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[This corrects the article DOI: 10.21037/jgo.2017.03.10.].

Background: The Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) study was a retrospective analysis of 606 patients with unresectable colorectal liver metastases treated with radioembolization (RE) using 90 Y-labeled resin microspheres. The first analysis of this study was completed with a last patient follow-up of 77.7 months. We now provide an updated survival analysis through September 15, 2016, with a last patient follow-up of 125 months., Methods: 90 Y-RE was considered for patients with advanced liver-only or liver-dominant metastatic colorectal cancer which was deemed not suitable for surgery, ablation, or systemic therapy, and which had progressed or become refractory to at least one line of systemic therapy. All patients with a diagnosis of metastatic colorectal cancer who had received at least 1 RE treatment and 1 follow-up visit were included in the analysis. Patients were treated between July 2002 and December 2011 at one of 11 U.S. tertiary care centers. Data were collected at baseline, on the day of the first 90 Y-RE treatment (day 0), and at all subsequent visits or until death. Patient medical charts and/or public records were accessed to obtain dates of death., Results: Dates of death were obtained for 574 out of a total of 606 patients, and overall survival (OS) data analyzed. Updated median OS was 10.0 months (95% CI: 9.2-11.8 months) at a median follow-up of 9.5 months versus the originally reported median OS of 9.6 months (95% CI: 9.0-11.1 months) at a follow-up of 8.6 months in the first MORE analysis. Patients received a median (range) of 2 (0 to 6) lines of chemotherapy. Baseline characteristics and factors significantly associated with patient survival (P<0.01) are consistent with those reported in the first safety analysis of the MORE study. These factors include poor ECOG performance status, markers of advanced disease such as increased extent of tumor-to-target liver involvement, poor baseline liver function, pre-treatment anemia, lung shunt fraction, and number of lines of prior chemotherapy. Patient age did not significantly affect survival outcomes., Conclusions: Long-term follow-up confirms that 90 Y-RE treatment offers favorable survival benefits for patients with unresectable metastatic colorectal cancer, even among patients who received 3 or more prior lines of chemotherapy. Our analysis also supports earlier reported prognostic factors for survival after 90 Y-RE. Overall, our updated analysis confirms that 90 Y-RE treatment provided a meaningful response and survival advantage for MORE patients across all ages and across diverse community and academic centers in the U.S., Competing Interests: Conflicts of Interest: Received research grants from Sirtex Medical (AKennedy, MS, AD); consultant to Sirtex Medical (AD, EW); participant in speakers’ bureau for Sirtex Medical (DC, MC, CN); owns stock holdings in Sirtex Medical (AD, SR). SR has also served as a consultant for Surefire Medical, XL Sci-Tech, and Guerbet.

Background: Patients with liver metastatic colorectal cancer (mCRC) often benefit from receiving 90 Y-microsphere radioembolization (RE) administered via the hepatic arteries. Prior to delivery of liver-directed radiation, standard laboratory tests may assist in improving outcome by identifying correctable pre-radiation abnormalities., Methods: A database containing retrospective review of consecutively treated patients of mCRC from July 2002 to December 2011 at 11 US institutions was used. Data collected included background characteristics, prior chemotherapy, surgery/ablation, radiotherapy, vascular procedures, 90 Y treatment, subsequent adverse events and survival. Kaplan-Meier estimates compared the survival of patients across lines of chemotherapy. The following values were obtained within 10 days prior to each RE treatment: haemoglobin (HGB), albumin, alkaline phosphatase (Alk phosph), aspartate aminotransferase (AST), alanine transaminase (ALT), total bilirubin and creatinine. Common Terminology Criteria Adverse Events (CTCAEs) 3.0 grade was assigned to each parameter and analysed for impact on survival by line of chemotherapy. Consensus Guidelines were used to categorize the parameter grades as either within or outside guidelines for treatment., Results: A total of 606 patients (370 male; 236 female) were studied with a median follow-up was 8.5 mo. (IQR 4.3-15.6) after RE. Fewer than 11% of patients were treated outside recommended RE guidelines, with albumin being the most common, 10.5% grade 2 (<3-2.0 g/dL) at time of RE. All seven parameters showed statistically significant decreased median survivals with any grade >0 (P<0.001) across all lines of prior chemotherapy. Compared to grade 0, grade 2 albumin decreased overall survival 67%; for grade 2 total bilirubin a 63% drop occurred, and grade 1 HGB resulted in 66% lower median survival., Conclusions: Review of pre-RE laboratory parameters may aid in improving median survivals if correctable grade >0 values are addressed prior to radiation delivery. HGB <10 g/dL is a well-known negative factor in radiation response and is easily corrected. Improving other parameters is more challenging. These efforts are important in optimizing treatment response to liver radiotherapy., Competing Interests: Conflicts of Interest: DM Coldwell is a consultant to Sirtex Medical; M Cohn, A Drooz, FM Moeslein, CW Nutting, SG Putnam III, SC Rose, EA Wang are proctors for Sirtex Medical; MA Savin is a speaker for BSD Medical. Prior presentations: AS Kennedy et al. ACRO Annual Meeting 2014.

