|
1
|
Noveiry BB, Hirbod-Mobarakeh A, Khalili N, Hourshad N, Greten TF, Abou-Alfa GK, Rezaei N. Specific immunotherapy in hepatocellular cancer: A systematic review. J Gastroenterol Hepatol 2017; 32:339-351. [PMID: 27206802 PMCID: PMC6377153 DOI: 10.1111/jgh.13449] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/07/2016] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIM In recent years, several novel immunotherapeutic approaches were developed and investigated in patients with hepatocellular carcinoma (HCC). We designed this systematic review, to evaluate clinical efficacy of specific immunotherapy in patients with HCC, according to the guidelines of Border of Immune Tolerance Education and Research Network (BITERN) and Cochrane collaboration. METHODS We searched Medline, Scopus, CENTRAL, TRIP, DART, OpenGrey, and ProQuest through the 9th of December 2015. One author reviewed and retrieved citations from these seven databases for irrelevant and duplicate studies, and two other authors independently extracted data from the studies and rated their quality. We collated study findings and calculated a weighted treatment effect across studies using Review Manager. RESULTS We found 12144 references in seven databases of which 21 controlled studies with 1885 HCC patients in different stages were included in this systematic review after the primary and secondary screenings. Overall, patients undergoing specific immunotherapy had significantly higher overall survival than those in control group (HR = 0.59; 95% CI = 0.47-0.76, P < 0.0001). There was a significant difference in recurrence-free survival between patients undergoing specific immunotherapy and patients in control groups and patients in immunotherapy groups overall had less recurrence than control group (HR = 0.54; 95% CI = 0.46-0.63, P < 0.00001). CONCLUSIONS Results of this systematic review based on the available literature suggest that overall specific immunotherapeutic approaches could be beneficiary for the treatment of patients with HCC. This further supports the current and ongoing evaluations of specific immunotherapies in the field.
Collapse
Affiliation(s)
- Behnoud Baradaran Noveiry
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Armin Hirbod-Mobarakeh
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran,Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran, Iran,Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nastaran Khalili
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niloufar Hourshad
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, USA,Weill Cornell Medical College, New York, USA
| | - Nima Rezaei
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran,Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran, Iran,Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran,Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Sheffield, UK
| |
Collapse
|
|
2
|
Ma J, Wang JH. 131I-Labeled-Metuximab Plus Transarterial Chemoembolization in Combination Therapy for Unresectable Hepatocellular Carcinoma: Results from a Multicenter Phase IV Clinical Study. Asian Pac J Cancer Prev 2016; 16:7441-7. [PMID: 26625741 DOI: 10.7314/apjcp.2015.16.17.7441] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE This study evaluated the safety and objective response of combining 131I-labeled-metuximab (Licartin) with transarterial chemoembolization (TACE) in the treatment of unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS In a multicenter open-label clinical trial, 341 enrolled patients with stage III/IV HCC according to TNM criteria were nonrandomly assigned to a trial group (n=167) and a control group (n=174), undergoing TACE following hepatic intra-arterial injection of licartin or TACE alone from July 2007 to July 2009. Radiopharmaceutical distribution was evaluated. The primary endpoint was overall survival; secondary endpoints included time-to-progression (TTP), toxicity and adverse events (AEs). RESULTS The radiobiological distribution demonstrated better localization of licartin in liver tumors than other tissues (P<0.01). The organ absorbed doses to liver and red marrow were 3.19 ± 1.01 Gy and 0.55 ± 0.22 Gy, respectively. The 1-year survival rate was significantly higher [79.47% vs. 65.59%, hazard ratio (HR), 0.598, P=0.041] and TTP significantly improved (6.82 ± 1.28 vs. 4.7 ± 1.14 months, P=0.037) compared with the control group. Patients at stage III achieved more benefit of one year survival than stage IV in the trial group (86.9% vs. 53.8%, P<0.001). There were significant different toxicities in leukocytopenia, thrombocytopenia and increased total bilirubin level [P<0.001, P=0.013, P<0.01, relative risk (RR) 1.63, 1.33, 1.43], but no differences in severe AEs of upper GI hemorrhage and severe liver dysfunction between the groups (5.39% vs. 2.3%, P=0.136). CONCLUSIONS Owing to excellent tumor-targeting, promised efficacy and favourable toxicity profile, the novel combination therapy of licartin and TACE could be applied in patients with unresectable HCC.
