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Unlabelled: Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF-κB) p65 subunit to positively regulate the transcription of HIF-1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1α and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1α proteins., Conclusion: IL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-κB and HIF-1α during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment., (© 2015 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Introduction: A lipiodol solution of (188)Re-4-hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol (HTDD) has been successfully developed for liver cancer therapy; however, its preparation requires a multi-step synthesis and it is characterized by a low labeling yield., Methods: We synthesized a new compound, 4-hexadecyl-4,7-diaza-1,10-decanedithioacetate (AHDD), without gem dimethyl groups to address these issues. AHDD was formulated into a kit and was labeled with (188)Re. Biodistribution study was performed using normal BALB/c mice., Results: The kit was labeled with (188)Re with a high efficiency (98.8±0.2%). After extraction with lipiodol, the overall yield of (188)Re-HDD/lipiodol was as high as 90.2±2.6%. A comparative biodistribution study of (188)Re-HTDD and (188)Re-HDD was performed in normal mice after intravenous injection. The lungs were identified as the main uptake site due to capillary-blockage. (188)Re-HDD/lipiodol showed a significantly higher lung uptake than that of (188)Re-HTDD/lipiodol (p<0.05)., Conclusion: The newly synthesized (188)Re-HDD/lipiodol showed improved radiolabeling yield and biodistribution results compared to (188)Re-HTDD/lipiodol, and may therefore be more suitable for liver cancer therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A multicenter study was sponsored by the International Atomic Energy Agency (IAEA) to assess the safety and efficacy of transarterial rhenium-188 ((188)Re) HDD lipiodol (radioconjugate to lipiodol using an HDD kit) in the treatment of unresectable hepatocellular carcinoma. During 5 years, 185 patients received at least 1 treatment of radioconjugate, and 51 were retreated. The level of radioconjugate administered was based on radiation-absorbed dose to critical normal organs, calculated after a "scout" dose of radioconjugate. The total injected activity, including the scout dose during the first treatment, ranged from 21 to 364 mCi (mean, 108 mCi/4 GBq). Immediate and late side-effects were minimal. Tumor size could be evaluated in 88 patients. Among these patients, the objective response rate was 25%; stable disease was observed in 53% and tumor progression in 22%. With a median follow-up of 455 days, the estimated 12- and 24-month overall survival was 46% and 23%. This multicenter study shows that (188)Re lipiodol is a safe and cost-effective method to treat primary hepatocellular carcinoma via the transarterial route and requires further evaluation by treatment of greater numbers of patients.

This work describes the installation, use, and quality control (QC) of the alumina-based tungsten-188 ((188)W)/rhenium-188 ((188)Re) generators provided by the Oak Ridge National Laboratory (ORNL). In addition, methods used for concentration of the (188)Re-perrhenate bolus and preparation of (188)Re-labeled HDD (4-hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol) for trans-arterial administration for therapy of nonresectable liver cancer also are described. The (188)W/(188)Re generator has a long useful shelf-life of several months and is a convenient on-site (188)Re production system. (188)Re has excellent therapeutic and imaging properties (T(1/2) 16.9 hours; E(betamax) 2.12 MeV; 155-keV gamma ray, 15%) and is cost effectively obtained on demand by saline elution of the generator. The clinical efficacy of a variety of (188)Re-labeled agents has been demonstrated for several therapeutic applications. Because of the favorable physical properties of (188)Re, several (188)Re-labeled agents are being developed and evaluated for the treatment of nonresectable/refractory liver cancer. (188)Re-labeled HDD has been the most widely studied of these agents for this application and has been introduced into clinical trials at a number of institutions. The trans-arterial administration of (188)Re-labeled agents for treatment of inoperable liver cancer requires use of high-level (1-2 Ci) (188)W/(188)Re generators. The handling of such high levels of (188)Re imposes radiological precautions normally not encountered in a radiopharmacy and adequate care and ALARA (ie, "As Low As Reasonably Achievable") principles must be followed. The ORNL generator provides consistently high (188)Re yields (>75%) and low (188)W parent breakthrough (<10(-3)%) over an extended shelf-life of several months. However, the high elution volumes (20-40 mL for 1-2 Ci generators) can require concentration of the (188)Re bolus by postelution passage through silver cation chloride trapping columns used in the cost-effective tandem cation/anion column system. The silver column removes the high levels of chloride anion as insoluble AgCl, thus allowing subsequent specific trapping of the perrhenate anion on the small (QMA SeaPak) anion column. This method permits subsequent elution of (188)Re-perrhenate with a small volume of saline, providing a very high activity-concentration solution. Because the (188)Re-specific volume-activity concentration continually decreases with time, the tandem system is especially effective method for extending the useful generator shelf-life. Low elution flow rates (<1 mL/min) minimize any high back pressure which may be encountered during generator/tandem column elution when using tightly packed, small-particle-size commercial columns. In-house preparation of silver cation columns is recommended since the chloride trapping capacity is essentially unlimited, it is inexpensive and not limited in availability to any one supplier, and back pressure can be eliminated by the use of larger particles. Methods for the preparation of (188)Re-HDD have been optimized and this agent can be obtained in high yield (80%).

