Mg Of Doxorubicin Research Articles

Cardiotoxicity after autologous hematopoietic stem cell transplantation (AHSCT): longitudinal and observational study

Objectives: To assess incidence and extent of early cardiotoxicity after autologous hematopoietic stem cell transplantation (AHSCT).
 Methods: Study carried out in two bone marrow transplant centers, in public and private hospital, located in interior of Minas Gerais, Brazil. All patients who underwent AHSCT at centers between March 2018 and May 2019 and October 2019 were included. Altered results were classified according to Brazilian Cardio-Oncology Guidelines.
 Results: Of the 36 patients evaluated, seven (21.2%) had cardiotoxicity on echocardiography, with mean left ventricular ejection fraction decreasing from 71.53 to 64.75% before and after conditioning (p = 0.00013). Clinical cardiovascular alterations were associated with advanced staging and time of more than one year between diagnosis and AHSCT (p=0.01 in both cases). Specific clinical signs of congestion were correlated with radiotherapy to the mediastinum and a dose >400 mg of doxorubicin before AHSCT (p=0.02 and p=0.01, respectively).
 Conclusions: Thus, higher incidence of cardiac injury was observed after AHSCT, which was related to type of pre-transplant therapy. This fact reflects our limitations and leads us to seek improvements in cardiovascular assessment of patients undergoing AHSCT, in order to reduce morbidity and mortality associated with myocardial injuries in these patients.

A NOVEL SILORANE-BASED BONE CEMENT FOR LOCAL DELIVERY OF CHEMOTHERAPY AGENTS

Osteosarcoma and other types of bone cancers often require bone resection, and backfill with cement. A novel silorane-based cement without PMMA's drawbacks, previously developed for dental applications, has been reformulated for orthopedic use. The aim of this study is to assess each cement's ability to elute doxorubicin, maintain its potency, and maintain suitable weight-bearing strength.The silorane-based epoxy cement was synthesized using a platinum-based Lamoreaux's catalyst. Four groups of cement were prepared. Two PMMA groups, one without any additives, one with 200 mg of doxorubicin. Two silorane groups: one without any additive, one with doxorubicin, added so that the w% of drug into both cements were equal. Pellets 6 × 12 mm were used for testing (ASTM F451). n=10. Ten pellets from each group were kept dry. All others were placed into tubes containing 2.5 mL of PBS and stored at 37 °C. Elution from doxorubicin-containing groups were collected every day for 7 days, with daily PBS changeout. Antibiotic concentrations were determined via HPLC. Compressive strength and compressive modulus of all groups were determined for unsoaked specimens, and those soaked for 7 and 14 days. MTT assays were done using an MG63 osteosarcoma cell line.Both cements were able to elute doxorubicin over 7 days in clinically-favorable quantities. For PMMA samples, the incorporation of doxorubicin was shown to significantly affect the compressive strength and modulus of the samples (p<0.01). Incorporation of doxorubicin into silorane had no significant effect on either (p>.05). MTT assays indicated that doxorubicin incorporated into the silorane cement maintained its effectiveness whereas that into PMMA did not. At the dosing used, both cements remained above the 70 MPa.Both PMMA and silorane-based cements can deliver doxorubicin. Doxorubicin, however, interacts chemically with PMMA, inhibiting polymerization and lowering the chemotherapeutic's effectiveness.

Polymer-nucleobase composites for chemotherapy drug capture.

Intravenous chemotherapy (e.g., doxorubicin (DOX)) is standard treatment for many cancers but also leads to side effects due to off-target toxicity. To address this challenge, devices for removing off-target chemotherapy agents from the bloodstream have been developed, but the efficacy of such devices relies on the ability of the underlying materials to specifically sequester small-molecule drugs. Anion-exchange materials, genomic DNA, and DNA-functionalized iron oxide particles have all been explored as drug-capture materials, but cost, specificity, batch-to-batch variation, and immunogenicity concerns persist as challenges. Here, we report a new class of fully synthetic drug-capture materials. We copolymerized methacrylic acid and ethylene glycol dimethacrylate in the presence of several nucleobases and derivatives (adenine, cytosine, xanthine, and thymine) to yield a crosslinked resin with nucleobases integrated into the material. These materials demonstrated effective DOX capture: up to 27 mg of DOX per g of material over 20 minutes from a phosphate-buffered saline solution with an initial concentration of 0.05 mg mL-1 of DOX. These materials use only the individual nucleobases for DOX capture and exhibit competitive capture efficacy compared to previous materials that used genomic DNA, making this approach more cost-effective and reducing potential immunological concerns.