Collapse
Affiliation(s)
- Jun Ma
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China E-mail :
| | | |
Collapse
|
|
3
|
Therapeutic Strategies in HCC: Radiation Modalities. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1295329. [PMID: 27563661 PMCID: PMC4987460 DOI: 10.1155/2016/1295329] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 05/24/2016] [Accepted: 06/05/2016] [Indexed: 12/22/2022]
Abstract
Patients with hepatocellular carcinoma (HCC) comply with an advanced disease and are not eligible for radical therapy. In this distressed scenario new treatment options hold great promise; among them transarterial chemoembolization (TACE) and transarterial metabolic radiotherapy (TAMR) have shown efficacy in terms of both tumor shrinking and survival. External radiation therapy (RTx) by using novel three-dimensional conformal radiotherapy has also been used for HCC patients with encouraging results while its role had been limited in the past for the low tolerance of surrounding healthy liver. The rationale of TAMR derives from the idea of delivering exceptional radiation dose locally to the tumor, with cell killing intent, while preserving normal liver from undue exposition and minimizing systemic irradiation. Since the therapeutic efficacy of TACE is being continuously disputed, the TAMR with 131I Lipiodol or 90Y microspheres has gained consideration providing adequate therapeutic responses regardless of few toxicities. The implementation of novel radioisotopes and technological innovations in the field of RTx constitutes an intriguing field of research with important translational aspects. Moreover, the combination of different therapeutic approaches including chemotherapy offers captivating perspectives. We present the role of the radiation-based therapies in hepatocellular carcinoma patients who are not entitled for radical treatment.
Collapse
|
|
4
|
Zeltsman M, Mayor M, Jones DR, Adusumilli PS. Surgical immune interventions for solid malignancies. Am J Surg 2016; 212:682-690.e5. [PMID: 27659157 DOI: 10.1016/j.amjsurg.2016.06.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 06/17/2016] [Accepted: 06/17/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND The purpose of this study was to systematically review clinically translatable immunotherapeutic agents that are delivered regionally for solid malignancies. DATA SOURCES PubMed and ClinicalTrials.gov were searched for published and registered clinical trials, respectively. The search yielded 334 relevant publications, of which 116 articles were included for review after exclusion criteria were applied. CONCLUSIONS There has been an increase in the regional administration of cell-based and viral vector-based clinical trials over the last 5 years. Surgical interventions have been developed for intrapleural, intracranial, intraperitoneal, and intratumoral routes of access to enhance the local delivery of these therapies. Multimodality therapies that combine regional immunotherapy with other local and systemic therapies are demonstrating continued growth as the field of immunotherapy continues to expand.
Collapse
Affiliation(s)
- Masha Zeltsman
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, USA
| | - Marissa Mayor
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, USA
| | - David R Jones
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, USA
| | - Prasad S Adusumilli
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, USA.
| |
Collapse
|
|
5
|
Carrasquillo JA, Pandit-Taskar N, O'Donoghue JA, Humm JL, Zanzonico P, Smith-Jones PM, Divgi CR, Pryma DA, Ruan S, Kemeny NE, Fong Y, Wong D, Jaggi JS, Scheinberg DA, Gonen M, Panageas KS, Ritter G, Jungbluth AA, Old LJ, Larson SM. (124)I-huA33 antibody PET of colorectal cancer. J Nucl Med 2011; 52:1173-80. [PMID: 21764796 DOI: 10.2967/jnumed.110.086165] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate (124)I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of (124)I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when (124)I-huA33 was given via hepatic arterial infusion (HAI). METHODS We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4-396 MBq) and 10 mg of (124)I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG. RESULTS Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8-22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human-antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33. CONCLUSION Good localization of (124)I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived (124)I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of (124)I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.