Purpose: Intra-arterial injections (IAI) of 131I-lipiodol is effective in treating hepatocellular carcinoma patients, but is expensive and requires a 7-day hospitalization in a radioprotection room. 188Re is inexpensive, requires no patient isolation, and can be used with lipiodol., Methods and Materials: This International Atomic Energy Agency-sponsored phase II trial aimed to assess the safety and the efficacy of a radioconjugate 188Re + lipiodol (188Re-Lip) in a large cohort of hepatocellular carcinoma patients from developing countries. A scout dose is used to determine the maximal tolerated dose (lungs <12 Gy, normal liver <30 Gy, bone marrow <1.5 Gy) and then the delivery of the calculated activity. Efficacy was assessed using response evaluation criteria in solid tumor (RECIST) and alpha-feto-protein (alpha FP) levels and severe adverse events were graded using the Common Toxicity Criteria of the National Cancer Institute scale v2.0., Results: The trial included 185 patients from eight countries. The procedure was feasible in all participating centers. One treatment was given to 134 patients; 42, 8, and 1 received two, three, and four injections, respectively. The injected activity during the first treatment was 100 mCi. Tolerance was excellent. We observed three complete responses and 19 partial responses (22% of evaluable patients, 95% confidence interval 16-35%); 1- and 2-year survivals were 46% and 23%. Some factors affected survival: country of origin, existence of a cirrhosis, Cancer of the Liver Italian Program score, tumor dose, absence of progression, and posttreatment decrease in alpha FP level., Conclusions: IAI of 188Re-Lip in developing countries is feasible, safe, cost-effective, and deserves a phase III trial.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is believed to promote tumor growth, and thus, is viewed as one of the most compelling cancer therapy targets. YC-1 is widely used as a potent inhibitor of HIF-1alpha both in vitro and in vivo, and is also being developed as a novel anticancer drug. However, little is known about the effects of YC-1 on tumor invasion or metastasis. In the present study, we found that the Hep3B cell migration-stimulatory effect of hypoxia was abolished by HIF-1alpha siRNA or YC-1. YC-1 also significantly inhibited the migrations of other cancer cells. Furthermore, YC-1 effectively inhibited cell invasion through Matrigel. In nude mice, GFP-expressing stable cell-lines of Hep3B or H1299 were inoculated into spleens to induce liver metastasis or into the pleural cavity to induce lung invasion. In untreated mice, many tumor lesions emitting strong fluorescence were found in livers or lungs, and fluorescence intensities and tumor lesion numbers were markedly reduced in YC-1-treated mice. These results suggest that YC-1 effectively inhibits tumor invasion and metastasis, and imply that YC-1 is worth while to further develop as a multipurpose anticancer drug.

Purpose: The aim of this study was to investigate the feasibility of administering increasing activities of (188)Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ((188)Re-HDD/lipiodol) for the treatment of hepatocellular carcinoma (HCC) in patients with well-compensated cirrhosis., Methods: The activity levels were increased by 1.1 GBq/step after a 6-week interval without unacceptable adverse events in at least five consecutive patients. Absorbed doses to the various organs were calculated according to the MIRD formalism, based on three gamma-scintigraphic studies. Response was assessed by means of MRI and alpha-fetoprotein (AFP) monitoring., Results: Thirty-five treatments were carried out in 28 patients. Activities from 4.8 to 7.0 GBq (188)Re-HDD/lipiodol were administered via a transfemoral catheter. The mean absorbed dose to the liver (including tumour) was 7.6+/-2.2, 9.8+/-4.9 and 15.2+/-4.9 Gy for the 4.8-, 5.9- and 7.0-GBq groups, respectively. Treatment was well tolerated at all activity levels. Further escalation of the administered activity was not feasible owing to limitations related to the radiolabelling procedure. Response assessment on MRI showed partial response, stable disease and disease progression in 1, 28 and 2 assessable treatments, respectively. In 8 of 17 treatment sessions with an initially elevated AFP, a reduction ranging from 19% to 97% was observed 6 weeks later., Conclusion: Following the intra-arterial administration of 4.8-7.0 GBq (188)Re-HDD/lipiodol in patients with HCC and well-compensated liver cirrhosis, no severe adverse events occurred. Further escalation was not feasible owing to limitations in the radiolabelling procedure.

