Degradable Starch Microspheres Research Articles

Idarubicin-loaded degradable hydrogel for TACE therapy enhances anti-tumor immunity in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common and deadly cancer, often diagnosed at advanced stages, limiting surgical options. Transcatheter arterial chemoembolization (TACE) is a primary treatment for inoperable and involves the use of drug-eluting microspheres to slowly release chemotherapy drugs. However, patient responses to TACE vary, with some experiencing tumor progression and recurrence. Traditional TACE uses agents like oil-based drug emulsions and polyvinyl alcohol particles, which can permanently block blood vessels and increase tumor hypoxia. Additionally, TACE can suppress the immune system by reducing immune cell numbers and function, contributing to poor treatment outcomes. New approaches, like TACE using degradable starch microspheres and hydrogel-based materials, offer the potential to create different tumor environments that could improve both safety and efficacy. In our research, we developed a composite hydrogel (IF@Gel) made of Poloxamer-407 gel and Fe3O4 nanoparticles, loaded with idarubicin, to use as an embolic material for TACE in a rat model of orthotopic HCC. We observed promising therapeutic effects and investigated the impact on the tumor immune microenvironment, focusing on the role of immunogenic cell death (ICD). The composite hydrogel demonstrated excellent potential as an embolic material for TACE, and IF@Gel-based TACE demonstrated significant efficacy in rat HCC. Furthermore, our findings highlight the potential synergistic effects of ICD with anti-PD-L1 therapy, providing new insights into HCC treatment strategies. This study aims to provide improved treatment options for HCC and to deepen our understanding of the mechanisms of TACE and tumor environment regulation.

In vivo revascularization and tissue effects of uterine artery embolization with starch microspheres in sheep.

In uterine artery embolization (UAE) for the treatment of fibroids, nondegradable particles permanently occlude the uterine artery (UA). These particles remain in the vessels and can cause secondary undesirable effects, such as severe pain after embolization and fertility issues. In this prospective experimental study, we aimed to evaluate the angiographic recanalization, local and systemic reactions, and uterine damage occurring after performing UAE with newly developed degradable starch microspheres (DSMs) in sheep. Under general anesthesia, eight nonpregnant sheep underwent bilateral UAE using DSMs to achieve stasis. Angiographic evaluation was performed on days 1, 3 and 7 after embolization to assess in vivo recanalization. In addition, the angiographic series were scored via a modified embolization score. A postmortem tissue examination was performed to determine whether DSMs and foreign body inflammatory reactions were present and to assess uterine necrosis. Complete bilateral embolization of the UA and cervicovaginal branches was achieved in all treated animals. Recanalization of the occluded arteries was evident in 25 of 27 arteries during the angiographic evaluation. In all sheep, there were multifocal areas of uterine necrosis, and some uterine vessels contained intraluminal material consistent with DSMs. The average weight of both uterine horns was significantly correlated with both the number of microspheres needed for complete embolization (r = 0.69, ρ<0.01) and the average percentage of necrosis in both uterine horns (r = 0.64, ρ<0.05). Our findings demonstrated the efficacy of vascular embolization with DSM by inducing ischemic changes in the uterus and subsequent recanalization of previously occluded arteries.

A Structural Study on Absorption of Lysozyme in Amorphous Starch Microspheres.

The potential of using proteins as drugs is held back by their low stability in the human body and challenge of delivering them to the site of function. Extensive research is focused on drug delivery systems that can protect, carry, and release proteins in a controlled manner. Of high potential are cross-linked degradable starch microspheres (DSMs), as production of these is low-cost and environmentally friendly, and the products are degradable by the human body. Here, we demonstrate that DSMs can absorb the model protein lysozyme from an aqueous solution. At low amounts of lysozyme, its concentration in starch microspheres strongly exceeds the bulk concentration in water. However, at higher protein contents, the difference between concentrations in the two phases becomes small. This indicates that, at lower lysozyme contents, the absorption is driven by protein-starch interactions, which are counteracted by protein-protein electrostatic repulsion at high concentrations. By applying small-angle X-ray scattering (SAXS) to the DSM-lysozyme system, we show that lysozyme molecules are largely unaltered by the absorption in DSM. In the same process, the starch network is slightly perturbed, as demonstrated by a decrease in the characteristic chain to chain distance. The SAXS data modeling suggests an uneven distribution of the protein within the DSM particles, which can be dependent on the internal DSM structure and on the physical interactions between the components. The results presented here show that lysozyme can be incorporated into degradable starch microspheres without any dependence on electrostatic or specific interactions, suggesting that similar absorption would be possible for pharmaceutical proteins.

