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Safety Study of Oxaliplatin and 5-fluorouracil Followed by FUDR for Unresectable Colorectal Liver Metastases

ABSTRACT: The purpose of this study is to determine the maximum tolerated dose and dose limiting toxicity of 5-FU in combination with Oxaliplatin delivered via isolated hepatic perfusion.

DISEASE(S): Neoplasm Metastasis,Liver Neoplasms,Colorectal Liver Metastases,Cancer

PROVIDER: 2046321 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Isolated Liver Perfusion With Oxaliplatin

Project description:The primary goal of this research study is to determine a safe dose for the drug oxaliplatin when delivered by isolated hepatic perfusion. The second goal of this research study is to determine if isolated hepatic perfusion with oxaliplatin can improve the efficacy of standard hepatic arterial infusional (HAI) therapy with floxuridine (FUDR)/leucovorin.

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NCIC CTG MA.22 phase I/II trial of epirubicin and docetaxel in locally advanced breast cancer on 2-weekly or 3-weekly schedules

Project description:This phase I/II neoadjuvant trial determined maximally-tolerated doses (MTD), dose-limiting toxicities (DLT), response-to-therapy, and explored the role of new response biomarkers. The combination regimens were delivered with acceptable toxicity, good clinical response, inducing changes in tumor RNA content and integrity. Pre-treatment gene expressions impacted clinical response, including several near 17q12, which with ERBB2, may better identify chemoresponsiveness.

2015-11-11 | GSE66999 | GEO

A Phase I Study of Isolated Hepatic Perfusion With Escalating Dose Melphalan Followed by Postoperative Hepatic Arterial Floxuridine and Leucovorin for Metastatic Unresectable Colorectal Cancers of the Liver

Project description:Patients with unresectable metastatic colorectal cancer confined to the liver will undergo a 1 hour hyperthermic isolated hepatic perfusion (IHP) with escalating dose melphalan. Postoperatively, patients will be treated with hepatic arterial infusion of floxuridine (FUDR), 0.2 mg/kg/day and leucovorin (LV), 15 mg/M2/day as a 2-week continuous infusion regimen. Hepatic and systemic toxicity, response to treatment, duration of response, and survival will be followed.

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Data in support of Prenatal intra-amniotic lipopolysaccharide induces neonatal renal immune activation after preterm birth

Project description:Preterm birth is often predisposed by chorioamnionitis (CA) and CA affects the fetal gut and lungs via intra-amniotic (IA) inflammation, thus accentuating the proinflammatory effects of preterm birth. It is not known if IA inflammation also affects other perfusion-sensitive organs (e.g., kidneys) before and after preterm birth. Using preterm pigs as model for preterm infants, we hypothesized that CA induces fetal and neonatal renal dysfunctions that can intially be detected via plasma proteome, partly explaining the frequent renal dysfunction in preterm infants. Fetal pigs (88% gestation) were given an IA dose of lipopolysaccharide (LPS, 1 mg/kg, n=28), delivered preterm by cesarean section three days later, and compared with controls (CON, n=26) at birth and postnatal day five. Plasma proteome and protein markers of inflammatory pathways were evaluated.

2021-03-25 | PXD014619 | Pride

Isolated Hepatic Perfusion With Melphalan Followed By Chemotherapy in Treating Patients With Unresectable Colorectal Cancer That is Metastatic to the Liver

Project description:RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving them in different ways may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of melphalan given as an isolated hepatic perfusion followed by chemotherapy infused into the liver in patients who have unresectable colorectal cancer that is metastatic to the liver.

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The comparison of gene expression profiles in hepatic stellate cells isolated from mouse livers by perfusion method at 37 degrees or 6 degrees

Project description:We compared transcriptome profiling (bulk RNA-seq) of hepatic stellate cells isolated from mouse livers by perfusion method using collagenase at 37 degrees or 6 degrees and evaluated the heat-stressed gene expression at 37 degrees.

2022-09-28 | GSE192598 | GEO

Isolated Hepatic Perfusion With Melphalan Followed by Combination Chemotherapy in Treating Patients With Unresectable Liver Metastases From Colorectal Cancer

Project description:RATIONALE: Drugs used in chemotherapy, such as melphalan, leucovorin, oxaliplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving the drugs in different ways may kill more tumor cells. PURPOSE: This phase II trial is studying how well isolated hepatic perfusion with melphalan followed by combination chemotherapy works in treating patients with unresectable liver metastases from colorectal cancer.

| 2012255 | ecrin-mdr-crc

Mpekris2017 - Role of vascular normalization in benefit from metronomic chemotherapy

Project description:Role of vascular normalization in benefit from metronomic chemotherapy. Mpekris F1, Baish JW2, Stylianopoulos T3, Jain RK4. Author information Abstract Metronomic dosing of chemotherapy-defined as frequent administration at lower doses-has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy. KEYWORDS: drug delivery; immune response; oxygenation; thrompospondin-1; tumor perfusion

2020-01-20 | MODEL2001200002 | BioModels

Phosphoproteomic analysis of IL-2 MSA and IL-12 MSA combination on T cell signaling

Project description:Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.

2024-01-26 | PXD044740 | Pride

CAR-T Hepatic Artery Infusions or Pancreatic Venous Infusions for CEA-Expressing Liver Metastases or Pancreas Cancer

Project description:This is an open label, fixed dose, phase Ib trial of anti-CEA CAR-T cell infusions delivered via the hepatic artery or splenic vein using the Surefire Infusion System (SIS) for patients with CEA-expressing liver metastases or pancreas cancer.

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