Unlabelled: The aim of this study was to investigate the pharmacokinetics, organ dosimetry, and toxicity after the intraarterial administration of (188)Re-labeled 4-hexadecyl-1,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ((188)Re-HDD/lipiodol) for palliative treatment of hepatocellular carcinoma (HCC). A secondary objective was to document the response., Methods: A mean activity of 3.60 GBq (188)Re-HDD/lipiodol (range, 1.86-4.14 GBq) was administered to 11 patients (16 treatment sessions) via a transfemoral catheter. The pharmacokinetic and dosimetric data were collected by means of venous blood samples, urine collections, and 4 or 5 gamma-scintigraphies over 76 h. Absorbed doses to the various organs were calculated according to the MIRD formalism, using the MIRDOSE3.1 software. The toxicity was assessed until 6 wk after administration by means of the Common Toxicity Criteria scale. The response was evaluated on MRI and by monitoring of the tumor marker., Results: A fast blood clearance of the injected activity was observed with a calculated effective half-life of 7.6 +/- 2.2 h (+/-SD) in blood. The predominant elimination of the activity was through urinary excretion with a mean renal clearance of 44.1% +/- 11.7% (+/-SD) of the injected activity within the 76 h after administration. Fecal elimination was negligible. The calculated whole-body effective half-life was 14.3 +/- 0.9 h (+/-SD). The absorbed dose to the liver tissue, the lungs, the kidneys, and the thyroid was 4.5 +/- 1.9, 4.1 +/- 1.2, 0.9 +/- 0.7, and 0.3 +/- 0.1 Gy, respectively. Treatment was well tolerated, except in 2 patients. One Child B patient experienced a worsening of his liver dysfunction (hyperbilirubinemia) and another patient experienced dyspnea and coughing. Response assessment on MRI showed 1 case of partial response, disease stabilization in 11 treatments, and progressive disease in 1 treatment. In 5 of 8 treatment sessions with an initially elevated alpha-fetoprotein, a reduction (range, 19%-90%) was observed 6 wk later., Conclusion: After the intraarterial administration of 3.60 GBq (188)Re-HDD/lipiodol, a fast clearance of the activity appearing in the blood is observed and the predominant elimination is through urinary excretion. The tolerance as well as the preliminary response rates of the present phase I study are encouraging.

Unlabelled: It has been reported that lipiodol solution of (188)Re-labeled 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol (TDD), an N(2)S(2) derivative, shows excellent targeting of liver cancer after transhepatic arterial embolization (TAE). However, its tumor retention is not high enough to treat liver cancer. Therefore, a new form of TDD, 4-hexadecyl-TDD (HDD), was developed to improve tumor retention by introducing a long alkyl chain. In this study, we compared the tumor retention properties of (188)Re-HDD/lipiodol and (188)Re-TDD/lipiodol, using a rabbit liver cancer model, and performed dosimetry using the results., Methods: The VX2 cancer cell line was implanted into the livers of 7 rabbits. TAE was performed on 3 rabbits with (188)Re-TDD/lipiodol and on 4 rabbits with (188)Re-HDD/lipiodol, and conjugated anterior and posterior planar scans were obtained at 1, 2, 6, 24, and 48 h after TAE. From these images, tumor retention was calculated and compared between (188)Re-TDD and (188)Re-HDD. Afterward, the required dose of radioactivity and the radiation dosimetry for exposure of major organs were calculated using MIRDOSE3.1 software., Results: The residence times of radioactivity in the liver were 10.2 +/- 1.0 h in the (188)Re-TDD group and 17.6 +/- 0.8 h in the (188)Re-HDD group (P = 0.034). The required radioactivity for 100 Gy of irradiation to 2.64- to 5.27-cm tumors was 142-1,070 MBq of (188)Re-HDD in the rabbit model. The radiation exposures for the major organs were within the tolerable range, and the S-value for the whole body (effective dose equivalent) was calculated to be 0.209 mSv/MBq., Conclusion: Introduction of a long alkyl chain significantly improved the tumor retention of (188)Re-HDD/lipiodol, compared with that of (188)Re-TDD/lipiodol. Moreover, the required radioactivity for humans and the radiation exposure were within the feasible range for clinical application.

