scholarly journals Liposomal Resiquimod for Enhanced Immunotherapy of Peritoneal Metastases of Colorectal Cancer

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1696
Author(s):  
Griffin Pauli ◽  
Po-Han Chao ◽  
Zhu Qin ◽  
Roland Böttger ◽  
Suen Ern Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Cationic Lipid ◽  
Peritoneal Metastases ◽  
Systemic Absorption ◽  
Interferon Α ◽  
High Morbidity ◽  
Systemic Level

Colorectal cancer with peritoneal metastases is currently treated by cytoreductive surgery and locoregional chemotherapeutics. This standard treatment is associated with high morbidity, mortality, and recurrence rate. To augment the existing therapy, we developed a liposome-based delivery system containing 1,2-stearoyl-3-trimethylammonium-propane chloride (DSTAP), a cationic lipid, to localize a toll-like receptor agonist, resiquimod (R848), in the peritoneal cavity (PerC) for enhancing the immune response against cancer that had spread to the PerC. The liposomes delivered by intraperitoneal injection increased peritoneal retention of R848 by 14-fold while retarding its systemic absorption, leading to a 5-fold decreased peak plasma concentration compared to free R848 in mice. Within the PerC, the DSTAP-liposomes were found in ~40% of the dendritic cells by flow cytometry. DSTAP-R848 significantly upregulated interferon α (IFN-α) in the peritoneal fluid by 2-fold compared to free R848, without increasing the systemic level. Combined with oxaliplatin, a cytotoxic agent inducing immunogenic cell death, DSTAP-R848 effectively inhibited the progression of CT26 murine colorectal tumor in the PerC, while the combination with free R848 only showed a mild effect. Moreover, the combination of oxaliplatin and DSTAP-R848 significantly increased infiltration of CD8+ T cells in the PerC compared to oxaliplatin combined with free R848, indicating enhanced immune response against the tumor. The results suggest that DSTAP-R848 exhibits potential in augmenting existing therapies for treating colorectal cancer with peritoneal metastases via immune activation.

The Effect of Dextran on the Pharmacokinetics of Lignocaine during Epidural Anaesthesia

1992 ◽  
Vol 20 (2) ◽  
pp. 127-135 ◽  
Author(s):  
A Alkhawajah ◽  
H Farag
Keyword(s):  
Epidural Anaesthesia ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Local Anaesthetics ◽  
Systemic Absorption ◽  
Onset Of Action ◽  
Time Curve ◽  
Duration Of Action ◽  
Treatment Groups ◽  
Group 2

The clinical significance of combining local anaesthetics with dextran is controversial. Although a number of investigators have found that dextran can prolong the action of local anaesthetics, others have not been able to demonstrate any significant change in the duration of anaesthesia. A study was carried out to investigate the effect of dextran on the pharmacokinetic behaviour of lignocaine during epidural anaesthesia in 20 adult male patients, who were randomly allocated to two treatment groups: group 1 ( n = 10) was given lignocaine – dextran; group 2 ( n = 10) was given lignocaine – saline. The results of the study demonstrated that the addition of dextran to epidural lignocaine significantly slowed systemic absorption of lignocaine as indicated by a smaller absorption rate constant, a reduced peak plasma concentration (Cmax), a delayed time to reach Cmax, and a smaller area under the concentration – time curve. The observed findings suggest that dextran reduces vascular uptake of lignocaine from epidural space and that it may prolong the duration of action. The significance of these findings on systemic toxicity, dosage and onset of action of lignocaine need to be investigated.

scholarly journals Serum lidocaine concentration after epidural administration in dogs

2012 ◽  
Vol 51 (No. 8) ◽  
pp. 432-436 ◽  
Author(s):  
D. Vnuk ◽  
N. Lemo ◽  
B. Radisic ◽  
V. Nesek-Adam ◽  
A. Musulin ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Epidural Injection ◽  
Daily Practice ◽  
Systemic Absorption ◽  
Epidural Administration ◽  
Single Shot ◽  
Lidocaine Concentration ◽  
Study Results ◽  
Vital Parameters

The pharmacokinetics of lidocaine deals with the measurement of lidocaine concentration in the blood and its changes over time. The toxicity of lidocaine is a function of its peak plasma concentration, which in turn depends on several factors including total dose and rates of systemic absorption and elimination. The aim of the study was to assess serum levels of lidocaine after a single shot epidural injection in dogs seen in daily practice. The study included nine dogs undergoing different types of surgery. The animals were anesthetized with a combination of diazepam and ketamine; then lidocaine was injected epidurally. Blood samples for measurement of serum lidocaine concentration were obtained before and at 10, 30, 60 and 120 min after single injection. Basic vital parameters of heart rate, respiratory rate, mean arterial pressure and hemoglobin saturation were recorded before induction of general anesthesia (T<sub>1</sub>), immediately after intubation (T<sub>2</sub>), and then at 10, 30, 60 and 120 min of epidural lidocaine administration. Study results indicated that serum lidocaine concentration did not reach the levels of potential toxicity in dogs upon epidural injection of 4 mg/kg lidocaine at a concentration of 2% and there were no significant alterations in basic vital parameters.