Safety and efficacy of drug-eluting microspheres chemoembolization under cone beam computed tomography control in patients with early and intermediate stage hepatocellular carcinoma.

BackgroundDrug-eluting microsphere transarterial chemoembolization (DEM-TACE) is the standard of care in patients with intermediate-stage hepatocellular carcinoma and ensures targeted and controlled cytotoxic and ischemic effects. Proper patient selection and optimized treatment techniques are associated with longer median survival. The aim of this single-institution retrospective study was to evaluate safety and efficacy of DEM-TACE under cone beam computed tomography (CBCT) control in patients with early and intermediate stage hepatocellular carcinoma.Patients and methodsA total of 144 patients (mean age 67.9 ± 8.0 years, 127 males and 17 females) between February 2010 and December 2018 were studied. Microparticles of different dimensions according to two manufacturers (diameter of 70–150 μm, 100–300 μm or 300–500 μm and 40-μm, 75-μm or 100-μm) were used and loaded with 50–150 mg of doxorubicin. The objective tumour response according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST), the time to progression, adverse events and overall survival were (OS) evaluated.ResultsIn total, 452 procedures were performed (median, 3 per patient). Four (0.9% of all procedures) major complications were noted. Postembolization syndrome occurred after 35% of procedures. At the first imaging follow-up 2–3 months after first treatment, 91% of patients achieved an objective response. The median time to progression was 10.2 months (95% CI: 8.3-12.1 months). OS rates at 1, 2, 3, 4, and 5 years were 85%, 53%, 33%, 20% and 14%, respectively. The median survival time was 25.8 months (95% CI: 22.1–29.5 months).ConclusionsDEM-TACE under CBCT control in patients with early and intermediate stage hepatocellular carcinoma is a safe and effective method of treatment with high objective tumour response and survival rates.

Polyethylene Glycol Drug-Eluting Embolic Microspheres Loaded with Doxorubicin for the Treatment of Hepatocellular Carcinoma: Feasibility, Safety, and Pharmacokinetic Study

PurposePolyethylene glycol drug-eluting microspheres (PEG-DEMs) can be loaded to elute doxorubicin. The current study evaluated the pharmacokinetic profile and safety of PEG-DEMs in the treatment of patients with hepatocellular carcinoma (HCC). Materials and methodsThe current prospective, multicenter, dose-escalation study enrolled 25 patients (68% men) with early or intermediate stage HCC and a performance status of 0. Patients in Cohort I were assigned to receive target doxorubicin doses of 75, 100, or 150 mg. Analyses were performed on the basis of the specific dose of doxorubicin that the patients received because some patients received less than the assigned dose. Patients in Cohort II received the maximum safe tested dose. Adverse events were classified according to the Common Terminology Criteria for Adverse Events version 4.03. The tumor response was evaluated every 3 months according to the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors. ResultsThe maximum tested safe dose of doxorubicin was 150 mg. For the groups that received ≤75, 75–100, and 101–150 mg of doxorubicin, the peak plasma concentrations were 286.7 ng/mL ± 220.1, 157.1 ng/mL ± 94.6, and 245.4 ng/mL ± 142.8, respectively; the areas under the curves calculated from 0 to 24 h were 421.7 (ng × h)/mL ± 221.2, 288.1 (ng × h)/mL ± 100.9, and 608.3 (ng × h)/mL ± 319.3, respectively, with almost complete clearance at 24 h. There was no death within 30 d. The best objective response rate was 81%, and the disease control rate was 91%. The median overall survival was 27.2 months (95% confidence interval [CI], 17.5 months to not evaluated [n.e.]); the median progression-free survival was 9.8 months (95% CI, 5.5 months to n.e.). ConclusionsPEG-DEMs demonstrated a favorable safety profile with low systemic concentration of doxorubicin, and promising efficacy.

Cone-Beam Computed Tomography-Based Spatial Prediction of Drug Dose After Transarterial Chemoembolization Using Radiopaque Drug-Eluting Beads in Woodchuck Hepatocellular Carcinoma.