Collapse
Affiliation(s)
- Jorge A Carrasquillo
- Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
6
|
Qiu-Jie S, Zhi-Yu H, Xiao-Xia N, Wen-Yuan S, Yuan-Yuan S, Liu H, Xin L, Ping L. Feasible temperature of percutaneous microwave ablation of dog liver abutting the bowel. Int J Hyperthermia 2011; 27:124-31. [PMID: 21204623 DOI: 10.3109/02656736.2010.508763] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
PURPOSE This study used a dog model to determine the optimal temperature of percutaneous microwave ablation that causes complete necrosis of liver but not the adjacent bowel, supporting the use of this method to specifically and effectively treat liver tumour abutting the bowel. MATERIALS AND METHODS Ultrasound-guided percutaneous microwave ablation of liver abutting the bowel was performed on healthy adult dogs. Temperature of the ablation margin was monitored and controlled through inserted thermal monitoring needles. Dogs were divided into three groups and received microwave ablation at 75-95°C, 65-75°C, or 55-65°C. Imaging and histological examination were used to evaluate the damage of the bowel adjacent to the ablated liver. RESULTS Within one hour of treatment, the bowel adjacent to the ablated liver was seriously burned in the group receiving 75-95°C microwave ablation. Inflammation and congestion were found in the submucosa of the bowel in the group receiving 65-75°C microwave ablation. Minor inflammation was found in the mucosa of the bowel in the group receiving 55-65°C microwave ablation. Moreover, in the group receiving 55-65°C microwave ablation, ablated liver areas were covered with omenta, and histological examination revealed inflammatory reaction of the omenta 28 days after ablation. CONCLUSIONS Microwave ablation at 55-65°C for 6 min is preferred for ablation of liver tissue abutting the bowel in dogs. These findings may provide some valuable reference for percutaneous microwave ablation of human liver tumour adjacent to the bowel.
Collapse
Affiliation(s)
- Shao Qiu-Jie
- Department of Interventional Ultrasound, General Hospital of PLA, Beijing
| | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Garin E, Bourguet P. Intra-arterial Therapy of Liver Tumours. Clin Nucl Med 2008. [DOI: 10.1007/978-3-540-28026-2_27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
8
|
Cormier JN, Thomas KT, Chari RS, Pinson CW. Management of hepatocellular carcinoma. J Gastrointest Surg 2006; 10:761-80. [PMID: 16713550 DOI: 10.1016/j.gassur.2005.10.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2005] [Accepted: 10/03/2005] [Indexed: 01/31/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors globally, with varying prevalence based on endemic risk factors. In high-risk populations, including those with hepatitis B or C or with cirrhosis, serum alpha-fetoprotein (AFP) and screening ultrasound have improved detection of resectable HCC. Treatment options, including surgical resection, for patients with HCC must be selected based on the number and size of hepatic tumors, underlying hepatic function, patient condition, and available resources. An approach, which has been summarized shows the corresponding treatment choices under given clinical circumstances. For cirrhotic patients with less than three tumor nodules of a size less than 3 cm or a solitary HCC less than 5 cm, liver transplantation offers long-term survival similar to that observed in patients transplanted for nonmalignant disease. Ablative treatment using either chemical or thermal techniques provides locally effective tumor destruction. Transcatheter arterial chemoembolization (TACE) is commonly used for palliation of unresectable tumors as well as an adjunct to surgical resection, treatment of tumors before transplant, and in conjunction with other ablative therapies in a multimodality approach. Regional approaches to chemotherapy have produced more encouraging results than systemic chemotherapy, although both remain ineffective for long-term tumor control. Several newer treatment modalities are under investigation, including gene therapy, tagged antibodies, isolated perfusion, and novel radiotherapy techniques.
