Therapy For Liver Metastases Research Articles

Combined treatment with selective cyclooxygenase-2 inhibitor and fluorinated pyrimidines for liver metastasis of colon cancer

Liver metastasis is a major contributor to mortality in patients with colorectal cancer. Hence, it is essential to establish preventive therapy to control liver metastasis. Recently, it has become widely accepted that cyclooxygenase (COX)-2 inhibitors possess anti-cancer activity for various types of tumor, especially colorectal. The clinical application of COX-2 inhibitors may therefore be beneficial. In this study, we have developed a combined treatment with a selective COX-2 inhibitor and fluorinated pyrimidines for liver metastasis of colorectal cancer, and examined the effect of these agents on proliferation and invasion of a highly metastatic human colon cancer cell line, LM-H3. The COX-2 inhibitor etodolac was found to inhibit cell invasion of LM-H3. 5-Fluorouracil (5-FU) inhibited proliferation of this line in vitro. Etodolac did not increase the inhibitory effect of 5-FU on cell proliferation. We also examined the inhibitory effect of etodolac and UFT, belonging to the fluorinated pyrimidines, on liver metastasis by using a liver metastatic model in the nude mouse. Combined treatment with etodolac and UFT markedly reduced liver metastasis. Serious side effects were not observed. In conclusion, combined treatment with etodolac and UFT might be a promising preventive therapy for liver metastasis of colon cancer.

A child with adrenocortical carcinoma who underwent percutaneous ethanol injection therapy for liver metastasis

The authors encountered a 2-year-old-girl with adrenocortical carcinoma who underwent percutaneous ethanol injection therapy (PEIT) for liver metastasis. The patient had functional adrenocortical carcinoma diagnosed and underwent excision of the tumor in the right adrenal gland. Because liver metastasis was detected 11 months after surgery, the patient underwent PEIT under general anesthesia. After the treatment, the size of the metastatic tumor was reduced with calcification and then disappeared. The patient was in a good condition 3 years, 3 months after the occurrence of liver metastasis.

Laser‐induced thermotherapy (LITT) of liver metastases: MR‐guided percutaneous insertion of an MRI‐compatible irrigated microcatheter system using a closed high‐field unit

To evaluate the efficacy and safety of a new MRI-compatible irrigated laser microcatheter system for thermal ablation of liver metastases. The new microcatheter system consists of a titanium needle with a diameter of 1.5 mm and a surrounding Teflon catheter with an outer diameter of 1.8 mm (5.5 F). In vitro laser-induced coagulation of bovine liver tissue was performed to determine the optimal perfusion rate of cooling saline flow, maximum laser energy, and ablation time. Laser-induced thermotherapy using the new microcatheter system, an Nd:YAG laser (Dornier), and a flexible laser light guide (Somatex GmbH, Berlin, Germany) was performed in 28 patients with liver metastases. Percutaneous insertion and positioning of multiple microcatheters in the lesion and monitoring of therapy was performed with a closed high-field MRI scanner using T1-weighted gradient-echo sequences during breath-hold. A perfusion rate of 0.75 mL/minute, a laser energy of 15 W, and an ablation time of 20 minutes were found suitable to achieve safe and sufficient ablation of metastatic tissue. The mean volume of induced coagulation in vitro was 23.9 mL. Ablation of liver metastases in patients was technically and clinically successful. The new microcatheter system allows for both catheter placement and monitoring of therapy using a single imaging modality. This shortens the procedure and enables more precise puncture and therapy of liver metastases. Due to the miniaturized design of the catheter and the real-time monitoring, the procedure is minimally invasive and very well tolerated by patients. This new technique seems to be a safe and feasible alternative in treating liver metastases.

Percutanesously Transfemoral Artery Implantation of PCS for Arterial Infusion Therapy of Liver Metastases

Objective To evaluate the Clinical effect of percutaneous transfemoral artery implantation of prot\|catheter system(PCS) Methods 30 patients with liver metastases were treated by intra\|arterial infusion therapy using PCS implanted by percutaneously transfemoral artey. We perfomed implantation of PCS under fluoroscopy according to blood supply artery of tumor. Results CR 3 cases,PR 14 cases, CR+PR 56.7% ,The 1/2, 1-, and2\|year overall survival rate was 100% ,53.3% and 16.7% , respectively. Serious complications had iccured no one. Conclusion Percutaneously transfemoral artery implantation of PCS for arterial infusion therapy of liver metastases is safe and effective.