Pharmacokinetics and Haemostatic Status During Consecutive Infusions of Recom binant Tissue-Type Plasminogen Activator in Patients with Acute Myocardial Infarction

1989 ◽  
Vol 61 (03) ◽  
pp. 497-501 ◽  
Author(s):  
E Seifried ◽  
P Tanswell ◽  
D Ellbrück ◽  
W Haerer ◽  
A Schmidt
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Plasminogen Activator ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Precise Control ◽  
Type Plasminogen Activator

SummaryPharmacokinetics and systemic effects of recombinant tissue type plasminogen activator (rt-PA) were determined during coronary thrombolysis in 12 acute myocardial infarction patients using a consecutive intravenous infusion regimen. Ten mg rt-PA were infused in 2 minutes resulting in a peak plasma concentration (mean ±SD) of 3310±950 ng/ml, followed by 50 mg in 1 h and 30 mg in 1.5 h yielding steady state plasma levels of. 2210±470 nglml and 930±200 ng/ml, respectively. All patients received intravenous heparin. Total clearance of rt-PA was 380±74 ml/min, t,½α was 3.6±0.9 min and t,½β was 16±5.4 min.After 90 min, in plasma samples containing anti-rt-PA-IgG to inhibit in vitro effects, fibrinogen was decreased to 54%, plasminogen to 52%, α2-antiplasmin to 25%, α2-macroglobulin to 90% and antithrombin III to 85% of initial values. Coagulation times were prolonged and fibrin D-dimer concentrations increased from 0.40 to 2.7 μg/ml. It is concluded that pharmacokinetics of rt-PA show low interpatient variability and that its short mean residence time in plasma allows precise control of therapy. Apart from its moderate effect on the haemostatic system, rt-PA appears to lyse a fibrin pool in addition to the coronary thrombus.

scholarly journals Dedicated MRI staging versus surgical staging of peritoneal metastases in colorectal cancer patients considered for CRS-HIPEC; the DISCO randomized multicenter trial

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
M. P. Engbersen ◽  
C. J. V. Rijsemus ◽  
J. Nederend ◽  
A. G. J. Aalbers ◽  
I. H. J. T. de Hingh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Diagnostic Laparoscopy ◽  
Controlled Trial ◽  
Peritoneal Metastases ◽  
Surgical Staging ◽  
Mri Findings ◽  
Mri Staging ◽  
Multicenter Randomized Controlled Trial ◽  
Colorectal Cancer Patients

Abstract Background Selecting patients with peritoneal metastases from colorectal cancer (CRCPM) who might benefit from cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is challenging. Computed tomography generally underestimates the peritoneal tumor load. Diagnostic laparoscopy is often used to determine whether patients are amenable for surgery. Magnetic resonance imaging (MRI) has shown to be accurate in predicting completeness of CRS. The aim of this study is to determine whether MRI can effectively reduce the need for surgical staging. Methods The study is designed as a multicenter randomized controlled trial (RCT) of colorectal cancer patients who are deemed eligible for CRS-HIPEC after conventional CT staging. Patients are randomly assigned to either MRI based staging (arm A) or to standard surgical staging with or without laparoscopy (arm B). In arm A, MRI assessment will determine whether patients are eligible for CRS-HIPEC. In borderline cases, an additional diagnostic laparoscopy is advised. The primary outcome is the number of unnecessary surgical procedures in both arms defined as: all surgeries in patients with definitely inoperable disease (PCI > 24) or explorative surgeries in patients with limited disease (PCI < 15). Secondary outcomes include correlations between surgical findings and MRI findings, cost-effectiveness, and quality of life (QOL) analysis. Conclusion This randomized trial determines whether MRI can effectively replace surgical staging in patients with CRCPM considered for CRS-HIPEC. Trial registration Registered in the clinical trials registry of U.S. National Library of Medicine under NCT04231175.