Radioisotope-labelled lipiodol has been used in the therapy of liver cancer. Recently a lipiodol solution of 188Re-labelled diaminedithiol (DD) has been reported to show a high uptake in the liver cancer. We synthesized long-chain alkyl DD derivatives to improve their uptake and retention in tissue. As the length of the alkyl chain increased, tissue uptake and retention also increased due to hydrophobic interaction with lipiodol. Among the synthesized compounds, the lipiodol solution of 188Re-HDD, the DD derivative with the longest side chain (C16), is a promising agent for therapy of liver cancer.

Introduction: The aim of this study was to investigate the potential of using 188Re Lipiodol for selective internal radiation therapy of inoperable hepatocellular carcinoma (HCC)., Clinical Picture: A 33-year-old female with poorly-differentiated multicentric HCC, elevated alpha-fetoprotein (AFP) and increased serum alkaline phosphatase., Treatment: Over a 2-month interval, the patient was treated twice with 4GBq of 188Re-TDD-Lipiodol., Outcomes: There was good localisation of 188Re Lipiodol in the tumours, but also in thyroid (first treatment) and gastrointestinal tract (both treatments). So far (5 months post-treatment), the patient remains well with stable disease., Conclusions: 188Re Lipiodol can be an effective radiopharmaceutical for the treatment of HCC; however, more work must be done to minimise the uptake in bowel.

Radiolabeled lipiodol has been used for targeting liver cancer. We developed a lipiodol solution of (188)Re-TDD (2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol) and investigated its feasibility for the treatment of liver cancer. The lipiodol solution of (188)Re-TDD was well-retained in the lipiodol phase in vitro. After injection through the tail veins of mice, high lung-uptake was investigated which is evidence of embolizing activity. We also found high accumulation in hepatoma after injection through the hepatic arteries of hepatoma-bearing rats. In conclusion, the lipiodol solution of (188)Re-TDD is a promising agent for liver cancer therapy.

Unlabelled: The purpose of this study was to evaluate the frequency and clinical significance of diffuse hepatic uptake on 131I whole-body scan in 399 patients (53 males, 348 females) with well-differentiated adenocarcinomas of the thyroid., Methods: Two hundred and ninety-one diagnostic scans were performed 2 days after the administration of 74-370 MBq (2-10 mCI) 131I, and 824 post-therapy scans were done 3-5 days after the administration of 1.11-7.4 GBq (30-200 mCI) 131I. There was no evidence of liver metastasis in these patients. Liver and thyroid visualization on each 131I scan were graded from 0-4. To evaluate the incorporation of radioiodine to thyroglobulin and thyroid hormones, a patient's serum was extracted by 80% ethanol/20% trichloroacetic acid solution and analyzed by silica gel thin-layer chromatography., Results: Diffuse hepatic uptake (> Grade 2) was definitely seen in 239 of 399 (59.9%) of the patients and 397 of 1115 (35.6%) of the studies. In the diagnostic scans, 36 (12.0%) showed uptake in the liver. In post-therapy scans, however, the incidence of liver uptake increased according to increased doses of 131I (39.1% with 1.11 GBq, 61.5% with 2.775-3.7 GBq and 71.3% with 5.55-7.4 GBq). The more that uptake appeared in the residual thyroid, the more it appeared in the liver. There were 13 patients whose scans showed metastatic and liver uptake without any thyroid uptake. Fifteen patients showed diffuse liver uptake without uptake by the thyroid or metastasis. Follow-up studies of seven of these patients revealed metastatic lesions. Liver uptake on scan related to the fraction of 131I-labeled thyroglobulin in the serum., Conclusion: Diffuse liver uptake indicated functioning thyroid remnant or metastasis. In a few cases, liver uptake without uptake by the thyroid or metastasis on whole-body scans suggests hidden metastases.