Experimental low‐level direct current therapy in liver metastases: influence of polarity and current dose

Several authors recently reported on the successful local treatment of malignant disease with low-level direct current therapy. However, antitumoral effects in colorectal metastases has not been investigated experimentally. The aim of the present study was to assess the effectiveness of this therapy and the influence of polarity and current dose. Colorectal metastases were established in BD IX rats by the injection of colon cancer cells under the liver capsule. After three weeks, the liver tumor volumes were determined by magnetic resonance imaging of the liver. Low-level direct current therapy was applied via five platinum electrodes. Four different applications were used: 60 C/cm3, anode at the center; 60 C/cm3, cathode at the center; 80 C/cm3, anode at the center; and 80 C/cm3, cathode at the center. In the control group, five electrodes were placed without applying any direct current. All animals were sacrificed on postoperative day 7. Liver metastases were histologically examined for vital tumor cells. Statistical analysis was performed with χ2-test. The mean initial tumor diameter before treatment was 3.6 ± 1.4 mm (volume: 25.2 ± 9.7 mm3). Histological examination of the removed livers revealed significant destruction of the metastases with localized necroses in all treatment groups; 37% had a complete response rate and 63% a partial response rate. There were no significant necroses in the control group (P < 0.0001). The best treatment results were obtained in the group with an anode at the center and a current dose of 80 C/cm3. Direct current therapy offers a new and safe method for the local treatment of liver metastases. We were able to observe that tumor damage is related to current dose but not to the polarity of the central electrode. Bioelectromagnetics 21:395–401, 2000. © 2000 Wiley-Liss, Inc.

Experimental low-level direct current therapy in liver metastases: influence of polarity and current dose

Several authors recently reported on the successful local treatment of malignant disease with low-level direct current therapy. However, antitumoral effects in colorectal metastases has not been investigated experimentally. The aim of the present study was to assess the effectiveness of this therapy and the influence of polarity and current dose. Colorectal metastases were established in BD IX rats by the injection of colon cancer cells under the liver capsule. After three weeks, the liver tumor volumes were determined by magnetic resonance imaging of the liver. Low-level direct current therapy was applied via five platinum electrodes. Four different applications were used: 60 C/cm(3), anode at the center; 60 C/cm(3), cathode at the center; 80 C/cm(3), anode at the center; and 80 C/cm(3), cathode at the center. In the control group, five electrodes were placed without applying any direct current. All animals were sacrificed on postoperative day 7. Liver metastases were histologically examined for vital tumor cells. Statistical analysis was performed with chi(2)-test. The mean initial tumor diameter before treatment was 3.6 +/- 1.4 mm (volume: 25.2 +/- 9.7 mm(3)). Histological examination of the removed livers revealed significant destruction of the metastases with localized necroses in all treatment groups; 37% had a complete response rate and 63% a partial response rate. There were no significant necroses in the control group (P < 0.0001). The best treatment results were obtained in the group with an anode at the center and a current dose of 80 C/cm(3). Direct current therapy offers a new and safe method for the local treatment of liver metastases. We were able to observe that tumor damage is related to current dose but not to the polarity of the central electrode.

A CASE OF LIVER RESECTION FOR METACHRONOUS AND MULTIPLE LIVER METASTASES OF GASTROINTESTINAL STROMAL TUMOR OF THE STOMACH

A 39-year-old man underwent a proximal gastrectomy in October 1997 for a preoperatively diagnosed submucosal tumor located in the upper stomach, and the pathological postoperative diagnosis of the tumor was gastrointestinal stromal tumor (GIST), uncommitted type. In October 1998, abdominal CT study revealed multiple liver tumors, and by abdominal ultrasonography and abdominal MRI study, the liver tumors were diagnosed as multiple metastases of the gastric GIST. In December, right hepatectomy and partial hepatectomy on S1, S3, and S4 segments were performed, and a hepatic arterial infusion port was implanted. Pathologically, liver tumor cells were similar to the primary gastric tumor cells, therefore, the liver tumor was diagnosed as metastases of the gastric GIST, uncommitted type. About 1 year is passed after hepatic resection, and no recurrence is detected. Hepatic resection seems to be effective therapy for liver metastasis of the gastric GIST as well as liver metastasis of the gastric leiomyosarcoma.

