we performed a bioinformatics screen to identify potential signals that contribute to cell competition between MCC and hepatocytes. We generate a new single-cell RNA-seq dataset that incorporates information from the developing mammary gland and breast cancer cells and identify genes enriched in both. Next, we validated genes by testing for their high expression in MCC when compared to hepatocytes. Then, we determined the impact of target genes on cell competition in our models. Results/Discussion Our models demonstrate that MCC use cell competition to create space in the liver by inducing apoptosis in neighboring hepatocytes. MCC induce apoptosis in neighboring hepatocytes through cell competition in in-vitro co-cultures by 11.7-fold compared to MCC apoptosis. Hydrodynamic tail-vein engraftment in NOD-scid-gamma mice with MCC also resulted in increased neighboring hepatocyte apoptosis. Using our bioinformatics screen, we identified SerpinE2, a protease inhibitor, as a target that could drive breast cancer metastasis and cell competition. Knock-out of SerpinE2 in MCC did not affect their viability or growth but resulted in MCC apoptosis adjacent to hepatocyte neighbors by 16.9-fold when compared to wild-type (WT) conditions. Further, co-culture of MCC that lacked SerpinE2 with hepatocytes resulted in decreased hepatocyte apoptosis by 2.3-fold compared to hepatocytes co-cultured with WT MCC. These findings suggest that perturbation of SerpinE2 successfully modulates competition between MCC and hepatocytes: Hepatocytes can selectively outcompete and kill MCC that lack SerpinE2. Future work focused on the perturbation of SerpinE2 may lead to novel therapies for patients at risk for or with BCLM. Citation Format: Katherine E Lake, Sakshi Mohta, Clayton A Smith, Venkata Repaka, Lily Xu, Kaitlyn Saunders, Vrushali Pandit, Emily Goff, Jacob Pena, Luise Chinea, Luisa Froessl, Sangeetha M Reddy, Heather L McArthur, Christine Hodges, Julia Maues, Elizabeth Chen, Isaac S Chan. Treating liver metastases by reversing cell competition between metastatic cancer cells and hepatocytes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A041.

Targeted IFNγ induction by a genetically engineered Salmonella typhimurium is the key to the liver metastasis inhibition in a mouse model of pancreatic neuroendocrine tumor.

Liver metastasis is one of the primary causes of death for the patients with pancreatic neuroendocrine tumors (PNETs). However, no curative therapy has been developed so far. The anti-tumor efficacy of a genetically engineered tumor-targeting Salmonella typhimurium YB1 was evaluated on a non-functional INR1G9 liver metastasis model. Differential inflammatory factors were screened by Cytometric Bead Array. Antibody depletion assay and liver-targeted AAV2/8 expression vector were used for functional evaluation of the differential inflammatory factors. We demonstrated that YB1 showed significant anti-tumor efficacy as a monotherapy. Since YB1 cannot infect INR1G9 cells, its anti-tumor effect was possibly due to the modulation of the tumor immune microenvironment. Two inflammatory factors IFNγ and CCL2 were elevated in the liver after YB1 administration, but only IFNγ was found to be responsible for the anti-tumor effect. Liver-targeted expression of IFNγ caused the activation of macrophages and NK cells, and reproduced the therapeutic effect of YB1 on liver metastasis. We demonstrated that YB1 may exhibit anti-tumor effect mainly based on IFNγ induction. Targeted IFNγ therapy can replace YB1 for treating liver metastasis of PNETs.

Holmium-166 Radioembolization of Hepatic Metastases in Salvage Setting: Preliminary Findings from a Single Center Experience

Abstract Purpose The aim of this study is to report the early outcomes of holmium-166 (166Ho) radioembolization in the treatment of liver metastases. Methods Nine patients with liver metastases originating from different primary sites were treated with 166Ho radioembolization between January 2019 and February 2020. The patients were assessed for pain using a visual analog scale (VAS) and quality of life (QoL) at various intervals during hospitalization and follow-up. Toxicity that may be attributable to radioembolization was graded according to CTCAE v5.0. The tumor dosimetry and tumor response were assessed with anatomic and metabolic imaging. Results The mean tumor dose was 150 Gy, 95% confidence interval (CI) was 135.2 to 164.8, with a range of 100 to 200 Gy based on single-photon emission computed tomography (SPECT)/CT, and distribution verified with inline T2/R2* magnetic resonance imaging (MRI) maps. No early (30-day) mortality or grade greater than 2 toxicities were noted, but one patient had chylous ascites. QoL assessed with the European Quality of Life 5-Dimensions 3-Level version (EQ-5D-3L) revealed mean index scores of 0.748 (range: 0.5–1), 95% CI of 0.6 to 0.9, before the procedure, and 0.7 (range: 0.5–1) and 95% CI of 0.6 to 0.8, at 1 month. The mean VAS was 70.6, 95% CI was 65.5 to 75.6, immediately after the procedure, and decreased to the mean VAS of 65.7 and 95% CI of 55.9 to 75.5 after 1 month. Five patients showed a partial response, three showed a stable disease, and one showed progressive disease at the first 2- to 3-month imaging follow-up. Conclusion Radioembolization with 166Ho microspheres for liver metastases appears to be safe, tolerable, and effective during the short term in this small-scale study.