Degradable Starch Microspheres Transarterial Chemoembolization with or without Lipiodol for Liver Metastases from Pancreatic Cancer: A Prospective Randomized Trial.

To evaluate and compare the outcome of patients with liver metastases from pancreatic cancer treated by transarterial chemoembolization (TACE) using two different protocols. In this prospective, randomized, single-center trial, patients were randomly assigned to receive TACE therapy either with degradable starch microspheres (DSM) alone or a combination of Lipiodol and DSM. From the initial 58 patients, 26 patients (13 DSM-TACE, 13 Lipiodol + DSM-TACE) who completed 3 TACE treatments at an interval of four weeks were considered for evaluation of tumor responses. Initial and final MRIs were used to evaluate local therapy response by RECIST 1.1; changes in diameter, volume, ADC value, and survival rate were statistically evaluated. The differences between the DSM-TACE and Lipiodol + DSM-TACE were identified for partial response (PR) as 15.4% versus 53.8%, stable disease (SD) as 69.2% versus 46.2%, progressive disease (PD) as 15.4% versus 0%, respectively (p = 0.068). Median overall survival times for DSM-TACE and Lipiodol + DSM-TACE were 20 months (95% CI, 18.1-21.9) and 23 months (95% CI, 13.8-32.2), respectively (p = 0.565). The one-year survival rates for DSM-TACE and Lipiodol + DSM-TACE were 85.4% and 60.4%, the two-year survival rates were 35.9% and 47.7%, and the three-year survival rates were 12% and 30.9%, respectively. The evaluated local therapy response by RECIST 1. was not significantly different between the two studied groups. A longer overall survival time was observed after Lipiodol + DSM-TACE therapy; however, it was not significantly different.

In vivo study of the utility of selective intra-arterial injection of thiopental for neuroprotection in reversible cerebral ischemia.

Neuroprotective agents are needed to reduce cerebral damage during surgical or neurointerventional procedures including stroke patients. To evaluate if thiopental can be used as a neuroprotective agent when injected intra-arterially in a transient ischemia model. In total, 24 rabbits were studied as four groups of six animals. Group 1 served as the control group. In group 2, transient ischemia was obtained by intracarotid administration of degradable starch microspheres (DSM). Group 3 was administered thiopental intra-arterially via the carotid artery. Group 4 (experimental group) received both thiopental and DSM intra-arterially. DSM and thiopental were administered through a microcatheter placed into the common carotid artery via the central ear artery access. After sacrifice, apoptotic cells in the cerebral tissues of the animals were evaluated in H&E and TUNEL stained slides. There was a significant increase in the number of apoptotic glial or neuronal cells in group 2 compared to the control group and group 3. The mean number of both the apoptotic neuronal cells (6.8 ± 2.1 vs. 2.5 ± 1.3, P < 0.001) and the apoptotic glial cells (9.4 ± 3.1 vs. 4.6 ± 1.6, P < 0.001) were higher in group 2 compared to group 4. In addition, a higher level of neurological improvement was observed in group 4 compared to group 2 based on neurological assessment score. The intra-arterial administration of thiopental has a protective effect on both glial and neuronal cells during temporary cerebral ischemia in low doses.

TACE for HCC: A critical review of the 2021 CIRSE recommendations with presentation of a technique for a degradable starch microsphere—TACE

AbstractThere is no consensus on which substances and which method should be used for transarterial chemoembolization. A publication commissioned by CIRSE 2021 attempted to formulate recommendations. However, only the spectrum of currently implemented procedures is outlined but no recommendation was made. In this article, therefore, basic considerations regarding the technique of chemoembolization are presented, and the authors discuss fundamental considerations about the embolic materials used, the cytostatic drugs and their dosage, as well as about pain therapy during treatment. Then, a technique is presented which used degradable starch microspheres as an embolic agent. This technique enables multiple treatments over a longer period. However, this proposal is not only evidence‐based but also eminence‐based. What we need are controlled studies that systematically compare different treatment techniques in a sufficient number of patients. This will hopefully help to find the best method for individual patients. Until then, the technique proposed by the authors can be applied.