Purpose To determine if high lung shunt fraction (LSF) is an independent prognostic indicator of poor survival in patients who undergo yttrium 90 radioembolization for unresectable liver-dominant metastatic colorectal cancer. Materials and Methods Retrospective data were analyzed from 606 patients (62% men; mean age, 62 years) who underwent radioembolization to treat liver metastases from colorectal adenocarcinoma between July 2002 and December 2011 at 11 U.S. centers. Institutional review board exemptions were granted prior to the collection of data at each site. Overall survival was estimated by using Kaplan-Meier survival and univariate Cox proportional hazards models to examine the effect of LSF on survival and to compare this to other potential prognostic indicators. Multivariate analysis was also performed to determine whether LSF is an independent risk factor for poor survival. Results LSF higher than 10% was predictive of significantly decreased survival (median, 6.9 months vs 10.0 months; hazard ratio, 1.60; P < .001) and demonstrated a mild but significant correlation to serum carcinoembryonic antigen levels and tumor-to-liver volume ratio (Pearson correlation coefficients, 0.105 and 0.113, respectively; P < .05). A progressive decrease in survival was observed as LSF increased from less than 5% to more than 20% (P < .05). LSF did not correlate with the presence of extrahepatic metastases or prior administration of bevacizumab. Conclusion Increased LSF is an independent prognostic indicator of worse survival in patients undergoing radioembolization for liver-dominant metastatic colorectal adenocarcinoma. High LSF correlates poorly to other potential markers of tumor size, such as tumor-to-liver volume ratio or serum carcinoembryonic antigen level, and does not correlate to the presence of extrahepatic metastases. © RSNA, 2016 Online supplemental material is available for this article.