Prospective dosimetry of intra-hepatic arterial holmium-166 microsphere therapy of liver metastases

Prospective dosimetry of intra-hepatic arterial holmium-166 microsphere therapy of liver metastases

Liver Metastases.

Liver metastases, especially from colorectal primary cancers, are treatable and potentially curable. Imaging techniques such as CT, MRI, and sonography have advanced in recent years and led to increased sensitivity and specificity in the diagnosis of liver metastases. Liver surgery also has been revolutionized in the past two decades. Dissections along nonanatomic lines have permitted the resection of multiple lesions that previously might have been considered unresectable. We regard resection of a solitary hepatic metastasis or up to four metastases from colorectal carcinoma as the best treatment for this condition. In patients over 70 years of age and those with medical conditions preventing surgery, we endorse expectant follow-up as long as the tumor remains stable. But if the tumor begins growing rapidly and local techniques cannot be used, we consider systemic chemotherapy. In patients with progressive metastatic liver disease, we initiate systemic therapy or hepatic arterial infusion. In young patients with metastatic disease, even when the disease is indolent or symptomatic, it may be difficult not to treat. We use either local regional therapy (resection or regional infusion) or systemic chemotherapy followed by regional therapy. In patients with neuroendocrine tumors metastatic to the liver, the first approach we use is not to treat because there may be a long period of stable disease. We use Sandostatin (Sandoz Pharmaceuticals, East Hanover, NJ) to treat symptoms. If the tumor progresses and symptoms cannot be controlled, these vascular tumors can be treated by embolization or chemoembolization, with high expectations of response. Newer approaches to liver metastases such as cryosurgery, chemoembolization, and interstitial radiation are also available. Cryosurgery is an ablative procedure that has not been proven yet to be as effective as surgical removal of metastases. However, in a situation where surgery cannot be performed, cryosurgery is an alternative. Chemoembolism has not been proven to be more effective than systemic therapy for liver metastases, but it allows another regional approach. External localized radiation can be used for patients who fail first-line treatment or in new protocols to delineate its value, perhaps in concert with chemotherapy. We also consider offering external localized radiation in patients who fail first-line treatment, perhaps in concert with chemotherapy. The usefulness of these techniques compared with surgery or regional therapy is being investigated.

Microwave coagulation therapy for liver metastasis

Microwave coagulation therapy for liver metastasis

Current concepts of tumor-induced angiogenesis.

Tumor induced angiogenesis is responsible for the nutrition of the growing tumor and can also increase the probability of hematogenous tumor dissemination. Data obtained from morphological analysis of tumor angiogenesis can contribute to the development of new anti-angiogenic therapies. Based on in vitro and in vivo observations several models of angiogenesis were introduced, explaining the mechanism of lumen formation and the timing of basement membrane depositon. (1) Lumen is formed either by cell body curving or by fusion of intracellular vacuoles of nonpolarized endothelial cells. New basement membrane is deposited after lumen formation. (2) Slit-like lumen is immediately formed by migrating polarized endothelial cells. Basement membrane is continuously deposited during endothelial cell migration, only cellular processes of the endothelial cell migrating on the tip of the growing capillary are free of deposited basement membrane material. (3) Development of transluminal bridges in larger vessels a process called intussusceptive growth leads to the division of the vessels. These models, however, describe angiogenesis in tissues rich in connective tissue. Different processes of angiogenesis take place in organs such as liver, lungs, adrenals, which are the most frequent sites of metastasis having high vessel density without sufficient space for capillary sprouting. In the case of liver metastases of Lewis lung carcinoma the proliferation of endothelial cells was elicited only by direct contact between tumor and endothelial cells, leading to the development of large convoluted vessels inside the metastases. These vessels were continuous with the sinusoidal system, suggesting that these metastases have dual blood supply. This observation, among others, is in contrast to the generally accepted view that liver tumors have arterial blood supply. The increasing number of data demonstrating the dual or venous blood supply of liver metastases should be taken into consideration in the therapy of liver metastasis.