Clinical Outcomes of Radiofrequency Ablation Combined with Transarterial Chemoembolization Using Degradable Starch Microsphere Mixed with Mitomycin C for the Treatment of Non-hepatocellular Carcinoma Malignant Liver Tumors

To retrospectively evaluate the outcomes of radiofrequency ablation combined with transarterial chemoembolization using degradable starch microspheres for non-hepatocellular carcinoma malignant liver tumors. A total of 15 patients (13 men, 2 women; median age, 67 years) who underwent radiofrequency ablation immediately after transarterial chemoembolization using degradable starch microspheres for liver tumors between July 2011 and September 2020 were included in this study. Thirteen patients had liver metastases from colorectal cancer (n = 6), esophageal cancer (n = 2), lung cancer (n = 2), and other tumors (n = 3), and 2 patients had primary liver tumor of cholangiocellular carcinoma (n = 1) and gastrinoma (n = 1). Twenty tumors (median size, 16 mm) were treated in 17 sessions. Technical success, safety, local tumor progression, and overall survival were evaluated. Safety was assessed according to the clinical practice guideline of the Society of Interventional Radiology. All treatment procedures were successfully completed. There were no major complications. Grade-B complications of self-limiting pneumothorax (n = 1), vomiting (n = 1), and fever (n = 1) occurred in 1 session each. Local tumor progression developed in two tumors (local tumor progression rate, 10%, 2/20). The local tumor progression rates were 5% and 11% at 1 year and at 3 and 5 years, respectively. Tumor size of more than 20 mm (P = 0.0003) and contact with major vessels (P = 0.03) were significant risk factors for local tumor progression. The patients were treated with repeat radiofrequency ablation combined with transarterial chemoembolization using degradable starch microspheres. During median follow-up of 48 months (range, 4-77 months), 5 patients died (33%, 5/15). The overall survival rates were 100%, 85%, and 57% at 1, 3, and 5 years, respectively. The median overall survival time was 69 months. Radiofrequency ablation combined with transarterial chemoembolization using degradable starch microspheres was safe and showed favorable local control for non-hepatocellular carcinoma malignant liver tumors.

Chemoembolization with Degradable Starch Microspheres (DSM-TACE): expanding indications in HCC multidisciplinary tumor board

The role of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) management has changed over the last twenty years. There has been a trend towards an overall decline in TACE procedures, but with a more aggressive approach, repeating multiple TACE sessions in case of tumor response. The survival of treated patients was prolonged because of better patient selection and advancements in TACE techniques aimed at preserving liver function. At present, TACE is approved by the International Guidelines also outside of the BCLC intermediate stage after evaluation of a multidisciplinary tumor board (MDTB), permitting a customized treatment for every patient. An alternative therapeutic strategy is represented by hepatic chemoembolization with Degradable Starch Microspheres (DSM-TACE), which is based on the chemotherapeutic effect rather than on the ischemic damage to the liver tumor, requiring multiple cycles of treatment. The higher safety profile of DSM-TACE has broadened the indications to patients waiting for liver transplantation (with bridging or downstaging intention), at high risk of liver failure and ineligible for systemic therapies. This review summarises the scientific publications supporting the use of DSM-TACE and illustrates its indications depending on the disease stage from the Interventional Radiologist’s perspective.

First interim analysis of the SirTac trial: A randomized phase II study of SIRT and DSM-TACE in patients with liver metastases from uveal melanoma.

9511 Background: The liver is the most common site of metastases in patients (pts) with uveal melanoma (UM). Here, we present results from the prespecified first interim analysis of the SirTac trial, a prospective, single-center, randomized, investigator-initiated, open-label phase 2 study of Selective Internal Radiation Therapy with Yttrium-90-bearing resin microspheres; SIR-Spheres (SIRT) vs Transarterial Chemoembolization with Cisplatin and degradable starch microspheres; EmboCept S (DSM-TACE) in pts with liver-dominant metastatic UM. Methods: Pts with histologically confirmed, liver-dominant metastatic UM and ECOG PS 0-2 were enrolled and randomized 1:1 to SIRT or DSM-TACE. Randomization was stratified by lactate dehydrogenase (&lt;2x vs ≥2x upper limit of normal) and pre-treatment with antiangiogenic agents. Extrahepatic metastases were allowed, if asymptomatic. Primary endpoint was progression-free survival (PFS). A total of 108 pts (54 per arm) were planned to be enrolled. Pts received TACE every 4-6 weeks until tumor devascularization or disease progression or intolerable toxicity was observed, and SIRT either as one whole-liver application or in two sequential sessions for each liver lobe. The primary objective of this prespecified analysis was to assess response by RECIST criteria v1.1 in the per-protocol (PP) population of the first 40 pts (20 pts in each arm). Results: Two patients had been treated with previous liver surgery, whereas all other patients had not received previous treatment for metastatic disease. There were no clinicopathological differences between the groups, except for a difference in age (median age SIRT arm 64 y vs 75 y in the TACE arm, p=0.018). All but 1 pt received treatment as randomized. This pt was excluded and replaced by the next TACE pt for this PP interim analysis. There were no differences in best overall response rates between the groups (no complete response, 1 partial response in both arms, stable disease in 19 (95%) and 17 (85%) pts in the SIRT and TACE arm, respectively, and 2 pts with progressive disease in the TACE arm). At a median follow-up of 13.9 mo from treatment start, median PFS in the PP population was 4.9 mo in the SIRT arm vs 2.2 mo in the TACE arm (p=0.037), with a higher median liver-PFS in the SIRT vs TACE arm (8.3 vs 2.2, p=0.026). Conclusions: In this planned interim analysis treatment in both arms was feasible with no differences in response. The explorativePFS analysis allows no conclusions on the final outcome after completion of the trial. The study continues recruitment. Clinical trial information: NCT02936388.

