Polymerisation of cyanoacrylates: The effect of sclero-embolic and contrast agents.

OBJECTIVES: The objective is to investigate the interaction of sclero-embolic and contrast agents with the polymerisation of medical grade n-butyl-cyanoacrylates. METHODS: An in vitro spectrophotometric absorbance method was developed to detect changes in light transmission to measure n-BCA polymerisation. The initiation and the rate-of-polymerisation of mixtures of n-BCA with sclero-embolic and contrast agents were investigated. RESULTS: Initiation of polymerisation: VENABLOCK™ and HISTOACRYL® were the fastest agents to polymerise, while VENASEAL™ was the slowest. Rate of polymerisation: Hypertonic saline inhibited the polymerisation of all n-BCAs, while hypertonic glucose prolonged the polymerisation rate. ETHANOL and detergent sclerosants had no effect. Contrast agents OMNIPAQUE™ and ULTRAVIST® initiated and prolonged the polymerisation of n-BCA, but in contrast, LIPIODOL® failed to initiate the process. CONCLUSIONS: The commercially available medical cyanoacrylates differ in their polymerisation rates. These polymerisation rates are further affected when these products are used in conjunction with other compounds, such as sclero-embolic and contrast agents.

Radioembolisation of liver metastases.

This review aims to present contemporary data for SIRT in the treatment of secondary hepatic malignancies including colorectal, neuroendocrine, breast and uveal melanoma.

LIPIODOL reduces the lytic activity of detergent sclerosants in vitro.

OBJECTIVES: Contrast agents are used widely in the interventional setting and in particularly in the management of vascular anomalies and have also been used in combination with sclero-embolic agents. There is limited information on the interaction of contrast agents with sclerosant agents when used as mixtures. The aim of this study was to determine the effect of mixing radiological contrast agents with detergent sclerosants and measuring the effect on change in lytic activity of detergent sclerosants in vitro and by proxy the change in potency. METHODS: Red blood cell lysis was assessed following the incubation of two commonly used contrast agents, LIPIODOL® and ULTRAVIST®, mixed with detergent sclerosants, FIBROVEIN®, sodium tetradecyl sulfate (STS), and AETHOXYSKLEROL®, polidocanol (POL). RESULTS: The density of both contrast agents was higher than STS and POL and neither of the detergent sclerosants were miscible in LIPIODOL. LIPIODOL on its own caused cell lysis (1.01%, p < 0.05) whereas ULTRAVIST did not. Fifty per cent cell lysis for sclerosant and LIPIODOL mix occurred at concentrations of: 0.041% (2.4 times greater than the control, p < 0.05) and 0.08% (3.6 times greater than the control, p = 0.06) for STS and POL, respectively. CONCLUSIONS: LIPIODOL, when mixed with sclerosant detergents (ratio 1:1) causes a reduction in the lytic activity of sclerosants and this effect was statistically significant and most prominent in lower sclerosant concentration mixtures.

The Post-SIR-Spheres Surgery Study (P4S): Retrospective Analysis of Safety Following Hepatic Resection or Transplantation in Patients Previously Treated with Selective Internal Radiation Therapy with Yttrium-90 Resin Microspheres.

BACKGROUND: Reports show that selective internal radiation therapy (SIRT) may downsize inoperable liver tumors to resection or transplantation, or enable a bridge-to-transplant. A small-cohort study found that long-term survival in patients undergoing resection following SIRT appears possible but no robust studies on postsurgical safety outcomes exist. The Post-SIR-Spheres Surgery Study was an international, multicenter, retrospective study to assess safety outcomes of liver resection or transplantation following SIRT with yttrium-90 (Y-90) resin microspheres (SIR-Spheres®; Sirtex). METHODS: Data were captured retrospectively at participating SIRT centers, with Y-90 resin microspheres, surgery (resection or transplantation), and follow-up for all eligible patients. Primary endpoints were perioperative and 90-day postoperative morbidity and mortality. Standard statistical methods were used. RESULTS: The study included 100 patients [hepatocellular carcinoma: 49; metastatic colorectal cancer (mCRC): 30; cholangiocarcinoma, metastatic neuroendocrine tumor, other: 7 each]; 36% of patients had one or more lines of chemotherapy pre-SIRT. Sixty-three percent of patients had comorbidities, including hypertension (44%), diabetes (26%), and cardiopathy (16%). Post-SIRT, 71 patients were resected and 29 received a liver transplant. Grade 3+ peri/postoperative complications and any grade of liver failure were experienced by 24 and 7% of patients, respectively. Four patients died <90 days postsurgery; all were trisectionectomies (mCRC: 3; cholangiocarcinoma: 1) and typically had one or more previous chemotherapy lines and presurgical comorbidities. CONCLUSIONS: In 100 patients undergoing liver surgery after receiving SIRT, mortality and complication rates appeared acceptable given the risk profile of the recruited patients.

Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review.

Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs. (Hepatology 2017;66:969-982).

Trans-arterial embolisation therapies for unresectable intrahepatic cholangiocarcinoma: a systematic review.

BACKGROUND: Unresectable intrahepatic cholangiocarcinoma (ICC) portends a poor prognosis despite standard systemic treatments which confer minimal survival benefits and significant adverse effects. This study aimed to assess clinical outcomes, complications and prognostic factors of TAE therapies using chemotherapeutic agents or radiation. METHODS: A literature search and article acquisition was conducted on PubMed (MEDLINE), OVID (MEDLINE) and EBSCOhost (EMBASE). Original articles published after January 2000 on trans-arterial therapies for unresectable ICC were selected using strict eligibility criteria. Radiological response, overall survival, progression-free survival, safety profile, and prognostic factors for overall survival were assessed. Quality appraisal and data tabulation were performed using pre-determined forms. Results were synthesized by narrative review and quantitative analysis. RESULTS: Twenty articles were included (n=929 patients). Thirty three percent of patients presented with extrahepatic metastases. After treatment, the average rate of complete and partial radiological response was 10% and 22.2%, respectively. Overall median survival time was 12.4 months with a median 30-day mortality and 1-year survival rate of 0.6% and 53%, respectively. Acute treatment toxicity (within 30 days) was reported in 34.9% of patients, of which 64.3% were mild to moderate in severity. The most common clinical toxicities were abdominal pain, nausea and vomiting, and fatigue. Multiplicity, localization and vascularity of the tumor may predict worse overall survival. CONCLUSIONS: Trans-arterial therapies are safe and effective treatment options which should be considered routinely for unresectable ICC. Consistent and standardized methodology and data collection is required to facilitate a meta-analysis. Randomized controlled trials will be valuable in the future.

Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference.

OBJECTIVES: Liver metastasis from a neuroendocrine tumour (NET) represents a significant clinical entity. A multidisciplinary group of experts was convened to develop state-of-the-art recommendations for its management. METHODS: Peer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed and the findings presented to a jury of peers. The therapies reviewed included transarterial embolization (TAE), transarterial chemoembolization (TACE) and radioembolization (RE). Two systems were used to evaluate the level of evidence in each publication: (i) the US National Cancer Institute (NCI) system, and (ii) the GRADE system. RESULTS: Eighteen publications were reviewed. These comprised 11 reports on TAE or TACE and seven on RE. Four questions posed to the panel were answered and recommendations offered. CONCLUSIONS: Studies of moderate quality support the use of TAE, TACE and RE in hepatic metastases of NETs. The quality and strength of the reports available do not allow any modality to be determined as superior in terms of imaging response, symptomatic response or impact on survival. Radioembolization may have advantages over TAE and TACE because it causes fewer side-effects and requires fewer treatments. Based on current European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines, RE can be substituted for TAE or TACE in patients with either liver-only disease or those with limited extrahepatic metastases.

Is yttrium-90 radioembolization a viable treatment option for unresectable, chemorefractory colorectal cancer liver metastases? A large single-center experience of 302 patients.

INTRODUCTION: We report the largest series to date on the safety and efficacy of yttrium-90 (90Y) radioembolization for the treatment of unresectable, chemorefractory colorectal cancer liver metastases (CRCLM). METHODS: A total of 302 patients underwent resin-based 90Y radioembolization for unresectable, chemorefractory CRCLM between 2006 and 2013 in Sydney, Australia. All patients were followed up with imaging studies at regular intervals until death. Radiologic response was evaluated with the response criteria in solid tumors criteria. Clinical toxicities were prospectively recorded. Survival was calculated by the Kaplan-Meier method, and potential prognostic variables were identified on univariate and multivariate analysis. RESULTS: Median follow-up in the complete cohort was 7.2 months (range 0.2-72.8), and the median survival after 90Y radioembolization was 10.5 months with a 24-month survival of 21%. On imaging follow-up of 293 patients who were followed up beyond 2 months, complete response to treatment was observed in 2 patients (1%), partial response in 111 (38%), stable disease in 96 (33%), and progressive disease in 84 (29%). Four factors were independently associated with a poorer prognosis: extensive tumor volume, number of previous lines of chemotherapy, poor radiological response to treatment, and low preoperative hemoglobin. One hundred fifteen (38%) developed clinical toxicity after treatment; most complications were minor (grade I/II) and resolved without active intervention. CONCLUSIONS: 90Y radioembolization is a safe and effective treatment for unresectable, chemorefractory CRCLM.