Outcomes after curatively intended treatment of limited peritoneal metastases and thermal ablation for liver metastases from colorectal cancer.

Peritoneal metastases (PM) and liver metastases (LM) are present simultaneously in up to 2 % of patients at the time of their colorectal cancer (CRC) diagnosis. Curatively intended treatment includes cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) combined with LM resection. A less invasive treatment for LM is ablation. We aimed to estimate overall survival (OS), disease-free survival (DFS) and postoperative data in patients managed simultaneously with CRS, HIPEC and radiofrequency ablation (RFA) as first choice. This was a retrospective national cohort study. All patients were treated at Aarhus University Hospital; the only CRS+HIPEC centre in Denmark. We included CRC patients managed with curative intent for simultaneously diagnosed PM and LM in the period January 2016- December 2021. LM was treated with RFA as first choice, if possible. Survival was calculated by the Kaplan-Meier method. A total of 25 patients were included, the median agewas 60 years (range 43-75 years) and 15 (60 %) were females. The median peritoneal cancer index was 7 (range 0-12), the median number of LM was 1 (range 1-3). Ablation was performed as the only treatment for LM in 18 (72 %) patients. After a median follow-up time of 17.1months (range4-36months), the median OS was 28.6months (95 % confidence interval (Cl) 15.8;36.1), 1-year OS was 84.0 % (95 % Cl 62.8;93.7). Median DFS was 6.1months (95 % Cl 4.0;10.3). Median LOS was ten days (range 5-26days). Both 30-day and 90-day mortality were 0 %. The selected treatment modality (RFA) for CRC patients with both LM and PM was safe. However, DFS was low. Further research is warranted to investigate if RFA is as effective as LM resection.

Treatment of Liver Metastases With Focused Ultrasound and Microbubbles in Patients With Colorectal Cancer Receiving Chemotherapy

Pre-clinical trials have obtained promising results that focused ultrasound (FUS) combined with microbubbles (MBs) increases tumor uptake and the therapeutic effect of drugs. The aims of the study described here were to investigate whether FUS and MBs could improve the effect of chemotherapy in patients with liver metastases from colorectal cancer and to investigate the safety and feasibility of using FUS+MBs. We included 17 patients with liver metastases from colorectal cancer, selected two lesions in each patient's liver and randomized the lesions for, respectively, treatment with FUS+MBs or control. After chemotherapy (FOLFIRI or FOLFOXIRI), the lesions were treated with FUS (frequency=1.67 MHz, mechanical index=0.5, pulse repetition frequency=0.33 Hz, 33 oscillations, duty cycle=0.2%-0.4% and MBs (SonoVue) for 35 min). Nine boluses of MBs were injected intravenously at 3.5 min intervals. Patients were scheduled for four cycles of treatment. Changes in the size of metastases were determined from computed tomography images. Treatment with FUS+MBs is safe at the settings used. There was considerable variation in treatment response between lesions and mixed response between lesions receiving only chemotherapy. There is a tendency toward larger-volume reduction in lesions treated with FUS+MBs compared with control lesions, but a mixed response to chemotherapy and lesion heterogeneity make it difficult to interpret the results. The combination of FUS and MBs is a safe, feasible and available strategy for improving the effect of chemotherapy in cancer patients. Therapeutic effect was not demonstrated in this trial. Multicenter trials with standardized protocols should be performed.

Lipid Nanoparticles-Based Therapy in Liver Metastasis Management: From Tumor Cell-Directed Strategy to Liver Microenvironment-Directed Strategy.

Metastasis to the liver, as one of the most frequent metastatic patterns, was associated with poor prognosis. Major drawbacks of conventional therapies in liver metastasis were the lack of metastatic-targeting ability, predominant systemic toxicities and incapability of tumor microenvironment modulations. Lipid nanoparticles-based strategies like galactosylated, lyso-thermosensitive or active-targeting chemotherapeutics liposomes have been explored in liver metastasis management. This review aimed to summarize the state-of-art lipid nanoparticles-based therapies in liver metastasis management. Clinical and translational studies on the lipid nanoparticles in treating liver metastasis were searched up to April, 2023 from online databases. This review focused not only on the updates in drug-encapsulated lipid nanoparticles directly targeting metastatic cancer cells in treating liver metastasis, but more importantly on research frontiers in drug-loading lipid nanoparticles targeting nonparenchymal liver tumor microenvironment components in treating liver metastasis, which showed promise for future clinical oncological practice.

In situ expansion and reprogramming of Kupffer cells elicit potent tumoricidal immunity against liver metastasis.