Trans-Arterial Chemoembolization with 50 μm Degradable Starch Microspheres Versus 300-500 μm Drug Eluting Beads in Hepatocellular Carcinoma: A Comparative Analysis of Initial Treatment Outcomes.

Background and Aims:Trans-arterial chemoembolization (TACE) has become a widely accepted treatment in unresectable hepatocellular carcinoma (HCC). We aimed at comparing the efficacy of Degradable Starch Microspheres (DSMs)-TACE with 50 ± 7 µm versus 300–500 μm Drug Eluting Beads (DEB)-TACE in terms of initial clinical and radiological treatment response parameters.Material and Methods:A total of 54 patients with unresectable HCC who underwent DEB-TACE (n = 25) or DSMs-TACE (n = 29) were included in this retrospective study. Baseline demographic and clinical characteristics, duration of follow-up, local recurrence and survival status, as well as treatment outcome including treatment response via modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria, viable and total tumor diameter and serum alpha-fetoprotein (AFP) levels were analyzed in both study groups.Results:No significant difference was noted between the two groups in terms of local recurrence (31.6 vs. 16.7%) or mortality (73.9 vs. 85.7%) rates after 36-month and 12-month follow-up, respectively. DSMs-TACE vs. DEB-TACE was associated with significantly higher complete response rate (27.6 vs. 0.0%, p = 0.011) and significant decrease in serum AFP levels (p = 0.013).Conclusion:Both DSMs-TACE with 50 ± 7 µm microspheres and 300–500 μm DEB-TACE are effective for local control of unresectable HCC. Our findings revealed superiority of DSMs-TACE over DEB-TACEnin terms of initial clinical and radiological tumor response; though no significant difference was noted between the two patient groups in terms of local recurrence or mortality during follow up.

Reversible occlusion of the pulmonary vasculature by transarterial embolisation with degradable starch microspheres: preclinical assessment in a human isolated lung perfusion model

BackgroundTranspulmonary embolisation (TPE) using degradable starch microspheres (DSM) is a potential approach to treat pulmonary metastases. However, there is a paucity of detailed information on perfusion dynamics. The aim of this study was to establish a human ex vivo isolated lung perfusion (ILP) model to observe and evaluate the effects of DSM-TPE in a near-physiologic setting.MethodsILP was carried out on six surgically resected lung lobes. At baseline, computed tomography (CT), including CT perfusion imaging (CTPI), and histopathological sampling were performed (t30). DSM-TPE was initiated and increased stepwise (t45, t60, t75, and t90) to be followed by CT imaging, histopathological sampling, and pulmonary arterial pressure (PAP). After the last assessment (t90), alpha-amylase was injected into the pulmonary artery to allow for DSM hydrolysation and two additional assessments (t105; t120). Histopathological specimens were evaluated using a semiquantitative ordinal score. CTPI was used for time to peak (TTP) analysis.ResultsAfter DSM administration, PAP and TTP increased significantly: PAP slope 95% confidence interval (CI) 0.104−0.483, p = 0.004; TTP t30 versus t45, p = 0.046. After the addition of alpha-amylase, functional parameters reverted to values comparable to baseline. In histopathological samples, embolisation grades increased significantly until t90 (slope 95% CI 0.027−0.066, p < 0.001) and decreased after addition of alpha-amylase (slope 95% CI -0.060−0.012, p = 0.165),ConclusionsThe ILP model demonstrated successfully both the physiologic effect of DSM-TPE on human lungs and its reversibility with alpha-amylase. Thus, it can be used as a near-physiologic preclinical tool to simulate and assess later clinical approaches.