Radioembolization for hepatocellular carcinoma: current role and future directions - the medical oncologist's perspective.

The incidence and impact of hepatocelluar carcinoma (HCC) continues to increase worldwide. While radical therapies such as resection, radiofrequency ablation or transplantation are potentially curative for patients with early-stage HCC, the majority of patients in routine practice present with more advanced tumors, where treatment goals are palliation and extending survival. With multiple new and promising treatment options emerging for these patients, the challenge for the medical oncologist is how best to integrate these therapies into routine clinical practice. Here we review the most recent data on the efficacy and safety of yttrium-90 radioembolization in HCC, the considerations involved in patient selection, and the optimal assessment and management of patients receiving treatment. We also examine the potential impact of several ongoing clinical trials.

Yttrium-90 radioembolization is a safe and effective treatment for unresectable hepatocellular carcinoma: a single centre experience of 45 consecutive patients.

INTRODUCTION: There is controversy regarding the role of yttrium-90 (90Y) radioembolization in the management of advanced, unresectable hepatocellular carcinoma (HCC). METHODS: Forty-five consecutive patients underwent resin-based 90Y radioembolization for unresectable, HCC between 2006 and 2013 in Sydney, Australia. All patients were followed up with imaging studies at regular intervals until death. Radiologic response was evaluated with the Response Criteria in Solid Tumors (RECIST) criteria. Clinical toxicities were prospectively recorded. Survival was calculated by the Kaplan-Meier method and potential prognostic variables were identified on univariate and multivariate analysis. RESULTS: Follow-up in the complete cohort was 7.8 (range, 0.1-41.8) months. The median survival after 90Y radioembolization was 27.7 months with a 36-month survival of 26%. By RECIST criteria of the 40 patients followed-up beyond 2 months, a complete response (CR) to treatment was observed in 1 patients (3%), partial response (PR) in 18 (45%), stable disease (SD) in 11 (22%) and progressive disease (PD) in 10 (25%). On multivariate analysis only radiological response to treatment was independently associated with improved survival: CR/PR to treatment vs. SD vs. PD; p < 0.001. Thirteen patients (29%) developed clinical toxicity after treatment; all complications were minor (grade I/II) and resolved without active intervention. CONCLUSION: Radioembolization with 90Y is a safe and effective treatment for unresectable HCC.

Botulinum toxin A in functional popliteal entrapment syndrome: a new approach to a difficult diagnosis.

Functional Popliteal Entrapment Syndrome (FPES) is caused by compression of neurovascular structures in the popliteal fossa by hypertrophic muscles, provoking severe leg pain with exercise. Treatment is limited to myotomy of hypertrophic musculature. 8 FPES patients underwent imaging and exercise studies, before receiving botulinum toxin A injections (BTX-A) into the gastrocnemius and plantaris muscles. 81.3 % of patients reported clinical improvement on follow-up, and pathological ankle-brachial indices were normalized. BTX-A injection may present a new, safe, effective and non-invasive approach to FPES.

Transarterial chemoembolisation and radioembolisation for the treatment of primary liver cancer and secondary liver cancer: a review of the literature.

Liver-directed therapies are continuing to evolve in the field of interventional oncology and are gaining increasing use in the treatment of unresectable primary and secondary liver cancers. In this article, we review two liver-directed therapies that are currently used for the palliative treatment of primary and secondary hepatic tumours: transcatheter arterial chemoembolisation (TACE), including a new type of TACE with drug-eluting beads (DEB-TACE), and radioembolisation. The concept of these transcatheter intraarterial therapies is to selectively deliver high doses of anticancer treatment to the tumour. While TACE delivers one or more chemotherapeutic drugs into the hepatic arteries supplying the tumour, radioembolisation uses non-embolic microspheres incorporating the radioactive isotope (90) Y. In this article, we discuss some technical aspects, patient selection, current clinical evidence, and future directions of TACE, TACE with drug-eluting beads (DEB-TACE) and radioembolisation for primary and secondary liver cancer.

Yttrium-90 radioembolization for unresectable, chemoresistant breast cancer liver metastases: a large single-center experience of 40 patients.