Collapse
Affiliation(s)
- Janice N Cormier
- Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-4753, USA
| | | | | | | |
Collapse
|
|
9
|
Lambert B, Van de Wiele C. Treatment of hepatocellular carcinoma by means of radiopharmaceuticals. Eur J Nucl Med Mol Imaging 2005; 32:980-9. [PMID: 16032439 DOI: 10.1007/s00259-005-1859-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Several techniques have been developed for radionuclide therapy of hepatocellular carcinoma (HCC). Medical literature databases (Pubmed, Medline) were screened for available literature and articles were critically analysed as to their scientific relevance. In a palliative setting, intra-arterial administration of 131I-Lipiodol yields responses in 17-92% of patients. According to a randomised study, 131I-Lipiodol was far better tolerated than classic chemo-embolisation. The additive value of a single 131I-Lipiodol administration following partial liver resection for HCC was evaluated and evidence is available that adjuvant radionuclide treatment reduces the recurrence rate. Data concerning the role of 131I-Lipiodol in bridging patient to liver transplantation are scarce but suggest a potential benefit in terms of reducing the drop-out rate while patients are listed for transplantation. 188Re- and 90Y-labelled conjugates are emerging and initial clinical data are promising. Treatment of HCC with 90Y-labelled microspheres is likely as efficacious as treatment with radiolabelled Lipiodol but pretreatment 99mTc-MAA scintigraphy is required in order to exclude patients with significant lung shunting. Several antibodies targeting antigens expressed on HCC have been radiolabelled, almost exclusively with 131I, and evaluated in a preclinical or clinical setting. The use of radiolabelled Lipiodol and microspheres allows for selective targeting of HCC with limited toxicity. Prospective, randomised controlled trials demonstrating that both treatment modalities may provide a survival benefit in a palliative setting are mandatory. In addition, future research should focus on the complementary role of radionuclide treatment in patients at risk for recurrent disease following partial liver resection or while awaiting liver transplantation.
Collapse
Affiliation(s)
- Bieke Lambert
- Nuclear Medicine Division, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium
| | | |
Collapse
|
|
10
|
Chen S, Li B, Xie H, Xu L, Niu G, Fan K, Fan Q. Phase I clinical trial of targeted therapy using 131I-Hepama-1 mAb in patients with hepatocellular carcinoma. Cancer Biother Radiopharm 2005; 19:589-600. [PMID: 15650451 DOI: 10.1089/cbr.2004.19.589] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES The aim of this study was to evaluate the response- and treatment-related toxicity for patients with unresectable hepatocellular carcinoma (HCC) treated with 131I-Hepama-1 mAb (DGDK-1). MATERIALS AND METHODS Seeking approval for the use of 131I-hepama-1 mAb, 32 patients with unresectable HCC were divided into 5 groups to take part in the Phase I clinical trial study. Systemic reactions and acute toxicity were evaluated weekly for at least 45 days following treatment with an intravenous injection of 10 mg of antibody radiolabeled with 740-3700 MBq (20-100 mCi), divided into 5 groups. RESULTS No patients demonstrated any evidence of fever, severe side effects, or impairments of important organs, such as the lung, liver, and heart. During, and for 45 days after, the treatment, most of their routine examinations of blood, functions of liver and kidneys, and the thyroid hormone were all normal. Hypothyroidism was not observed during the course of monitoring. None of the 32 patients developed human antimurine antibodies (HAMA) within 15 days of therapy; however, 82% of patients were HAMA-positive by 45 days of therapy. According to the pilot study of prognosis, survival from the start of radioimmunotherapy (RIT) was a median of 4 months, and the 1-year survival rate was 31%. The median survival time of 15 patients without metastases was 10 months, and the 1-year survival rate was 60%. Of alpha-fetoprotein (AFP)-positive patients, 75% of AFP levels decreased by at least 50% or became normal. Of all patients, 84% showed an improved Eastern Cooperative Oncology Group (ECOG) performance status. CONCLUSION This phase I clinical trial demonstrated that it was safe to use 131I-hepama- 1 mAb by peripheral intravenous administration. The recommended dose of DGDK-1 for clinical use is 1480-2960 MBq/10 mg.