The aims of this study were to develop a model to estimate drug dose delivered to tumors after transarterial chemoembolization (TACE) with radiopaque drug-eluting beads (DEBs) based on DEB density on cone-beam computed tomography (CT) and to evaluate drug penetration into tissue in a woodchuck hepatoma model. Transarterial chemoembolization was performed in woodchucks with hepatocellular carcinoma (N = 5) using DEBs (70-150 μm, LC Bead LUMI) loaded with doxorubicin. Livers were resected 45 minutes after embolization, immediately frozen, and cut using liver-specific, 3D-printed sectioning molds. Doxorubicin levels in tumor specimens were measured by high-performance liquid chromatography and correlated with DEB iodine content that was measured using prototype cone-beam CT-based embolization treatment planning software. Doxorubicin penetration into tissue surrounding DEBs was assessed by fluorescence microscopy of tumor sections. Fluorescence intensity was converted into doxorubicin concentration using calibration standards. Intensity-thresholded color heatmaps were generated representing extravascular drug penetration. Consistent segmentation of DEBs on cone-beam CT was achieved using a semiautomated intensity thresholding method. A positive linear correlation (0.96) was found between DEB iodine content measured on cone-beam CT and the amount of doxorubicin measured in tumor specimens. Prediction of doxorubicin levels in tumor sections that were not included in model development was accurate, with a root-mean-square error of 0.08 mg of doxorubicin. Tumor penetration of eluted doxorubicin resulted in concentration gradients where drug content decreased with increasing distance from blood vessels containing DEBs. Drug penetration was greater for blood vessels containing DEB clusters compared with single DEB, with higher doxorubicin concentrations extending further away from the vessels. Estimation of drug dose delivered during transarterial chemoembolization in a woodchuck hepatocellular carcinoma model was possible using DEB radiopacity on cone-beam CT as a surrogate marker. Doxorubicin penetration was greatest adjacent to vessels containing DEB clusters compared with single DEB. Intraprocedural estimation of the spatial distribution of drug dose within the tumor could enable real-time adjustments to DEB delivery, to maximize treatment coverage or identify regions of tumor at risk for undertreatment.

Nivolumab (NIVO) and drug eluting bead transarterial chemoembolization (deb-TACE): Updated results from an ongoing phase 1 study of patients (pts) with liver limited hepatocellular carcinoma (HCC).

437 Background: TACE is a standard of care for liver limited HCC and impacts the immune microenvironment, potentially augmenting the effects of immune checkpoint inhibitors. Methods: This is a multicenter phase 1 study of NIVO and deb-TACE in unresectable HCC pts and Child Pugh A cirrhosis (NCT03143270). The primary objective is to assess safety. Secondary objectives include response rate by RECIST v1.1, progression-free and overall survival by Kaplan-Meier methodology, and blood/tumor immune correlates. A 3 + 3 design with expansion cohort sequentially evaluates 3 cohorts of differing schedules of NIVO relative to deb-TACE. Deb-TACE (75mg of doxorubicin) is administered on Day 0. NIVO is dosed at 240mg IV every 14 days for 1 year (Cohort 1: NIVO begins day +14 after deb-TACE; Cohort 2, interrupted NIVO dosing begins at Day -28 but is held on the Day 0 then restarted on Day +14; Cohort 3, continuous NIVO dosing begins on Day -28 without interruption). Results: As of September 2021, 19 pts were treated [median 67 years (range: 54-78), male (80%), ECOG PS 0 (47%), Child Pugh A (100%), 3 pts in each cohort 1 and 2, 13 pts in cohort 3]. No cases of treatment related liver failure or Grade 5 adverse events (AEs) were observed. 1 DLT of Grade 3 transaminitis was observed in cohort 3 and resolved without intervention and did not recur with drug rechallenge. Median ALT at baseline, day 28, day 56, and end of treatment (EOT) were 27, 43.5, 36.5, and 29 U/L. Median bilirubin at baseline, day 28, day 56, and EOT were 0.6, 0.6, 0.5, and 0.6 mg/dL. Mean ALBI score at baseline (N=19) and EOT (N=14) were -2.75 ± 0.48 vs. -2.55 ± 0.50. The most common treatment-related AEs of any grade were fatigue (53%), ALT/AST increase (42%), fever (37%), and pruritis (32%). The objective response rate by RECIST v 1.1 was 21% (Table). 5/19 pts remained on study with SD or better for ≥12 (range 12-43) months. Updated survival analysis will be presented at the meeting; correlatives at a separate venue. Conclusions: Nivolumab administered with deb-TACE is safe with antitumor activity. This study provides a needed benchmark for the safety of embolization along with anti-PD1 therapy in liver limited HCC. The clinical question of combining immunotherapy with embolization to improve outcome over embolization alone remains investigational and several, pivotal, phase 3 studies are ongoing. Clinical trial information: NCT03143270. [Table: see text]

