Treatment Of Liver Metastases Research Articles

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.

GATA2-Mediated Transcriptional Activation of Notch3 Promotes Pancreatic Cancer Liver Metastasis.

The liver is the predominant metastatic site for pancreatic cancer. However, the factors that determine the liver metastasis and the specific molecular mechanisms are still unclear. In this study, we used human pancreatic cancer cell line Hs766T to establish Hs766T-L3, a subline of Hs766T with stable liver metastatic ability. We performed RNA sequencing of Hs766T-L3 and its parental cell line Hs766T, and revealed huge differences in gene expression patterns and pathway activation between these two cell lines. We correlated the difference in pathway activation with the expression of the four core transcriptional factors including STAT1, NR2F2, GATA2, and SMAD4. Using the TCGA database, we examined the relative expression of these transcription factors (TFs) in pan-cancer and their relationship with the prognosis of the pancreatic cancer. Among these TFs, we considered GATA2 is closely involved in tumor metastasis and may serve as a potential metastatic driver. Further in vitro and in vivo experiments confirmed that GATA2-mediated transcriptional activation of Notch3 promotes the liver metastasis of Hs766T-L3, and knockdown of either GATA2 or Notch3 reduces the metastatic ability of Hs766T-L3. Therefore, we claim that GATA2 may serve as a metastatic driver of pancreatic cancer and a potential therapeutic target to treat liver metastasis of pancreatic cancer.

Single-centre survival analysis over 10\xa0years after MR-guided radiofrequency ablation of liver metastases from different tumour entities

BackgroundRadiofrequency ablation (RFA) is a minimal-invasive, local therapy in patients with circumscribed metastatic disease. Although widely used, long time survival analysis of treated liver metastases is still pending while also analysing the patients’ experience of MR-based radiofrequency.MethodsMonocentric, retrospective analysis of long-time overall and progression free survival (OS; PFS) of 109 patients, treated with MRI-guided hepatic RFA between 1997 and 2010, focusing on colorectal cancer patients (CRC). Complimentary therapies were evaluated and Kaplan Meier-curves were calculated. Patients’ experience of RFA was retrospectively assessed in 28 patients.Results1-, 3-, 5-, 10-year OS rates of 109 patients with different tumour entities were 83.4%, 53.4%, 31.0% and 22.9%, median 39.2 months, with decreasing survival rates for larger metastases size. For 72 CRC patients 1-, 3-, 5-, 10-year OS rates of 90.2%, 57.1%, 36.1% and 26.5% were documented (median 39.5 months). Thereof, beneficial outcome was detected for patients with prior surgery of the CRC including chemotherapy (median 53.0 months), and for liver metastases up to 19 mm (28.5% after 145 months). Hepatic PFS was significantly higher in patients with liver lesions up to 29 mm compared to larger ones (p = 0.035). 15/28 patients remembered RFA less incriminatory than other applied therapies.ConclusionsThis is the first single-centre, long-time OS and PFS analysis of MRI-guided hepatic RFA of liver metastases from different tumour entities, serving as basis for further comparison studies. Patients’ experience of MR based RFA should be analysed simultaneously to the performed RFA in the future.

Nanodrug shows spatiotemporally controlled release of anti-PD-L1 antibody and STING agonist to effectively inhibit tumor progression after radiofrequency ablation

The PD-1/PD-L1 blockade failed to prolong the progression-free survival of patients after radiofrequency ablation (RFA) treatment of liver metastases from colorectal cancers. We found that the PD-1/PD-L1 immune checkpoint blockade (ICB) therapy after RFA in mice model only had a temporary inhibition of tumor progression due to the limited number of mature dendritic cells (DCs) and the insufficient tumor infiltration/activation of cytotoxic T lymphocytes (CTLs). Our study further revealed that the activation of stimulator of interferon gene (STING) affecting tumor-infiltrating DCs and CD8+ T cells was only transient after RFA of tumor. Therefore, a nanovesicle capable of releasing the anti-PD-L1 antibody (αPD-L1) and STING agonist inside tumor in a spatiotemporally controlled manner was developed to evoke a robust anti-cancer immune response and immune memory for a long-term inhibition of tumor progression after RFA. The nanovesicle entrapping the hydrophilic STING agonist 5,6-dimethylxanthenone-4-acetate sodium salt (DMXAAst) in its lumen and anchoring αPD-L1 via an MMP-2-sensitive peptide linker was coated with PEG layer sheddable in acidic tumor microenvironment. The nanodrug design allowed the PEG coating to block off-target interaction between αPD-L1 and PD-L1-positive normal cells in blood and normal tissues, thereby reducing the immune-related adverse effects (irAEs). APD-L1 was firstly released in response to MMP-2 overexpressed in tumor tissue for ICB therapy, which promote the intracellular delivery of DMXAAst to activate STING in DCs. The synergistic effect of αPD-L1, DMXAAst and RFA evoked a robust anti-tumor immunity and long-term immune memory for a potent cancer therapy.

Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced uveal melanoma (CHOPIN): study protocol for a phase Ib/randomized phase II trial

BackgroundWhile immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease.MethodsOpen-label, single-center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first-line treatment, with or without the limited extrahepatic disease. The primary objective is to determine the safety, toxicity, and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at 1 year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, chi-square test). To study the association between risk factors and toxicity, a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves.DiscussionThis is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver.Trial RegistrationThis trial was registered in the US National Library of Medicine with identifier NCT04283890. Registered as per February 2020 - Retrospectively registered.EudraCT registration number: 2018-004248-49.Local MREC registration number: NL60508.058.19.

Multidisciplinary approach to the diagnosis and treatment of patients with potentially resectable colorectal cancer liver metastasis: results of a multicenter study.

This study sought to review colorectal cancer liver metastasis (CRLM) patients at multiple centers to analyze the factors affecting the success of conversion therapy in patients whose CRLM was initially evaluated as potentially resectable, to explore the effect of different treatment approaches on patient survival, and to provide a scientific reference for clinical treatment of CRLM. Fifty patients whose CRLM was initially evaluated as potentially resectable at 3 large Chinese general hospitals were enrolled in this retrospective study. Statistical analyses were carried out on the general data and pathological characteristic data to examine the clinical efficacy of the treatment approaches. The factors affecting the success of conversion therapy were analyzed by logistic regression. Additionally, follow-up appointments were conducted to examine survival, and survival curves were plotted using the Kaplan-Meier estimator. The effect of different clinical and pathological characteristics on CRLM patients was analyzed. Seventeen patients achieved no evidence of disease (NED) status through surgical resection/ablation after undergoing conversion therapy. The multifactor analysis demonstrated that the number of liver metastases was the primary risk factor affecting the efficacy of conversion therapy (P<0.05). Survival analysis results showed statistically significant difference in overall survival (OS) between the NED group and theinconspicuous/progressivegroup (P<0.0001). Also, there was a statistically significant difference in the progression-free survival (PFS) between the NED group and theinconspicuous/progressive group (P<0.0001). Patients in the surgical resection group had better OS and PFS than those in the ablation group (P<0.0001 and P<0.01, respectively). The monofactor analysis demonstrated that the number and maximum diameter of liver metastases, serum Carcino-Embryonic Antigen (CEA) level, and BRAF V600E mutation status were factors affecting the OS of CRLM patients (P<0.05), of which BRAF V600E mutation was the primary determinant (P<0.05). Among the patients whose CRLM was initially evaluated as unresectable, those who underwent surgical resection of the primary lesions and liver metastases after receiving conversion therapy had the best prognosis. Thus, a thorough evaluation should be conducted to determine the effect of and survival factors affecting conversion therapy in the treatment of liver metastases.

Examining the use of abdominal compression in stereotactic body radiotherapy for liver metastases - a single center's experience of 10 years.

IntroductionStereotactic body radiotherapy (SBRT) with abdominal compression (AC) stands out due to the high tolerance and ease of application in the treatment of liver metastases. The present study aimed to report the safety and efficacy of the AC technique with 10-year follow-up outcomes.Materials and methodsA retrospective review was made of patients in the database who had liver metastases, who did not undergo surgery or any other ablative approach for metastases, and who underwent SBRT with AC. In-field local control (ifLC) and toxicity were evaluated as primary endpoints.ResultsThe study examined 79 patients who underwent SBRT with AC between 2012 and 2021. Colorectal adenocarcinoma was the most common type of primary tumor (n = 32, 40.5%). The median follow-up was 14 (4–73) months. After treatment, one-year ifLC was 46.4%, six-month ifLC was 76%, one-year out-field local control (ofLC) was 13.6%, and six-month ofLC was 25%. According to the Common Terminology Criteria for Adverse Events Version 5.0, only 8 patients had low-grade acute gastrointestinal toxicity, and no patients had late toxicity.ConclusionsSBRT with AC is a well-tolerated and effective treatment modality for patients with liver metastases.

CalliSpheres drug-eluting beads transarterial-chemoembolization in the treatment of liver metastases from breast cancer: Initial experience in 14 patients.

Breast cancer patients with liver metastases are associated with high mortality. However, no standardized treatment approach is available for these patients who have undergone chemotherapy and hormonal therapy. We aimed to assess the clinical outcomes of patients with breast cancer liver metastases (BCLM) who underwent drug-eluting beads used for transarterial-chemoembolization (DEB-TACE).We retrospectively enrolled 14 patients with 39 lesions who underwent DEB-TACE for liver metastases following mastectomy for primary breast cancer. The incidence of complications, overall survival (OS), and local tumor progression-free survival (PFS) were assessed.A total of 14 patients with 39 liver metastases were treated with DEB-TACE from July 2017 to July 2020. The objective response rates (ORR) and disease control rates (DCR) were 71.4% and 92.8% at the 3-month period and 50% and 71.4% at the 6-month period, respectively. During the follow-up period the local tumor PFS was 8.0 months. The median OS was 20.0 months (range, 8–40 months) and the 1-, 2-year OS rates were 84.4% and 47.4%, respectively. No severe complications caused by this technique were detected.DEB-TACE for BCLM was characterized as a low trauma technique, with a limited number of complications. The results indicated that this method was safe and effective for patients with BCLM and could be widely adopted as a palliative treatment in clinical practice.