INTRODUCTION: There are a paucity of data on the treatment of unresectable, chemoresistant breast cancer liver metastases (BRCLM) with yttrium-90 (Y90) radioembolization. METHODS: Forty patients underwent resin-based Y90 radioembolization for unresectable, chemoresistant BRCLM between 2006 and 2012 in a single institution. All patients were followed up with imaging studies at regular intervals as clinically indicated until death. Radiologic response was evaluated with the Response Criteria in Solid Tumors criteria. Clinical toxicities were prospectively recorded as per the National Cancer Institute Common Toxicity Criteria. Survival was calculated by the Kaplan-Meier method and potential prognostic variables were identified on univariate and multivariate analysis. RESULTS: Follow-up was complete in all patients. The median follow-up was 11.2 (range 0.6-30.5) months and the median survival after Y90 radioembolization was 13.6 months, with a 24-month survival of 39 %. On imaging follow-up of 38 patients who survived beyond 1 month of treatment, a complete response (CR) to treatment was observed in two patients (5 %), partial response (PR) in 10 patients (26 %), stable disease (SD) in 15 patients (39 %), and progressive disease (PD) in 11 patients (29 %). Two factors were associated with an improved survival on multivariate analysis: CR/PR to treatment (vs. SD vs. PD; p < 0.001) and chemotherapy after radioembolization (vs. no chemotherapy; p = 0.004). Sixteen patients (40 %) developed clinical toxicity after treatment; all complications were minor grade I/II and resolved without active intervention. CONCLUSION: This study provides supportive evidence of the safety and efficacy on Y90 radioembolization for the treatment of unresectable, chemoresistant BRCLM. Further prospective investigation is required to assess the suitability of this treatment in this population.

Current role of transarterial chemoembolization and radioembolization in the treatment of metastatic colorectal cancer.

In this article, we review two liver-directed therapies that are currently used for the palliative treatment of primary and secondary hepatic malignancies, transcatheter arterial chemoembolization (TACE), including a new type of TACE with drug-eluting beads, and radioembolization. Important developments and administration techniques for all therapies are discussed, as well as their integration into the current routine clinical care for management of metastatic colorectal cancer. According to published data from clinical trials, as presented in this review, both radioembolization and TACE/TACE with drug-eluting beads have been proven to be safe and effective in selected patients with chemorefractory liver metastases from colorectal cancer. For patients with unresectable liver-only or liver-dominant disease who have failed standard chemotherapy options or for whom chemotherapy is contraindicated, new modalities, such as those discussed, are particularly valid and promising if clinical guidelines for patient selection and treatment administration are followed.

Impact of prior hepatectomy on the safety and efficacy of radioembolization with yttrium-90 microspheres for patients with unresectable liver tumors.

OBJECTIVES: Yttrium-90 (Y) radioembolization is increasingly used as a minimally invasive therapy for unresectable liver tumors; however, previous hepatectomy must be considered to avoid excessive hepatic insult. A retrospective analysis was undertaken to investigate the viability of performing radioembolization on a remnant liver. METHODS: A retrospective analysis was performed on data collected from December 2005 to August 2011 to identify the effect of prior hepatectomy on radioembolization outcomes. Survival and complications were reviewed for up to 3 months after radioembolization. RESULTS: Of 427 patients eligible for analysis, 89 underwent previous hepatectomy. Immediate adverse events included abdominal pain (7.9% of hepatectomy patients vs. 18.0% of non-hepatectomy patients; P = 0.02), nausea (4.5% vs. 8.0%; P > 0.05), and emesis (0.0% vs. 0.9%; P > 0.05). The prevalence of intermediate complications 1 month after radioembolization was low. Late complications included radiation-induced liver disease (3.4% vs. 1.5%; P > 0.05), ulceration (2.2% vs. 2.7%; P > 0.05), and gallbladder and biliary tree-related outcomes (2.2% vs. 1.8%; P > 0.05). Imaging analysis demonstrated a significant relationship between prior hepatectomy patients and a partial response to radioembolization, as well as progressive disease. The median overall survival after radioembolization for hepatectomy patients was 7.8 months, versus 5.8 months for non-hepatectomy patients (P = 0.108). CONCLUSIONS: Our results indicate that radioembolization is safe to be performed on a remnant liver. Although imaging analysis demonstrated varying responses to radioembolization when comparing hepatectomy patients to non-hepatectomy patients, overall survival was shown to be similar between the 2 groups.

A systematic review on the safety and efficacy of yttrium-90 radioembolization for unresectable, chemorefractory colorectal cancer liver metastases.