Asimetrična melanonihija prouzrokovana hemioterapijom

Introduction: Chemotherapy may cause various nail damages, including chromonychia, melanonychia, onycholisis, and onychomadesis. Melanonychia is characterized by melanin-derived brown-to-black nail pigmentation. It may occur as a result of nail matrix melanocytic activation or melanocytic hyperplasia, and nail invasion by melanin-producing pathogens. Case report: We present a case of a patient who developed an extremely rare event of asymmetric melanonychia during systemic treatment of non-Hodgkin lymphoma. The melanonychia developed in dose-dependent manner after 500 mg of doxorubicin. One of the most incriminating agents for melanonychia development are doxorubicin and to a less extent cyclophosphamide. Our patient received both drugs as combined chemotherapy. After treatment completion, the phenomenon disappeared. An extremely unexpected event was skin melanoma occurrence. Conclusion: It has not been clarified yet whether this event was causally related to previous nail-related melanocyte activation or it was just a coincidence.

Effects of photobiomodulation (660 nm laser) on anthracycline extravasation: An experimental study.

Objective: to investigate the effect of using different agents (topical hyaluronidase, photobiomodulation, and the association of photobiomodulation with topical hyaluronidase) in preventing the formation of lesions caused by doxorubicin extravasation, as well as in the reduction of lesions formed by extravasation of this drug. Method: a quasi-experimental study conducted with 60 Wistar rats, randomized into four groups with 15 animals each. Group 1 (Control); Group 2 (Hyaluronidase); Group 3 (Photobiomodulation); and Group 4 (Hyaluronidase + Photobiomodulation). A wound was induced by applying 1 mg of doxorubicin to the subcutaneous tissue of the back of the animals. The concentration of topical hyaluronidase was 65 turbidity units/g and the energy employed was 1 joule of 100 mW red laser per square centimeter. With macroscopic evaluation every two days for 28 days, the following variables were observed: skin integrity, presence of blisters, hyperemia, exudate, bleeding, edema, crust, peeling and granulation tissue. Results: the animals from the groups subjected to photobiomodulation obtained better results in the assessment of the following variables: bleeding, hyperemia, exudate, intact skin and edema. Conclusion: it was evidenced that the association of photobiomodulation with topical hyaluronidase was effective in reducing the local effects and assisted in the wound healing process, and that PBM alone was able to prevent appearance of lesions.

131Iodine-DEM TACE vs. conventional TACE in cirrhotic patients with hepatocellular carcinoma: a single center experiment.

To evaluate the safety and efficacy of transcatheter arterial chemoembolization (TACE) with 131iodine-doxorubicin-eluting gelatin microspheres (131I-DEM TACE) compared with conventional TACE (cTACE) with polyvinyl alcohol foam (PVA) embolization microspheres. A total of 22 patients diagnosed with hepatocellular carcinoma were equally divided into 2 groups. The patients who underwent TACE with 131I-DEM (25.7×107 Bq of 131iodine and 10 mg of doxorubicin) were compared to controls who received cTACE with PVA embolization microspheres. Therapeutic effects were evaluated by the tumor regression rates, levels of alpha-fetoprotein in serum, survival rates, and complications. The operative complications of the 2 groups were not significantly different (P=0.753). The radioactivity ratio of the tumor to the liver was approximately 4.1:1 for the 131I-DEM TACE group. In the 131I-DEM TACE group, 54.5% of patients achieved tumor regression of more than 50%, compared to 36.6% of patients in the cTACE group. AFP levels in serum declined in 100% of patients in the 131I-DEM TACE group and 50% of patients in the cTACE group. The median survival time of the patients was 12.0±3.3 months for the 131I-DEM TACE group and 10.0±3.3 months for the cTACE group. There were no significant differences in survival between the 2 groups (P=0.414). 131I-DEM may become a potential radiochemoembolization agent to treat patients with unresectable hepatocellular carcinoma through TACE.