Clinical effects and safety of different transarterial chemoembolization methods for bridging and palliative treatments in hepatocellular carcinoma

PurposeWe assessed and compared clinical effects and safety endpoints of three methods of transarterial chemoembolization (TACE), conventional (cTACE), with drug-eluting beads (DEB-TACE), and with degradable starch microspheres (DSM-TACE), used in patients with hepatocellular carcinoma (HCC) in the bridging to liver transplant (LT) and the palliative setting.MethodsIn our center, 148 patients with HCC underwent 492 completed TACE procedures between 2008 and 2017 (158 for bridging to LT; 334 for palliative treatment) which we analyzed retrospectively. Of these procedures, 348 were DEB-TACE, 60 cTACE, and 84 DSM-TACE.ResultsThe cTACE procedure revealed a significantly longer period of hospitalization (p = 0.02), increased occurrence of nausea (p = 0.025), and rise in alanine transaminase (ALT) levels (p = 0.001), especially in the palliative setting. In the bridging to LT cohort, these clinical endpoints did not reach statistical significance.ConclusionsThe clinical safety of different TACE methods for HCC in both the palliative and the bridging to LT setting was equivalent. In the palliative setting, the cTACE procedure revealed an increased risk for adverse clinical effects such as nausea, elevation of ALT, and a prolonged period of hospitalization what might either be related to the systemic effects of the chemotherapeutic agent or to the differences in both collectives. Thus, further studies must be conducted on a larger number of TACE procedures to effectively explore the clinical side effects of the various TACE variants.

European Multicenter Study on Degradable Starch Microsphere TACE: The Digestible Way to Conquer HCC in Patients with High Tumor Burden.

Simple SummaryIn this European multicenter study, we investigated the treatment efficacy and safety of degradable starch microsphere transarterial chemoembolization (DSM-TACE) for HCC treatment in 121 patients in whom other standard therapies failed or patients were not eligible. Patients survived a median of 15.5 months with a median time to tumor progression of 9.5 months and a disease control rate of 83.2%. The patients who survived longer had HCC lesions ≤10 cm, the involvement of one liver lobe only, lower Child–Pugh class and Barcelona Clinic Liver Cancer (BCLC) tumor stage, absence of vascular invasion, and the absence of extrahepatic metastases. Of these factors, a lesion of ≤10 cm and unilobar disease were identified as independent survival factors. Safety analysis revealed low rates of adverse events and maintained liver function after several treatments regardless of the treated liver volume. Thus, DSM-TACE is a veritable treatment alternative for unresectable HCC, where other treatments fail or cannot be offered due to contraindications.To evaluate the safety and efficacy of transarterial chemoembolization with degradable starch microspheres (DSM-TACE) for the treatment of hepatocellular carcinoma (HCC) with a high tumor burden ineligible for or failing other palliative therapies, 121 patients from three European centers were included. Kaplan–Meier analysis was used for median overall survival (OS) and time to progression (TTP, mRECIST criteria) in months with a 95% confidence interval (95% CI). Uni- (UVA) and multivariate (MVA) analyses were performed using the Cox Proportional Hazard Model. The median OS of the study cohort was 15.5 (13.3–18.7) months. The UVA identified HCC lesions ≤10 cm, unilobar involvement, lower Child–Pugh class and Barcelona Clinic Liver Cancer (BCLC) stage, absence of vascular invasion, and extrahepatic metastases as factors for prolonged survival. MVA confirmed lesions of ≤10 cm and unilobar disease as independent OS factors. Median TTP was 9.5 (7.6–10.3) months. The best response was achieved after a median of 3 (range: 1–6) treatments with CR/PR/SD/PD in 13.5%/44.5%/25.2%/16.8%, respectively. DSM-TACE was well tolerated with no major clinical adverse events and only limited major laboratory events. Preserved liver function was observed after repetitive DSM-TACE treatments. Repetitive DSM-TACE is a safe, well-tolerated and effective treatment option for HCC patients with high tumor burden ineligible or failing other palliative therapies.