Background: The effects of advancing age on clinical outcomes after radioembolization (RE) in patients with unresectable liver-dominant metastatic colorectal cancer (mCRC) are largely unknown., Patients and Methods: This study was a retrospective analysis of 160 elderly (≥ 70 years) and 446 younger (< 70 years) consecutive patients from 11 US centers who received RE using ytrrium-90 ((90)Y) resin microspheres ((90)Y radioembolization [(90)Y-RE]) between July 2002 and December 2011. A further analysis was conducted in 98 very elderly patients (≥ 75 years). Statistical analyses of safety, tolerability, and overall survival were conducted., Results: Mean ages (± standard deviation) in the younger (< 70 years), elderly (≥ 70 years), and very elderly (≥ 75 years) cohorts were 55.9 ± 9.4 years, 77.2 ± 4.8 years, and 80.2 ± 3.8 years, respectively. Overall survival was similar between elderly and younger patients: 9.3 months (95% confidence interval [CI], 8.0-12.1) and 9.7 months (95% CI, 9.0-11.4) (P = .335). There were no differences between cohorts for any grade adverse events (P = .433) or grade 3+ events (P = .482). Analysis of patients ≥ 75 years and < 75 years confirmed similar overall survival (median, 9.3 months vs. 9.6 months, respectively; P = .987) and grade 3+ events (P = .398) or any adverse event (P = .158) within 90 days of RE., Conclusion: For patients with unresectable liver-dominant mCRC who meet eligibility criteria for RE, (90)Y-RE microspheres appear to be effective and well-tolerated, regardless of age. Criteria for selecting patients for RE should not include age for exclusion from this potentially beneficial intervention., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Image-guided ablation is used to treat patients with unresectable malignant hepatic tumors that are limited in number and size, especially hepatocellular carcinoma (HCC) and colorectal hepatic metastases. While radiofrequency ablation (RFA) has been the most popular technique, several alternate options for focal tissue destruction have recently attracted attention. These technologies appear to be able to overcome some specific limitations of RFA. Currently, there is no accepted algorithm for the use of the different techniques for image-guided ablation., Summary: A panel of physicians practicing in North America or Europe met to develop a set of recommendations aimed at providing directions for clinical validation of energy-based, thermal and non-thermal image-guided ablation technologies in the treatment of malignant liver tumors. The recommendations were developed through a critical appraisal of potential advantages and disadvantages of each ablation technology, based on experimental findings and available data, as well as on critical considerations for their clinical validation in hepatic tumor treatment from a Western perspective., Key Messages: Significant variability appears to exist among the different equipment and devices within each type of technology. A comprehensive understanding of the data and a critical appraisal of the efficacy and safety profile of each ablation system is required. Clinical practice guidelines should include specific information of the recommended techniques and protocols instead of a generic indication of the technology.

Background: To assess response and the impact of imaging artifacts following radioembolization with yttrium-90-labeled resin microspheres ((90)Y-RE) based on the findings from a central independent review of patients with liver-dominant metastatic colorectal cancer (mCRC)., Methods: Patients with mCRC who received (90)Y-RE (SIR-Spheres(®); Sirtex Medical, Sydney, Australia) at nine US institutions between July 2002 and December 2011 were included in the analysis. Tumor response was assessed at baseline and 3 months using either the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1. For each lesion, known artifacts affecting the interpretation of response (peri-tumoral edema and necrosis) were documented. Survivals (Kaplan-Meier analyses) were compared in responders [partial response (PR)] and non-responders [stable (SD) or progressive disease (PD)]., Results: Overall, 195 patients (mean age 62 years) received (90)Y-RE after a median of 2 (range, 1-6) lines of prior chemotherapy. Using RECIST 1.0 and RECIST 1.1, 7.6% and 6.9% of patients were partial responders, 47.3% and 48.1% had SD, and 55.0% and 55.0% PD, respectively. RECIST 1.0 and RECIST 1.1 showed excellent agreement {Kappa =0.915 [95% confidence interval (CI): 0.856-0.975]}. Peri-tumoral edema was documented in 32.8%, necrosis in 48.1% and both in 57.3% of cases (using RECIST 1.0). Although baseline characteristics were similar in responders and non-responders (P>0.05), responders survived significantly longer in an analysis according to RECIST 1.0: PR median (95% CI) 25.2 (range, 9.2-49.4) months vs. SD 15.8 (range, 9.3-21.1) months vs. PD 7.1 (range, 6.0-9.5) months (P<0.0001)., Conclusions: RECIST 1.0 and RECIST 1.1 imaging responses provide equivalent interpretations in the assessment of hepatic tumors following (90)Y-RE. Radiologic lesion responses at 3 months must be interpreted with caution due to the significant proportion of patients with peri-tumoral edema and necrosis, which may lead to an under-estimation of PR/SD. Nevertheless, 3-month radiologic responses were predictive of prolonged survival.