Development of rotational intraperitoneal pressurized aerosol chemotherapy to enhance drug delivery into the peritoneum

This study aims to evaluate the drug distribution, tissue concentrations, penetration depth, pharmacokinetic properties, and toxicities after rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs. Because relevant medical devices have not been introduced, we developed our prototype of pressurized intraperitoneal aerosol chemotherapy (PIPAC) and RIPAC by adding a conical pendulum motion device for rotating the nozzle. RIPAC and PIPAC were conducted using 150 ml of 1% methylene blue to evaluate the drug distribution and 3.5 mg of doxorubicin in 50 ml of 0.9% NaCl to evaluate the tissue concentrations and penetration depth, pharmacokinetic properties, and toxicities. All agents were sprayed as aerosols via the nozzle, DreamPen® (Dalim Biotech, Gangwon, South Korea), with a velocity of 5 km/h at a flow rate of 30 ml/min under a pressure of 7 bars, and capnoperitoneum of 12 mmHg was maintained for 30 min. As a result, RIPAC showed a wider distribution and stronger intensity than PIPAC. Compared with PIPAC, RIPAC demonstrated high values of the tissue concentration in the central, right upper, epigastrium, left upper, left lower, right lower, and right flank regions (median, 375.5–2124.9 vs. 161.7–1240 ng/ml; p ≤ .05), and higher values of the depth of concentrated diffusion and depth of maximal diffusion (median, 232.5–392.7 vs. 116.9–240.1 μm; 291.2–551.2 vs. 250.5–362.4 μm; p ≤ .05) in all regions except for bowels. In RIPAC, the pharmacokinetic properties reflected hemodynamic changes during capnoperitoneum, and there were no related toxicities. Conclusively, RIPAC may have the potential to enhance drug delivery into the peritoneum compared to PIPAC.

Liver Abscess and Portal Vein Thrombosis Complicating TACE for HCC: Case Study and Literature Review

Embolization made by 120 mg of Doxorubicin, carried by 16 ml of Lipiodol ultra-fluid (UF). The mixture is made stable by the combination of 4 ml of Ultravist (Iopromide). The patient received 100% of the resulting emulsion. Embolization was completed with ¼ gelatin platelet.

Multicentre prospective study of drug-eluting bead chemoembolisation safety using tightly calibrated small microspheres in non-resectable hepatocellular carcinoma

PurposeTo assess the safety and tolerability of transarterial drug-eluting bead chemoembolisation (DEB-TACE) using tightly calibrated 100-μm microspheres in hepatocellular carcinoma (HCC). MethodThis multicentre prospective study included 131 patients with a 2-year follow-up. All patients had Child-Pugh scores ≤ B7, a good performance status, and Barcelona Clinic Liver Cancer stage A or B. Beads were loaded with 50 mg of doxorubicin per millilitre. Overall, 223 nodules were treated (mean size: 27.6 mm, average number of nodules per patient: 1.7). Toxicity was assessed using Common Terminology Criteria for Adverse Events 4.03 and response according to the modified Response Evaluation Criteria in Solid Tumours. The primary endpoint was safety. Secondary endpoints included technical success, post-embolisation syndrome (PES), local tumour response, and 2-year survival. ResultsA total of 214 DEB-TACE procedures were performed (mean per patient: 1.64), with a technical success rate of 97.6 % and a PES rate of 9.3 %. Major complications occurred in 6.8 % of patients and 4.1 % of procedures. There were no treatment-related deaths. Doxorubicin dose was an independent predictor of complications (p = 0.01). Four patients were lost to follow-up and 18 received liver transplants. Objective response rates were 74.6 %, 45.7 %, and 44.1 % at 6, 12, and 24 months, respectively. The cumulative 24-month overall survival rate was 55.96 %. Median survival was 22 months (interquartile range = 13–24). Co-morbidities and tumour response were independent predictors of survival (p = 0.0012 and 0.0052, respectively). Complications did not affect survival (p = 0.24). ConclusionsDEB-TACE with tightly calibrated 100-μm beads is safe and not associated with increases in biliary toxicity or complications. Tumour response and survival are in the expected range for chemoembolisation therapy. (Clinical trials ID: NCT02670122).

4:03 PM Abstract No. 234 Prospective pilot evaluation testing the safety and efficacy of the surefire infusion system for delivery of drug-eluting embolic transarterial chemoembolization