INTRODUCTION: The management of unresectable, chemorefractory colorectal cancer liver metastases (CRCLM) is a clinical dilemma. Yttrium-90 (Y90) radioembolization is a potentially safe and effective treatment for patients with CRCLM who have failed conventional chemotherapy regimens. METHODS: A systematic review of clinical studies before November 2012 was performed to examine the radiological response, overall survival and progression-free survival of patients who underwent Y90 radioembolization of unresectable CRCLM refractory to systemic therapy. The secondary objectives were to evaluate the safety profile of this treatment and identify prognostic factors for overall survival. RESULTS: Twenty studies comprising 979 patients were examined. Patients had failed a median of 3 lines of chemotherapy (range 2-5). After treatment, the average reported value of patients with complete radiological response, partial response and stable disease was 0% (range 0-6%), 31% (range 0-73%) and 40.5% (range 17-76%), respectively. The median time to intra-hepatic progression was 9 months (range 6-16). The median overall survival was 12 months (range 8.3-36). The overall acute toxicity rate ranged from 11 to 100% (median 40.5 %). Most cases of acute toxicity were mild (Grade I or II) (median 39%; range 7-100%) which resolved without intervention. The number of previous lines of chemotherapy (≥ 3), poor radiological response to treatment, extra-hepatic disease and extensive liver disease (≥ 25%) were the factors most commonly associated with poorer overall survival. CONCLUSION: Y90 radioembolization is a safe and effective treatment of CRCLM in the salvage setting and should be more widely utilized.

Radioembolisation with Yttrium-90 microspheres: an effective treatment modality for unresectable liver metastases.

PURPOSE: To compare the outcomes (survival and adverse events) of the authors' use of (90) Y microsphere radioembolisation in patients with chemotherapy-refractory liver metastases with published data from other groups using radioembolisation. To retrospectively evaluate the efficiency, in particular survival benefits, of radioembolisation in the treatment of liver metastases. METHODS AND MATERIALS: Over 5 years, 339 patients underwent (90) Y microsphere radioembolisation for unresectable liver metastases and were evaluated for adverse events at the time of treatment and 1 and 3 months after treatment. Overall survival (OS) was calculated by the Kaplan-Meier method. The results from the present retrospective study were compared with a number of prospective and retrospective clinical trials which have addressed the use of (90) Y microspheres as a salvage treatment for liver metastases. RESULTS: The OS time of the present study (12.0 months) compares favourably with survival times reported by other groups. The incidence of late grade 2 adverse events (e.g. duodenal or gastric ulceration, radiation-induced liver disease, gall bladder complications) is comparable to previous studies, with a lower prevalence of grade 2/3 ulcerations (3.7%) at our centre. CONCLUSIONS: The survival results, together with the low acute and late toxicity observed in our data and previous studies, support the use of radioembolisation to aid in the local control of unresectable liver metastases in the salvage setting. The present study contributes to the growing evidence for efficiency, in particular survival gains, of radioembolisation in the treatment of liver metastases.

A method for coronary artery calcium scoring using contrast-enhanced computed tomography.

BACKGROUND: Limitations to the coronary calcium score include its requirement for noncontrast imaging and radiation exposure that approaches current methods for contrast-enhanced CT angiography. OBJECTIVES: We sought to derive and validate a method of measuring the coronary artery calcium score (CACS) from standard contrast-enhanced CT, obviating the need for a second non-contrast calcium scan. METHODS: The volume of intramural calcium of >320 HU in major coronary vessels was measured in 90 contrast-enhanced and traditional non-contrast calcium scan pairs. An empiric conversion factor was derived to convert the small voxel contrast-enhanced calcium volume to an Agatston calcium score. The accuracy of this technique was then prospectively validated in 120 consecutive patients undergoing clinical calcium scans and contrasted-enhanced coronary CT. Eleven patients were excluded from analysis because of the prespecified criteria of excessive noise in the contrast-enhanced CT or total coronary artery occlusion. RESULTS: The Pearson correlation of the contrast scan-derived calcium score with the measured CACS was r2 = 0.99. With standard CACS risk bands, agreement of the contrast-enhanced calcium score estimate with the measured CAC by quadratic weighted κ was 0.96. The 95% limits of agreement (Agatston units) were given by ±(3.2 + 0.14 × CACS + 4.44 mean square root of CACS). Inter-observer and intra-observer reliability with the intraclass correlation was 0.99. CONCLUSION: The calcium score can be accurately measured from contrast-enhanced cardiac CT scans with the use of a Hounsfield unit threshold of 320.