Simultaneous Ipsilateral Dual Embolization (transarterial chemoembolization with degradable starch microspheres and portal vein embolization) of the liver- “SIDE” technique for preoperative augmentation of future liver remnant (FLR) in patients with solid liver malignancies

Portal vein embolization (PVE) is gold standard strategy to increase future liver remnant (FLR). Up to 30% of patient with liver malignance still couldn't underwent surgery after PVE due to tumor progression and/or insufficient FLR regeneration during waiting period. Nine patients with colorectal liver metastases (CRLM) and small FLR, in close proximity to FLR critical structures (portal and/or hepatocaval confluence), having more than three criteria of Fong Clinical Risk Score for CRLM were approved by Ethical Committee for Simultaneous PVE and Transarterial Chemoembolization with Degradable Starch Microspheres (DSM-TACE). For those patients, standard PVE was simultaneously followed by oxaliplatin based DSM-TACE with short-term embolic material of the whole tumor bearing liver to be resected that allowed to achieve both tumor control and postembolic infarction in liver to be removed, as a trigger of increased FLR regeneration, without biliary tree damage. Results were compared with 23 patients in control group after standard PVE. Unprecedented FLR regeneration with kinetic growth rate 23.5 cc/day (range from 17.6 to 57.25 cc/day) was observed enabling extended hepatectomies within 2 weeks compared with 5 weeks waiting period in control group. In all CRLM about 60% (range from 40% to 90%) necrosis was achieved. There was no severe morbidity (including posthepatectomy liver failure) and mortality. We propose method of preoperative FLR adaptation which is not only second to none in the achieving liver regeneration rate but also is the only one that allows tumor control targeting both main reasons for patient dropout during waiting period for FLR regeneration.

Measuring enzymatic degradation of degradable starch microspheres using confocal laser scanning microscopy

Degradable starch microspheres (DSM) have long been used for topical haemostasis, temporary vascular occlusion and as drug delivery systems. When used for the latter, exact degradation rates of DSM have high importance, as this ensures a controlled and timed drug delivery. Current methods of analysing degradation rates are based on whole batch measurements, which does not yield information regarding individual times of degradation nor does it provide direct correlation measurements between sphere diameter and specific degradation time.In this paper we present an alternative method for measuring degradation rates of biodegradable starch microspheres using confocal laser scanning microscopy (CLSM). We succeeded in visualizing the degradation by staining the DSM and then following the spheres over time in a confocal microscope, after the addition of α-amylase.Individual degradation rates of single spheres could be followed, allowing a precise correlation measure between sphere size and degradation time. Furthermore, physical abnormalities such as internal cavities were detected within some spheres. These physical differences also had a measurable effect on the rate of degradation. Finally, complete degradation rates could be determined very accurately.To our knowledge, this is the first paper in which DSM degradation is visualized and measured using CLSM. Statement of significanceUsing degradable starch microspheres as a drug delivery system, is a continuously evolving field which shows promise in several different areas of illnesses. This paper presents a new method which visualizes enzymatic degradation of starch microspheres in real-time using confocal microscopy. The method is simple, yet the versatility of it suggests that it could be broadly applied within the field of biodegradation. Here, it illuminates a previously uninvestigated parameter: the effect of physical sphere deformities on the rate of degradation. It also provides precise correlation measures between initial sphere size and time of complete degradation.

Evaluation of two different transarterial chemoembolization protocols using Lipiodol and degradable starch microspheres in therapy of hepatocellular carcinoma: a prospective trial

BackgroundThis prospective randomized trial is designed to compare the performance of conventional transarterial chemoembolization (cTACE) using Lipiodol-only with additional use of degradable starch microspheres (DSM) for hepatocellular carcinoma (HCC) in BCLC-stage-B based on metric tumor response.MethodsSixty-one patients (44 men; 17 women; range 44–85) with HCC were evaluated in this IRB-approved HIPPA compliant study. The treatment protocol included three TACE-sessions in 4-week intervals, in all cases with Mitomycin C as a chemotherapeutic agent. Multiparametric magnetic resonance imaging (MRI) was performed prior to the first and 4 weeks after the last TACE. Two treatment groups were determined using a randomization sheet: In 30 patients, TACE was performed using Lipiodol only (group 1). In 31 cases Lipiodol was combined with DSMs (group 2). Response according to tumor volume, diameter, mRECIST criteria, and the development of necrotic areas were analyzed and compared using the Mann–Whitney-U, Kruskal–Wallis-H-test, and Spearman-Rho. Survival data were analyzed using the Kaplan–Meier estimator.ResultsA mean overall tumor volume reduction of 21.45% (± 62.34%) was observed with an average tumor volume reduction of 19.95% in group 1 vs. 22.95% in group 2 (p = 0.653). Mean diameter reduction was measured with 6.26% (± 34.75%), for group 1 with 11.86% vs. 4.06% in group 2 (p = 0.678). Regarding mRECIST criteria, group 1 versus group 2 showed complete response in 0 versus 3 cases, partial response in 2 versus 7 cases, stable disease in 21 versus 17 cases, and progressive disease in 3 versus 1 cases (p = 0.010). Estimated overall survival was in mean 33.4 months (95% CI 25.5–41.4) for cTACE with Lipiosol plus DSM, and 32.5 months (95% CI 26.6–38.4), for cTACE with Lipiodol-only (p = 0.844), respectively.ConclusionsThe additional application of DSM during cTACE showed a significant benefit in tumor response according to mRECIST compared to cTACE with Lipiodol-only. No benefit in survival time was observed.