Treatment of uveal melanoma metastatic to the liver. A review of the M.D. Anderson Cancer Center experience and prognostic factors

Background. Liver metastasis develops in approximately two-thirds of patients with recurrent uveal melanoma. Despite therapy, the median survival of those with liver metastasis is 5 to 7 months. The recognition of a grave prognosis associated with liver metastasis has led to evaluation of new modalities of therapy, including the use of regional therapies such as intrahepatic arterial chemotherapy and either embolization or chemoembolization of hepatic metastases. In this study, the results of an institutional experience over the past 2 decades are reviewed and prognostic factors that affect survival from the time the liver metastasis is diagnosed are assessed. Methods. In this study of 201 patients with uveal melanoma involving the liver who were treated at M. D. Anderson Cancer Center between 1968 and 1991, the authors retrospectively reviewed the cases and compared the results of systemic therapies, hepatic infra-arterial chemotherapies, and chemoembolization of liver metastases. Cox's multivariate analysis and stepwise logistic regression were then computed to determine significant prognostic variables. Results. The systemic therapies produced a response rate of less than 1%. Chemoembolization was the most effective treatment, inducing responses in 36% of patients. Survival curves were calculated using the life-table method of Kaplan and Meier. Patient-and tumor-related characteristics were examined and their relation to on survival from the time of diagnosis of liver metastasis was determined. Levels of serum alkaline phosphatase, total bilirubin, and lactic dehydrogenase plus response to treatment showed a strong relation to survival. In contrast, univariate analysis showed that patient age and gender, metastasis free interval, presence of extrahepatic metastasis, and type of therapy for liver metastasis did not influence survival. Multivariate stepwise regression analysis identified serum alkaline phosphatase and metastasis free interval as the main independent prognostic factors for survival after liver metastasis diagnosis. Conclusions. Of the three modalities of therapy used for choroidal melanoma metastatic to the liver, only chemoembolization using cisplatin-based regimens produced a meaningful response rate. Information from this analysis can be used to predict the outcome of patients with uveal melanoma metastatic to the liver. Patients with metastatic ocular melanoma confined to the liver should be treated with chemoembolization and should not be included in chemotherapy trials designed for cutaneous melanoma. Cancer 1995; 76:1665–70.

Treatment of uveal melanoma metastatic to the liver: a review of the M. D. Anderson Cancer Center experience and prognostic factors.

Liver metastasis develops in approximately two-thirds of patients with recurrent uveal melanoma. Despite therapy, the median survival of those with liver metastasis is 5 to 7 months. The recognition of a grave prognosis associated with liver metastasis has led to evaluation of new modalities of therapy, including the use of regional therapies such as intrahepatic arterial chemotherapy and either embolization or chemoembolization of hepatic metastases. In this study, the results of an institutional experience over the past 2 decades are reviewed and prognostic factors that affect survival from the time the liver metastasis is diagnosed are assessed. In this study of 201 patients with uveal melanoma involving the liver who were treated at M. D. Anderson Cancer Center between 1968 and 1991, the authors restrospectively reviewed the cases and compared the results of systemic therapies, hepatic intra-arterial chemotherapies, and chemoembolization of liver metastases. Cox's multivariate analysis and stepwise logistic regression were then computed to determine significant prognostic variables. The systemic therapies produced a response rate of less than 1%. Chemoembolization was the most effective treatment, inducing responses in 36% of patients. Survival curves were calculated using the life-table method of Kaplan and Meier. Patient- and tumor-related characteristics were examined and their relation to on survival from the time of diagnosis of liver metastasis was determined. Levels of serum alkaline phosphatase, total bilirubin, and lactic dehydrogenase plus response to treatment showed a strong relation to survival. In contrast, univariate analysis showed that patient age and gender, metastasis free interval, presence of extrahepatic metastasis, and type of therapy for liver metastasis did not influence survival. Multivariate stepwise regression analysis identified serum alkaline phosphatase and metastasis free interval as the main independent prognostic factors for survival after liver metastasis diagnosis. Of the three modalities of therapy used for choroidal melanoma metastatic to the liver, only chemoembolization using cisplatin-based regimens produced a meaningful response rate. Information from this analysis can be used to predict the outcome of patients with uveal melanoma metastatic to the liver. Patients with metastatic ocular melanoma confined to the liver should be treated with chemoembolization and should not be included in chemotherapy trials designed for cutaneous melanoma.