Liver metastasis represents one of the most frequent malignant diseases with no effective treatment. Functional reprogramming of Kupffer cells (KCs), the largest population of hepatic macrophages, holds promise for treating liver cancer, but remains seldom exploited. Taking advantage of the superior capacity of KCs to capture circulating bacteria, we report that a single administration of attenuated Escherichia coli producing clustered regularly interspersed short palindromic repeats CasΦ (CRISPR/CasΦ) machinery enables efficient editing of genes of interest in KCs. Using intravital microscopy, we observed a failure of tumor control by KCs at the late stage of liver metastasis due to KC loss preferentially in the tumor core and periphery, resulting in inaccessibility of these highly phagocytic macrophages to cancer cells. Simultaneous disruption of MafB and c-Maf expression using the aforementioned engineered bacteria could overcome KC dysfunction and elicit remarkable curative effects against several types of metastatic liver cancer in mice. Mechanistically, bacterial treatment induced massive proliferation and functional reprogramming of KCs. These cells infiltrated into the tumor, dismantled macrometastases by nibbling cancer cells, and skewed toward proinflammatory macrophages to unleash antitumor T cell responses. These findings provide an immunotherapy strategy that could be applicable for treating liver metastasis and highlight the therapeutic potential of targeting tissue-resident macrophages in cancer.

Thrombus formation in the suprahepatic inferior vena cava after microwave ablation in patients with hepatic metastasis: a case report

BackgroundMicrowave ablation (MWA) via ultrasound guidance is an important tool in the treatment of liver metastases. The most common postoperative complications are abdominal hemorrhage and bile leakage, whereas thrombosis in the suprahepatic inferior vena cava (IVC) is very rare, and clinical management is very difficult when the head end of the thrombus reaches the right atrium.Case presentationThis is a case report of a 52-year-old man with hepatic metastasis 21 months after radical resection of rectal cancer. After chemotherapy combined with targeted therapy, metastasis in segment IV (S4) of the liver was treated with microwave ablation. Two months after treatment, the hepatic metastasis in S4 showed a microwave ablation zone on MRI.Enhanced MRI showed venous thrombosis located in the left hepatic vein and IVC, and the head of the thrombus reached the right atrium. After two weeks of anticoagulation and thrombolytic treatment, the follow-up MRI showed that the venous thrombus had nearly disappeared.ConclusionWhen liver metastases are close to the hepatic vein, clinicians should pay attention to the occurrence of hepatic vein and IVC thrombosis following MWA; through early diagnosis and anticoagulation, pulmonary thromboembolism (PTE) can be minimized.

Influence of Colorectal Tumor Characteristics on the Treatment of Liver Metastases: A Retrospective Review

Influence of Colorectal Tumor Characteristics on the Treatment of Liver Metastases: A Retrospective Review

Yttrium-90 transarterial radioembolization for liver metastases from medullary thyroid cancer.

Liver metastases occur in 45% of patients with advanced metastatic medullary thyroid cancer (MTC). Transarterial radioembolization (TARE) has been proposed to treat liver metastases (LM), especially in neuroendocrine tumors. The aim of this study was to investigate the biochemical (calcitonin and carcino-embryonic antigen) and objective response of liver metastases from MTC to TARE. TARE is an internal radiotherapy in which microspheres loaded with β-emitting yttrium-90 (90Y) are delivered into the hepatic arteries that supply blood to LM. Eight patients with progressive multiple LM underwent TARE and were followed prospectively. They were clinically, biochemically and radiologically evaluated at 1, 4, 12 and 18 months after TARE. Two patients were excluded from the analysis due to severe liver injury and death due to extrahepatic disease progression, respectively. One month after TARE, a statistically significant (P = 0.02) reduction of calcitonin was observed in all patients and remained clinically relevant during follow-up; reduction of CEA, although not significant, was found in all patients. Significant reduction of liver tumor mass was observed 1, 4 and 12 months after TARE (P = 0.007, P = 0.004, P = 0.002, respectively). After 1 month, three of six patients showed partial response (PR) and three of six stable disease (SD) according to RECIST 1.1, while five of six patients had a PR and one of six a SD according to mRECIST. The clinical response remained relevant 18 months after TARE. Excluding one patient, all others showed only a slight and transient increase in liver enzymes. TARE is effective in LM treatment of MTC. The absence of severe complications and the good tolerability make TARE a valid therapeutic strategy when liver LM are multiple and progressive.

Thermal ablation of the most challenging cases of liver metastases.

Patient selection for image-guided thermal ablation of liver metastases has to be taken in a multidisciplinary tumor board given the extreme complexity of cancer metastatic disease, and the numerous treatment options offered to oligometastatic patient today.The role of image-guided thermal ablation increases over years in the treatment of liver metastases. In order to fulfill the expected outcomes which are to have a local control rate equivalent to surgery, interventional oncologist have to take every measure that will help when treating most challenging metastases including image guidance, anesthesia, respiration monitoring, ablation technique, confirmation software that can favor positive outcomes, and in some way to render challenging metastases easy to treat.