To prospectively assess the feasibility, safety and efficacy of performing DEE-TACE using the Surefire Infusion System. This was an IRB-approved prospective study registered in clinicaltrials.gov (NCT03211598). A total of 15 patients with BCLC stage A or B HCC were enrolled. All patients underwent a standard angiogram and embolization using SIS (TriSalus, Westminster, CO). Embolization was performed using 1 vial of 100 micron Oncozene (Boston Scientific, Marlborough, MA) loaded with 50 mg of Doxorubicin and 100 or 250 micron Embozene (Boston Scientific, Marlborough, MA), as required. Treatment end-point was defined as reflux of contrast with catheter tip expanded or development of intrahepatic collaterals. All embolization procedures were performed by one of 3 fellowship trained interventional radiologist (AYK, GEL, EC). Initial follow-up imaging was obtained 8 weeks post treatment and every 8 weeks for the first 6 months then at 52 weeks post treatment. Disease response was evaluated based on the mRECIST criteria by 1 of 2 fellowship trained abdominal imager (DD or PK). Patients with recurrent or residual disease at any follow-up were treated in an “on-demand” fashion. Adverse events were assessed at 2 and 8 weeks post treatment and graded per CTCAE v 4.03. Pathologic assessment was performed by a pathologist specializing in HCC (BK). 15 patients with a total of 23 lesions underwent 20 separate treatments. During the study follow-up, 1 patient died, 2 enrolled in other trials, 1 treated with ablation, and 8 underwent transplantation. 2 patients were alive at 12 months and 1 is currently undergoing follow-up. There were no procedural complications or grade 3 or higher toxicities. The rates of CR, PR and SD at 8 weeks was 6/15 (40%), 7/15 (47%) and 2/15 (13%), respectively. The rates of CR, PR and PD at 6 month follow-up was 6/11 (55%), 4/11 (36%) and 1/11 (9%). Complete pathologic response was seen in 5/8 (63%) patients. The other 3 patients had >80% necrosis of their tumors. The SIS is safe for delivery of DEE-TACE with promising efficacy. A comparative study is needed to assess its potential benefit over standard catheters.

Nivolumab (NIVO) and drug eluting bead transarterial chemoembolization (deb-TACE): Preliminary results from a phase I study of patients (pts) with liver limited hepatocellular carcinoma (HCC).

525 Background: Regional therapies in HCC impact the immune microenvironment and may augment the effects of immune checkpoint inhibitors. Methods: This is a multicenter phase 1 study of NIVO and deb-TACE in unresectable HCC pts (BCLC Stage B) and Child Pugh A cirrhosis (NCT03143270). The primary objective is to assess safety. Secondary objectives include response rate by RECIST v1.1, progression-free and overall survival by Kaplan-Meier methodology, and blood/tumor immune correlates. A 3 + 3 design sequentially evaluates 3 cohorts of differing schedules of NIVO relative to deb-TACE. Deb-TACE (75mg of doxorubicin) is administered on Day 0. NIVO is dosed at 240mg IV every 14 days for 1 year (Cohort 1: NIVO begins day +14 after deb-TACE; Cohort 2, interrupted NIVO dosing begins at Day -28 but is held on the Day 0 then restarted on Day +14; Cohort 3, continuous NIVO dosing begins on Day -28 without interruption). Results: As of July 2019, 9 pts have been treated [median 65 years (range: 54-76), male (89%), viral (44%;1 HBV, 3 HCV), non-viral (56%;2 EtOH, 1 NASH, 2 unknown), prior resection (44%), prior regional therapy (44%), 3 pts in each cohort]. No cases of treatment related liver failure, dose-limiting toxicity, or Grade 5 adverse events (AEs) were observed. Grade ≥3 AEs possibly related to nivolumab, deb-TACE, or both included: transaminase elevation (1 pt: day 1 post TACE resolved in 7 days without treatment; 2 pts: ≥30 days post TACE resolved with steroids between 20-41 days), post-embolization syndrome (1 pt: resolved in 5 days), asymptomatic lipase increase (1 pt: resolved in 14 days), post-procedural groin hematoma (1 pt: resolved in 2 days). All 9 pts were evaluable for efficacy: 2 (22%) confirmed PR and 7 (78%) SD. 4/9 pts remain on study with SD or better—2 pts continue > 18 months post embolization with durable PRs. 12 months OS rate was 71%. Ongoing correlates will be presented at a separate meeting. Conclusions: Nivolumab given at various times relative to deb-TACE appears safe and tolerable. Cohort 3 continues to accrue to provide a better estimate of safety and antitumor activity of the combination. Clinical trial information: NCT03143270.

Targeted and Reduction-Sensitive Cross-Linked PLGA Nanotherapeutics for Safer and Enhanced Chemotherapy of Malignant Melanoma