Safety and Efficacy of Degradable Starch Microspheres Transcatheter Arterial Chemoembolization as a Bridging Therapy in Patients with Early Stage Hepatocellular Carcinoma and Child-Pugh Stage B Eligible for Liver Transplant.

In patients with early-stage hepatocellular carcinoma, awaiting liver transplantation, current guidelines by AASLD and ESMO recommend a bridging therapy with a loco-regional treatment to prevent progression outside transplantation criteria. The standard of care in delaying disease progression has been recognized to be the transarterial chemoembolization. Permanent occlusion of tumor feeding vessels has effects on tumour stromal microenvironment by inducing intra- and intercellular signaling processes counteracting hypoxia, such as the release of vascular endothelial growth factor, a promoter of neoangiogenesis, tumour proliferation and metastatic growth. Among chemoembolization interventions, TACE with degradable starch microspheres represents an alternative to conventional cTACE and DEB-TACE and it minimizes detrimental effects on tumour stromal microenvironment, guaranteeing a transient occlusion of tumour feeding arteries and avoiding VEGF overexpression.Between January 2015 and September 2020, 54 consecutive patients with early-stage hepatocellular carcinoma and Child-Pugh stage B, who had undergone DSM-TACE as a bridging therapy while awaiting liver transplantation, were eligible for the study. A total of 154 DSM-TACE was performed, with a mean number of 2.85 procedures per patient. 18 patients (33.3%) succeeded in achieving liver transplantation, with a mean waiting time-to-transplantation of 11.7 months. The cumulative rates of patients still active on the WL at 6 months were about 91 and 93% when considering overall drop-out and tumour-specific drop-out respectively. Overall survival was about 96% at 6 months and 92% at 12 months. 17 patients experienced adverse events after the chemoembolizations. For patients with HCC in the transplant waiting list and within the Child-Pugh B stage, life expectancy may be dominated by the liver dysfunction, rather than by the tumour progression itself. In this population subset, the choice of LRT is critical because LRT itself could become a dangerous tool that is likely to precipitate liver dysfunction to an extent that survival is shortened rather than prolonged. Hence, the current study demonstrates that DSM-TACE is not far from being an ideal LRT, because it has an excellent safety profile, maintaining an efficacy that guarantees a clear advantage on the dropout rate with respect to the non-operative strategy, thus justifying its use.

Safety and Efficacy of Degradable Starch Microspheres Transcatheter Arterial Chemoembolization (DSM-TACE) in the Downstaging of Intermediate-Stage Hepatocellular Carcinoma (HCC) in Patients With a Child-Pugh Score of 8-9.

According to the EASL Guidelines for the management of hepatocellular carcinoma, transcatheter arterial chemoembolization is the first-line treatment recommended for intermediate-stage HCC. Furthermore, it is widely accepted that patients beyond the Milan criteria can be considered for a liver transplant after successful downstaging to within the Milan criteria. Response to downstaging treatments significantly influences not just drop-outs, but also the rate of post-transplantation tumor recurrences. TACE with degradable starch microspheres represents an alternative to conventional TACE with lipiodol and TACE with drug-eluting beads, and it leads to transient arterial occlusion allowing lower activation of hypoxia-inducible factors and less release of vascular endothelial growth factor, a promoter of neoangiogenesis, tumor proliferation, and metastatic growth. In patients with intermediate-stage HCC and a Child-Pugh score of 8 or 9, life expectancy may be dominated by cirrhotic liver dysfunction, rather than by the tumor progression itself; hence, locoregional treatments might also be detrimental, precipitating liver dysfunction to an extent that survival is shortened rather than prolonged. Data on tolerability, toxicity, and effectiveness of DSM-TACE are limited but encouraging. Between January 2015 and October 2020, 50 consecutive patients with intermediate-stage hepatocellular carcinoma and a Child-Pugh score of 8/9, who had undergone DSM-TACE as the first-line treatment, were eligible for the study. A total of 142 DSM-TACEs were performed, with a mean number of 2.84 procedures per patient. The mean time-to-downstaging was 19.2 months, with six patients successfully downstaged. OS was about 100% at six months, 81.8% at 12 months, and 50% at 24 months. Twenty-two patients experienced adverse events after chemoembolization. The median OS and safety of DSM-TACE in this study are comparable with other published investigations in this field. Furthermore, 12% of patients were successfully downstaged. Hence, the results of the current investigation demonstrate that DSM-TACE is effective and safe in intermediate-stage HCC, achieving an interesting downstaging rate. Such data were observed in the population subset with a Child-Pugh score of 8 or 9, in which life expectancy may be determined by cirrhotic liver dysfunction, so the achievement of a balance between the safety and efficacy profile of the TACE treatment is crucial.