Liver Toxicity Induced by Combined External-Beam Irradiation and Radioimmunoglobulin Therapy

High-dose radiation therapy for liver metastases of gastrointestinal malignancies might be improved by combining external-beam irradiation and radioimmunoglobulin therapy. We studied the liver toxicity of the proposed combination in healthy beagle dogs. A total dose of 30 Gy to the whole liver, delivered in 2-Gy fractions over 3 weeks, resulted in mild, temporary veno-occlusive disease (VOD) in three of three dogs. Reversible bone marrow damage was noted after two intravenous injections of 18.5 MBq of yttrium-90-labeled monoclonal antibody ZCE025 per kg body weight in three of three dogs. Administrations of the antibody were separated by 1 week. Three dogs treated by irradiation of the liver with radioimmunoglobulin therapy added during the last 2 weeks of the irradiation showed signs of radiation hepatitis (VOD) starting around 35 days after treatment. One dog had a complete recovery, and two dogs were euthanized in a stage of terminal liver failure around day 90 after treatment. Temporary bone marrow damage was observed after the combined treatment, similar to the bone marrow damage observed after radioimmunoglobulin therapy alone. Earlier studies in the same dog model showed that bone marrow is the dose-limiting organ if radioimmunoglobulin therapy is used alone. The addition of irradiation of the liver to radioimmunoglobulin therapy changes the dose-limiting organ from bone marrow to liver. The radiation hepatitis observed in dogs is very similar to that observed in humans and is reflected in early platelet consumption in the irradiated liver plus late elevations of liver enzymes and VOD in central hepatic veins on histological analysis. Future applications of combined liver irradiation and radioimmunoglobulin therapy in humans should use radioimmunoglobulin therapy agents which show minimal uptake by normal liver.

The regional treatment of liver metastases from breast cancer.

To determine the effect of aggressive regional therapy for liver metastasis from breast cancer, we retrospectively reviewed data on 74 patients identified with liver metastases. Forty had only liver metastases. In this group of 40 patients, 18 were treated with regional therapy only, i.e., surgical resection and/or regional chemotherapy via hepatic artery or portal vein catheters whereas 22 patients had systemic chemotherapy. The two groups were comparable. The regional chemotherapy regimen was 5-FU, Adriamycin, methotrexate, and cytoxan. Median survival (27 months) for those patients treated with regional therapy (N = 18) was significantly longer than for those (N = 22) treated with systemic therapy (5 months) (P = 0.001). Only 45% of the regional treatment group failed in the liver. Our data, although retrospective and selective, suggest that certain subgroups of breast cancer patients with metastatic liver disease may benefit from aggressive regional therapy.

An interstitial light delivery system for photodynamic therapy within the liver

The design and application of an interstitial light delivery system suitable for photodynamic therapy of liver metastases is presented. The device incorporates an optical portion and a localization portion. Accurate geometric positioning of four 200 μm diameter optical fibres can be achieved and orientated within a metastasis after initial placement of a single fibre using real time ultrasound imaging. The device can either be applied using the percutaneous route or directly into the liver at laparotomy.

OR Software

Colorectal cancer (CRC) is among the top 3 leading causes of cancer-related deaths, and tumor malignant progression and metastases contribute to the high mortality of advanced CRC. Immune components in the tumor microenvironment can modulate tumor progression and are attractive therapeutic targets. Recently, intra-tumor mutational diversification of colorectal cancer cells at the single cell level was conducted. However, single cell transcriptome analysis of the microenvironment composition and characteristics in CRC liver metastases has yet to be performed. In this study, samples of liver metastasis cancer tissue and adjacent tissue from CRC patients were examined by single cell RNA sequencing. A total of 12 clusters corresponding to 6 cell types, including cancer cells, T cells, myeloid cells, endothelial cells, fibroblasts and B cells, were identified. Expression clustering of 445 cell cluster deregulated genes (CCDGs) identified 6 gene modules and functional enrichment was conducted to analyse the pathways in cancer cell and T cell populations. Next, the clinical significance of the expression of 93 cell cluster specifically deregulated genes (CCSDGs) in tumor-infiltrating immune cells and the correlation of the expression of these genes with patients’ survival rates were investigated with the TCGA dataset. Then, the mechanisms for increased proportion of granulocytes in the cancer sample were explored, and abnormal ferroptosis-mediated granulocyte cell death was proposed. Finally, the Wnt signalling pathway was found to be activated and promote granulocytes migration. This single cell RNA sequencing study may shed light on the tumor microenvironment composition and pave the way for CRC liver metastasis therapy.