PLGA-based nanoparticles are the most studied for cancer therapy. Insufficient stability and sustained drug release, however, often lead to reduced targetability and antitumor efficacy in vivo. In this work, we report on cRGD-installed reduction-responsive cross-linked nanotherapeutics based on a star PLGA-lipoic acid conjugate (cRGD-sPLGA XNPs) for potent and targeted chemotherapy of B16F10 melanoma in mice. cRGD-sPLGA XNPs exhibited nearly quantitative encapsulation of doxorubicin (DOX), giving DOX-cRGD-sPLGA XNPs with 13.2 wt % DOX and a small size of 91.0 ± 0.6 nm. DOX-cRGD-sPLGA XNPs with a cRGD surface density of 48% exhibited the best cellular uptake in αvβ3 overexpressing B16F10 cells and delivered DOX into the cell nuclei after 6 h of incubation, in contrast to nontargeted DOX-sPLGA XNPs that delivered DOX mainly in the cytoplasm. Cell viability experiments showed that DOX-cRGD-sPLGA XNPs had about 2-fold better inhibitory activity in B16F10 cells than nontargeted DOX-sPLGA XNPs. Interestingly, DOX-cRGD-sPLGA XNPs achieved a great melanoma accumulation of 10.96% ID/g and significantly better suppression of B16F10 melanoma than DOX-sPLGA XNPs and Lipo-DOX. DOX-cRGD-sPLGA XNPs brought about marked improvement of the survival rate of B16F10 melanoma-bearing mice at 20 mg of DOX equiv/kg. Smart nanotherapeutics based on the star PLGA-lipoic acid conjugate have emerged as an appealing nanoplatform for targeted tumor therapy.

Chemoembolization of liver cancer with doxorubicin-loaded CalliSpheres microspheres: plasma pharmacokinetics, intratumoral drug concentration, and tumor necrosis in a rabbit model.

The purpose of this work was to investigate the plasma pharmacokinetics, intratumoral drug concentration, and tumor necrosis after transarterial chemoembolization (TACE) with doxorubicin-loaded CalliSpheres microspheres (CSMs). Sixty rabbits with liver VX2 tumors were assigned into five groups of 12 rabbits each, which received 4mg of doxorubicin via intravenous injection (IV group), hepatic arterial infusion (IA group), conventional TACE (cTACE group), CSM-TACE (CSM low-dose group), and 8mg of doxorubicin via CSM-TACE (CSM high-dose group), respectively. Doxorubicin concentrations in plasma, tumor, and adjacent hepatic parenchyma were measured at various timepoints after treatment, and tumor necrosis percentage and liver enzymes were also assessed. The peak plasma concentration of doxorubicin was significantly lower in the three TACE groups compared to IV and IA group (P < 0.05), while doxorubicin concentrations in tumor and adjacent hepatic parenchyma were higher in the two CSM groups compared with IV, IA, and cTACE groups at 3days and 7days after treatment (P < 0.05). The percentages of tumor necrosis at 3 and 7days after treatment were significantly higher in three TACE groups (all higher than 50%) compared with IV group and IA group (both lower than 25%) (P < 0.05), and the highest tumor necrosis percentage was achieved in CSM high-dose group. The three TACE groups showed transient increases in transaminases levels after treatment, in which the peak transaminases levels were significantly lower in the two CSM groups than those in cTACE group (P < 0.05). CSM achieves an effective delivery of doxorubicin into liver cancer. High-dose doxorubicin improves tumoricidal capacity while not impairing the safety of the doxorubicin-loaded CSM.

Imaging of Chemotherapy-Induced Acute Cardiotoxicity with 18F-Labeled Lipophilic Cations.

Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation PET tracers may be suitable for early detection of cardiotoxicity. This study aimed to evaluate an 18F-labeled lipophilic phosphonium cation, [1-(2-18F-fluoroethyl),1H[1,2,3]triazole-4-ethylene]triphenylphosphonium bromide (18F-MitoPhos), as a cardiac imaging agent, comparing it with leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin model. Methods: Cardiac uptake and response to decreased mitochondrial membrane potential of 18F-MitoPhos and 99mTc-sestamibi were tested in isolated perfused rat hearts. Baseline pharmacokinetic profiles of 18F-MitoPhos and 18F-fluorobenzyltriphenylphosphonium and their response to acute doxorubicin-induced cardiotoxicity were assessed in rats in vivo (10, 15, or 20 mg of doxorubicin per kilogram, intravenously, 48 h beforehand). Results: Cardiac retention of 18F-MitoPhos was more than double that of 99mTc-sestamibi in isolated perfused rat hearts. A favorable biodistribution of 18F-MitoPhos in vivo was observed, with heart-to-tissue ratios of 304 ± 186, 11.2 ± 1.2, and 3.8 ± 0.6 for plasma, liver, and lung, respectively (60 min). A significant dose-dependent loss of cardiac retention of 18F-MitoPhos was observed on doxorubicin treatment, with average cardiac SUV from 30 to 60 min (mean ± SD) decreasing from 3.5 ± 0.5 (control) to 1.8 ± 0.1 (doxorubicin, 20 mg/kg). Other assessed biomarkers showed no alterations. Conclusion:18F-MitoPhos showed pharmacokinetic parameters suitable for cardiac imaging. A significant dose response of cardiac uptake to doxorubicin treatment was observed before detectable biomarker alterations. 18F-MitoPhos is therefore a promising tracer for imaging chemotherapy-induced cardiotoxicity. To our knowledge, this is the first demonstration of radiolabeled lipophilic cations being used for the PET imaging of chemotherapy-induced cardiotoxicity and indicates the potential application of these compounds in this area.