Exogenous Amylase Reverses Cerebral Ischemia Induced by Selective Intraarterial Injection of Degradable Starch Microspheres: An Angiographic and Histological Study in a Novel in Vivo Animal Model.

To validate a new particulate embolization method using degradable starch microspheres (DSM) and intraarterial exogenous amylase administration, which allow for regulated temporary cerebral arterial embolization without compromising tissue perfusion. Twenty-four male New Zealand rabbits were randomly divided into three groups. All animals underwent routine angiography. The control group received no additional intervention. In the ischemia group, 0.2ml DSM was administered to the animals via the right carotid artery with pulsed, gentle injections to induce ischemia in the cerebral microcirculation. Animals in the reperfusion group received 0.05 ml of exogenous amylase along with DSM administration. Six hours after the procedure, the animals were sacrificed and histopathological analysis was performed. The ischemia group was the most adversely affected group by embolization, with the highest number of pyknotic neurons. The reperfusion group, which received exogenous amylase, had lower pyknotic neurons than the ischemia group. The pyknotic neuron count was similar in some regions between reperfusion and control groups. Exogenous amylase can rapidly attenuate cerebral ischemia caused by microembolization with DSM.

Simultaneous ipsilateral dual (DSM-TACE and PVE) embolization (SIDE Technique) for preoperative augmentation of future liver remnant (FLR)

Purpose: Portal Vein Embolization(PVE) is a gold standard strategy to increase FLR at level of Kinetic Growth Rate (KGR) about 2.3 cc/day and to prevent posthepatectomy liver failure (PHLF). Up to 30% of patient with liver malignance still couldn't underwent surgery after PVE due to tumor progression and/or insufficient FLR regeneration during waiting period. Currently there are no methods that resolves both mentioned issues. Our aim was to develop new method that potentially will increase number of the patients with insufficient FLR that will succeed to underwent liver surgery. Results also were compared with currently developed methods of FLR augmentation such as extended liver venous deprivation (eLVD) and ALPPS. Method: 9 initially unresectable, due to small FLR, patients with colorectal liver metastases (CRLM) having more than three criteria of Fong Clinical Risk Score for CRLM, in close proximity to FLR critical structures ), were approved by Ethical Committee for Simultaneous PVE and Transarterial Chemoembolization with Degradable Starch Microspheres (DSM-TACE). Simultaneously, immediately after standard PVE, was performed oxaliplatin based DSM-TACE with short-term embolic material of the whole tumor bearing liver to be resected that safely allowed to achieve I) postembolic infarction II) pharmacologically induced hepatic Veno-Occlusive Disease(VOD(Fig 2d)) in liver to be removed, as a trigger of increased FLR regeneration(Fig.1), without biliary tree damage(Fig. 2 a,c) and what distinguishes it advantageously III) local tumor control. Results: Unprecedented FLR regeneration with KGR 23.5 cc/day(range from 17.6 to 57.25 cc/day) was observed. The latter allow us to achieve safe FLR volume to perform extended hepatectomies within recommended 2-3 weeks period to avoid chemotherapy related neutropenic window in all 9 patients even so there were no myelosuppression observed. This allows us safely shortening time to resection to 15 days in 5 last consecutive patients. In all CRLM about 60% (range from 40% to 90%) necrosis was achieved(Fig. 2 a). All patients have successfully underwent major liver resection with 0% dropout. There was no severe morbidity and mortality. Conclusion: We propose safe method of preoperative FLR adaptation which is not only second to none in the achieving liver regeneration rate but also is the only one that allows local tumor control and/or downsize borderline resectable tumors.