scholarly journals Identification and validation of a miRNA-related expression signature for tumor mutational burden in colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lijun Xu ◽  
Qing Zheng
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Validation Cohort ◽  
Expression Profiles ◽  
Functional Enrichment ◽  
Immune Checkpoints ◽  
Positive Correlation ◽  
Expression Signature ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Abstract Background Tumor mutational burden (TMB) is a promising predictor, which could stratify colorectal cancer (CRC) patients based on the response to immune checkpoint inhibitors (ICIs). MicroRNAs (miRNAs) act as the key regulators of anti-cancer immune response. However, the relationship between TMB and miRNA expression profiles is not elucidated in CRC. Methods Differentially expressed miRNAs (DE miRNAs) between the TMBhigh group and the TMBlow group were identified for the CRC cohort of the TCGA database. In the training cohort, a miRNA-related expression signature for predicting TMB level was developed by the least absolute shrinkage and selection operator (LASSO) method and tested with reference to its discrimination, calibration, and decision curve analysis (DCA) in the validation cohort. Functional enrichment analysis of these TMB-related miRNAs was performed. The correlation between this miRNA-related expression signature and three immune checkpoints was analyzed. Results Twenty-one out of 43 DE miRNAs were identified as TMB-related miRNAs, which were used to develop a miRNA-related expression signature. This TMB-related miRNA signature demonstrated great discrimination (AUCtest set = 0.970), satisfactory calibration (P > 0.05), and clinical utility in the validation cohort. Functional enrichment results revealed that these TMB-related miRNAs were mainly involved in biological processes associated with immune response and signaling pathways related with cancer. This miRNA-related expression signature showed a median positive correlation with PD-L1 (R = 0.47, P < 0.05) and CTLA4 (R = 0.39, P < 0.05) and a low positive correlation with PD-1 (R = 0.16, P < 0.05). Conclusion This study presents a miRNA-related expression signature which could stratify CRC patients with different TMB levels.

scholarly journals A Versatile Theranostic Platform for Colorectal Cancer Peritoneal Metastases: Real‐Time Tumor‐Tracking and Photothermal‐Enhanced Chemotherapy

2021 ◽  
pp. 2102256
Author(s):  
Tao Sun ◽  
Guangping Zhang ◽  
Tingting Ning ◽  
Qinjun Chen ◽  
Yongchao Chu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Real Time ◽  
Peritoneal Metastases ◽  
Tumor Tracking

scholarly journals The features of host immune response with respect to microsatellite status of colorectal cancer

2007 ◽  
Vol 15 (1-2) ◽  
pp. 5-9
Author(s):  
Attila Fenyvesi
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Immune Responses ◽  
Continuous Production ◽  
Tumor Infiltrating Lymphocytes ◽  
Host Immune Response ◽  
Genetic Alterations ◽  
Clinicopathological Characteristics ◽  
Melting Point Analysis ◽  
Peritumoral Stroma

Background: The genetic alterations in colorectal cancer (CRC) progression are determined by two separate pathways, chromosomal and microsatellite instability (MSI). The CRCs with MSI have distinct clinicopathological characteristics with pronounced tumor-associated immune responses. The aim of our study was to investigate the intensity of host immune response in CRC tissue by comparing microsatellite stable (MSS) and instable tumors. Methods: The study was performed on CRC specimens from 28 patients with MSI and compared with 30 MSS tumors. The microsatellite status was evaluated with two markers by PCR and melting point analysis. The immunostaining with anti-CD3 pan-T cell antibody was used to quantify the number of tumor infiltrating lymphocytes. The lymphocytes in peritumoral stromal and the Crohn?s-like peritumoral reaction were counted on H&E slides. Results: No significant differences were found in the average number of lymphocytes in peritumoral stroma and in clinicopathological characteristics of CRCs. The conspicuous Crohn?s-like lymphoid reactions were present in 67.86% of CRCs with MSI versus 26.66% of MSS cases. The CRCs with MSI cases carried significantly higher numbers of tumor infiltrating T-lymphocytes (13.21 versus 7.47) (p<0.0001). Conclusion: The presences of peritumoral Crohn?s-like lymphoid and intraepithelial lymphocytic reaction were intensive markers for MSI in colorectal carcinomas in our study. The peculiar genetic instability in MSI tumors may lead to a continuous production of abnormal peptides, which act as neoantigens. They could induce specific antitumor immune responses effective in limiting tumor growth and spread. Abnormal peptides are potentially promising in immunotherapy advancing and in the design of a vaccine against colorectal tumors with MSI.

Sign in / Sign up

Export Citation Format

Share Document