Interstitial thermotherapy for liver tumours: Studies of different fibres and radiation characteristics

Interstitial thermal laser destruction is an attractive modality for treatment of primary and metastatic liver tumours. Using a bare fibre the volume of tissue destroyed is limited and repeated therapy is necessary. This is time consuming and it is not easy to be certain that the entire lesion is treated. We have investigated the use of a modified laser fibre. The tip of this fibre is provided with a cap made of quartz glass emitting the laser radiation laterally and circumferentially. The necrosis had an ellipsoid shape with a size amounting to 2.1±0.63 cm on 1.6±0.58 cm using 3 W power with an exposure of 600s. These lesions were much larger than the necrosis induced by bare laser fibre photocoagulation which, at most, amounts to 1.2±0.46 cm using 1.5W power for 600s. These sizes were very suitable for using the method clinically. However, the lesions were not always reproducible due to damage of the fibre during long time exposure. We conclude that further research is necessary to increase the reliability of the fibre before clinical application for therapy of liver metastasis.

Therapeutic effect of neuraminidase-treated LAK cells on liver metastasis of Colon 26.

To improve the lymphokine-activated killer (LAK) cell therapy for liver metastasis, two methods which enhance accumulation of LAK cells in the liver were examined for their effects on the liver metastasis of Colon 26 cancer cells in BALB/c mice. Distribution of LAK cells in the mice was examined by the 51Cr labeling method. Portal vein infusion of LAK cells or tail vein infusion of neuraminidase treated-LAK (N-LAK) cells showed an augmented accumulation of infused cells in the liver. In the first experiment, LAK cells (5 x 10(7) cells) were infused in the portal vein or tail vein at days 3 and 7 after the inoculation of 5 x 10(4) tumor cells and 1 x 10(4) units of IL-2 were given three times a day from day 3 to day 7. The portal infusion of LAK cells produced a greater reduction of liver metastases compared with the peripheral infusion. In the second experiment, 5 x 10(7) LAK cells or N-LAK cells were infused via the tail vein on days 1 and 3, and 1 x 10(4) units of IL-2 were given once a day from day 1 to day 5 after the inoculation of 1 x 10(4) tumor cells. The therapeutic effect of N-LAK cells was greater than non-treated LAK cells on the number of metastatic lesions and the survival time of mice. Since access to the human portal vein is difficult and risky in clinical situation, peripheral infusion of N-LAK cells is preferable.

A CASE OF LUNG ADENOCARCINOMA METASTASIZED TO THE LIVER RESPONDING TO ARTERIAL CHEMOEMBOLIZATION THERAPY WITH DSM + MMC

Liver metastases from advanced lung carcinoma have not been the target of aggressive treatment probablybecause of poor results. However, the recent progress of arterial chemoembolization therapy may make it possibleto improve the response. We present a case of multiple liver metastases detected 18 months after curative resectionof lung adenocarcinoma responding to the intermittent arterial infusion with degradable starch microsphere (DSM). With this therapy tumor markers markedly decreased, and all small metastatic lesions disappeared onimaging examinations. Single residual metastatic lesion in the liver diminished from 55mm to 30mm in diameter, so the lesion was surgically resected.The resected specimen was mostly necrotic with a few surviving colonies ofsignet ring cell carcinoma.The patient died of liver recurrence 17 months later, i.e., 25 months after initiation ofarterial infusion therapy. This type of chemoembolization therapy has been employed for 7 cases of small cellcarcinoma of the liver metastasized from lung cancer in the literature, and 4 of the 7 cases responded to the therapy.Aggresive application of this therapy for liver metastasis of lung cancer may bring better prognosis to these patients.