Safety Profile and Efficacy of Chemoembolization with Doxorubicin - Loaded Polyethylene Glycol Microspheres in Patients with Hepatocellular Carcinoma.

AIM:This study was designed as a preliminary investigation of safety and efficacy of LifePearl, polyethylene glycol microspheres loaded with doxorubicin for treatment of locally untreatable (i.e., unresectable and not suitable for local thermal ablation) hepatocellular carcinoma (HCC).MATERIAL AND METHODS:Patients with locally untreatable HCC (mono- or bilobar disease, ECOG performance status 0-1, Chilg-Pugh score < 11) were analysed for this single arm Unicenter retrospective study. All the information were acquired through our local hospital information system. DEB-TACE was performed with 100-200 microns LifePearl loaded with 75-150 mg of doxorubicin depending on tumour size. One interventional radiologist with experience of more than 350 TACE procedures and one fellow in radiology performed all embolisations.RESULTS:Twenty subjects with 29 tumours were treated (mean age 66.2 years). Child-Pugh status was A for 12 pts. (60%), B for 6 pts. (30%) and C for 2 pts. (10%). Three patients had insignificant ascites. Most patients (70%) underwent < 3 DEB-TACE procedures. Average doxorubicin dose was 71.1 mg per procedure. One patient had procedure-related SAE (acute pancreatitis) within the postembolization period which was induced due to non-target embolisation of the superior pancreaticoduodenal artery. Six-month freedom from procedure-related SAE or death was 95% (one necrotizing pancreatitis). Tumor response or stable disease was achieved in 95% (19/20) of subjects. Freedom from tumor progression or death at 6 months was 95%. One-year survival rate was 90% overall.CONCLUSION:The results from this investigation suggest that LifePearl microspheres, Terumo loaded with doxorubicin can provide an excellent local tumour control with very few side effects in a relatively homogeneous group of patients with locally untreatable HCC.

Pulmonary Complication following Drug-Eluting Bead Hepatic Chemoembolization

A 70-year-old man with a history of essential hypertension presented to his gastroenterologist with a 6-month history of unintentional weight loss. After an unremarkable colonoscopy, a computed tomographic (CT) scan of the abdomen was performed demonstrating a 6.2-cm arterially enhancing hepatic mass with delayed washout and extension into the hepatic vein ([Fig. 1a], [b]). The patient was found to have no associated liver disease or serologic evidence of viral hepatitis. A biopsy of the mass was performed demonstrating poorly differentiated hepatocellular carcinoma (HCC), and the patient was referred to interventional radiology for locoregional therapy. Prior to liver-directed therapy, imaging demonstrated a small pleural effusion felt to be related to venous invasion and narrowing of inferior vena cava (IVC). The drug-eluting beads transarterial chemoembolization (DEB-TACE) was performed with 100- to 300-µm drug-eluting beads loaded with 75 mg of doxorubicin (LC Beads, BTG, West Conshohocken, PA) followed by 300 to 500 µm “bland” particle (Embosphere; Merit Medical, Salt Lake City, UT) embolization. An angiographic endpoint of 5-beat stasis was reported. No angiographic images were stored demonstrating arteriovenous shunting; however, in retrospect, shunting could have been suspected based on attenuation of caval blood surrounding the tumor on arterial phase imaging on both CT and angiography ([Fig. 1c], [d]). Approximately 48 hours after discharge, the patient presented to his primary care physician with fevers and mild dyspnea. This was attributed to an increased right pleural effusion following DEB-TACE, which was managed conservatively without thoracentesis. The patient's oxygen saturation was incidentally noted to be decreased at 92%; however, patient was judged not to be symptomatic enough to require treatment and as such was discharged from medical care with instructions to follow up if symptoms worsened. The patient improved over the course of the next month, but follow-up imaging demonstrated a minimal response of the treated HCC. After discussion with the patient, repeat DEB-TACE was performed.