Background: Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) was an investigator-initiated case-control study to assess the experience of 11 US centers who treated liver-dominant metastases from colorectal cancer (mCRC) using radioembolization [selective internal radiation therapy (SIRT)] with yttrium-90-((90)Y)-labeled resin microspheres., Methods: Data from 606 consecutive patients who received radioembolization between July 2002 and December 2011 were collected by an independent research organization. Adverse events (AEs) and survival were compared across lines of treatment using Fisher's exact test and Kaplan-Meier estimates, respectively., Results: Patients received a median of 2 (range, 0-6) lines of prior chemotherapy; 35.1% had limited extrahepatic metastases. Median tumor-to-liver ratio and -activity administered at first procedure were 15% and 1.17 GBq, respectively. Hospital stay was <24 hours in 97.8% cases. Common grade ≥3 AEs over 184 days follow-up were: abdominal pain (6.1%), fatigue (5.5%), hyperbilirubinemia (5.4%), ascites (3.6%) and gastrointestinal ulceration (1.7%). There was no statistical difference in AEs across treatment lines (P>0.05). Median survivals [95% confidence interval (CI)] following radioembolization as a 2(nd)-line, 3(rd)-line, or 4(th)-plus line were 13.0 (range, 10.5-14.6), 9.0 (range, 7.8-11.0), and 8.1 (range, 6.4-9.3) months, respectively; and significantly prolonged in patients with ECOG 0 vs. ≥1 (P=0.009). Statistically significant independent variables for survival at radioembolization were: disease stage [extrahepatic metastases, extent of liver involvement (tumor-to-treated-liver ratio)], liver function (uncontrolled ascites, albumin, alkaline phosphatase, aspartate transaminase), leukocytes, and prior chemotherapy., Conclusions: Radioembolization appears to have a favorable risk/benefit profile, even among mCRC patients who had received ≥3 prior lines of chemotherapy.

Purpose: Therapy for patients with unresectable liver metastases from breast cancer that were refractory to multiple treatment regimens was performed using radioactive microspheres. High doses of radiation were delivered to tumors from these permanently implanted yttrium-90 ((90)Y) microspheres, delivered through the hepatic arterial vessels., Methods and Materials: Women from three institutions were selected for treatment, after screening that demonstrated vascular access to all tumors and after imaging confirmed that microspheres would be implanted only in the liver tumors. All patients were followed with laboratory and imaging studies at regular intervals until death. Toxicities, both acute and late were recorded, and actuarial survival determined., Results: A total of 44 women were treated from April 2002 to April 2005. Median follow-up of these women was 14 months (1-42 months). No treatment-related procedure deaths or radiation related veno-occlusive liver failures were found. Computed tomographic imaging partial response was 47% and positron emission tomographic response 95%., Conclusion: In this group of heavily pretreated patients, radioactive microspheres produced an encouraging median survival, with acceptable toxicity and a significant objective response rate, suggesting that further investigation of this approach is warranted.

Purpose: To evaluate the safety and effectiveness of retrieval of the Günther Tulip inferior vena cava (IVC) filter., Materials and Methods: This was a nonrandomized, single-armed, multicenter prospective investigation. Patients at temporary high risk for pulmonary embolism (PE) or deep vein thrombosis (DVT) who did not require a permanent filter were eligible. Forty-one patients received 42 Günther Tulip filters: 22 men and 19 women with a mean age of 47.7 years. Indications for filter placement included prophylaxis, PE, and DVT. Three months after filter retrieval, contrast agent-enhanced computed tomography of the abdomen, jugular vein ultrasonography, and clinical follow-up were performed., Results: The filter retrieval rate was 57% (23 of 41). Günther Tulip filters were removed at a mean of 11.1 days (range, 2-14 d). The technical and clinical success rates for filter retrieval were both 100%. One placement complication and two protocol deviations occurred. These patients were excluded in terms of retrieval-related outcomes. One case of PE occurred with a filter in place, and one filter migrated to the heart. There were no acute complications caused by filter retrieval. At 3-month follow-up, there was no recurrent PE, DVT, jugular vein occlusion, or IVC stenosis or occlusion., Conclusion: In this multicenter study, retrieval of the Günther Tulip filter was safe and without recurrent thromboembolic events or evidence of IVC or jugular vein damage at 3-month follow-up.

The mechanism of acetate vasorelaxation is unknown. In the rat caudal artery, acetate has a vasorelaxant effect and also increases cyclic AMP. Here we evaluate the role of adenosine, of possible glycolysis inhibition by acetate, of the lyotropic properties of acetate and other anions, and of intracellular calcium and pH. Adenosine per se did not relax the caudal artery in the range of 10(-8) to 10(-2) M. Preincubation with adenosine deaminase (ADA, 5.0 U/ml) or with 8-phenyltheophylline (8-PT, 10(-6) to 10(-4) M) increased, rather than blocked the vasorelaxant effect of acetate. Oxypurinol (10(-3) M) or the nucleoside transport inhibitor NBMPR (10(-4) M) had no effect on acetate relaxation. Whereas acetate increased tissue cyclic AMP content, 10(-3) M adenosine or 10(-6) M PIA had no effect. In strips studied under conditions of inhibited glycolysis (no glucose, with 11 mM 2-deoxyglucose, 1.0 mM pyruvate, and 0.5 mM 5-iodoacetate), acetate-induced relaxation, as well as acetate-induced cyclic AMP generation, tended to be reduced but not significantly so. Other anions relaxed vascular strips in relation to their lyotropic number, but only at higher doses, and they did not stimulate cyclic AMP formation. Acetate (10 mM) caused a transient fall in Ca2+i followed by a slight, sustained rise. A concomitant decrease in pHi was seen. DIDS, which blocks the relaxant and cyclic AMP effects of acetate, had no effect on the pHi decrease, but did decrease the rate of pHi recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetate relaxes rat caudal artery and increases tissue adenosine 3',5'-cyclic monophosphate (cAMP) levels. The present study's purpose was to determine whether related ultrashort chain (volatile) fatty acids, propionate (C3), butyrate (C4), and octanoate (C8) would do so as well. It was found that butyrate and propionate had very similar vasorelaxant profiles to acetate; they relaxed caudal artery strips precontracted with KCl, phenylephrine, arginine vasopressin, and prostaglandin F2 alpha. The vasorelaxation was endothelium independent, was not blocked by indomethacin, and was associated with a rise in tissue cAMP levels but not in guanosine 3',5'-cyclic monophosphate (cGMP) levels. The mean effective concentration for butyrate (0.8 mM) was lower than that for acetate (2.0 mM) or propionate (1.9 mM). Propionate-mediated relaxation was blocked by the stilbene inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). Vasorelaxant effects of octanoate were also not dependent on endothelium and were not affected by indomethacin. Maximal vasorelaxant effect of octanoate was greater than that of acetate, propionate, or butyrate; vasorelaxant effect of octanoate was only slightly attenuated by DIDS and was associated with only a minimal effect on tissue cAMP levels. Results suggest that vasodilatory effects of acetate generalize to propionate and butyrate, but that vasorelaxant effects of octanoate may be occurring via a separate mechanism.

We theorized that H-8, N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, an inhibitor of cyclic nucleotide-dependent protein kinases, might be a useful probe to assess cyclic nucleotide-dependent relaxation of blood vessels. However, working in the rat caudal artery and aorta, we found that neither cyclic AMP- nor cyclic GMP-mediated relaxations were diminished by even large doses of H-8. For example, in the caudal artery, relaxation of a phenylephrine contraction by 8-bromo-cGMP (10(-5) M) was unaffected by H-8: control, 33 +/- 6.2%; 10 microM H-8, 41 +/- 12%; 30 microM H-8, 30 +/- 16% (p NS). The amount of relaxation by 8-bromo-cAMP (3 x 10(-4) M) was actually increased by H-8: control, 29 +/- 7.6%; 10 microM H-8, 34 +/- 7.4%; 30 microM H-8, 80 +/- 14%. In the rat aorta, H-8 also failed to diminish relaxation induced by 8-bromo-cGMP, or by atriopeptin II or sodium nitroprusside. In both caudal artery and aorta, H-8 of itself caused a dose-dependent suppression of alpha-adrenergic contraction: for example, in the caudal artery, with 10 or 30 microM H-8, peak contraction to phenylephrine was reduced to 70 (SEM) +/- 12% or 52 +/- 7% of control, respectively. The results suggest that the protein kinase inhibitor H-8 is not a useful probe to study cyclic nucleotide-dependent relaxation.