Collapse
Affiliation(s)
- Shaoliang Chen
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
| | | | | | | | | | | | | |
Collapse
|
|
11
|
|
|
12
|
Deng XD, Shen YZ, Huang M, Yan Y, Sun Q. Contrast-enhanced Doppler Ultrasound for Guiding Percutaneous Microwave Ablation of Hepatocellular Carcinoma: A Report of 32 Cases. J Med Ultrasound 2004. [DOI: 10.1016/s0929-6441(09)60068-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
|
|
13
|
Xu HX, Yin XY, Lu MD, Liu GJ, Xu ZF. Estimation of liver tumor volume using a three-dimensional ultrasound volumetric system. ULTRASOUND IN MEDICINE & BIOLOGY 2003; 29:839-846. [PMID: 12837499 DOI: 10.1016/s0301-5629(02)00775-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
The usefulness of a new three-dimensional ultrasound (3DUS) volumetric system developed recently was validated in volume measurement of liver tumor in the present study. The system was used to estimate the volumes of 22 regular phantoms, 25 irregular phantoms and 37 liver tumors from 33 patients. The results showed that the consumed time of measurement with the system ranged from 1 to 15 min, depending on different rotation angles. The measured volumes at different rotation angles all significantly correlated with the true volumes and there were no significant differences among measured volumes at different angles. The measurement error of 3DUS was 0.3% +/- 3.3% in regular phantoms, -0.4% +/- 3.7% in irregular phantoms and 0.9% +/- 11.3% in liver tumors, respectively, as compared with -5.3 +/- 9.4%, 13.6 +/- 28.0% and 15.3 +/- 37.3% for two-dimensional ultrasound, respectively (all p < 0.05). The volume estimation with 3DUS also had significant intraobserver and interobserver reproducibility both in vitro and in vivo. It can be concluded that the new system that we used can greatly reduce the consumed time and manual labor for volume measurement with high accuracy and reproducibility. 3DUS volumetry using the new system is more acceptable and valuable in clinical practice and is expected to be useful for evaluation of the efficacy of tumor therapy in situ in patients with hepatic tumors.
Collapse
Affiliation(s)
- Hui-Xiong Xu
- Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | | | | | | | | |
Collapse
|
|
14
|
Myers KA, Ryan MG, Stern PL, Shaw DM, Embleton MJ, Kingsman SM, Carroll MW. Targeting immune effector molecules to human tumor cells through genetic delivery of 5T4-specific scFv fusion proteins. Cancer Gene Ther 2002; 9:884-96. [PMID: 12386827 DOI: 10.1038/sj.cgt.7700513] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2002] [Indexed: 11/09/2022]
Abstract
Although several clinical trials have shown beneficial effects by targeting tumor-associated antigens (TAAs) with monoclonal antibodies, a number of issues, including poor penetration of the tumor mass and human antimouse antibody responses, remain. The use of recombinant single-chain Fv (scFv) fragments has the potential to address these and other issues while allowing the addition of different effector functions. To develop therapeutic strategies that recruit both humoral and cellular arms of the immune response, we have constructed chimeric proteins linking either the human IgG1 Fc domain or the extracellular domain of murine B7.1 to a scFv specific for the oncofetal glycoprotein, 5T4. This TAA is expressed by a wide variety of carcinomas and is associated with metastasis and poorer clinical outcome. We have engineered retroviral constructs that produce fusion proteins able to interact simultaneously with both 5T4-positive cells and with the receptor/ligands of the immune effector moieties. Genetic delivery through a murine leukemia virus vector to 5T4-positive tumor cells results in the secreted scFv fusion protein binding to the cell surface. Furthermore, the scFv-HIgG1 fusion protein is able to direct lysis of 5T4-expressing human tumor cell lines through antibody-dependent cell cytotoxicity, indicating its potential as a gene therapy for human cancers.
Collapse
Affiliation(s)
- Kevin A Myers
- Oxford BioMedica (UK) Ltd., Medawar Centre, Oxford Science Park, UK
| | | | | | | | | | | | | |
Collapse
|
|
15
|
Zeng ZC, Jiang GL, Wang GM, Tang ZY, Curran WJ, Iliakis G. DNA-PKcs subunits in radiosensitization by hyperthermia on hepatocellular carcinoma hepG2 cell line. World J Gastroenterol 2002; 8:797-803. [PMID: 12378618 PMCID: PMC4656564 DOI: 10.3748/wjg.v8.i5.797] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of DNA-PKcs subunits in radiosensitization by hyperthermia on hepatocellular carcinoma HepG2 cell lines.
METHODS: HepG2 cells were exposed to hyperthermia and irradiation. Hyperthermia was given at 45.5 °C. Cell survival was determined by an in vitro clonogenic assay for the cells treated with or without hyperthermia at various time points. DNA DSB rejoining was measured using asymmetric field inversion gel electrophoresis (AFIGE). The DNA-PKcs activities were measured using DNA-PKcs enzyme assay system.
RESULTS: Hyperthermia can significantly enhance irradiation-killing cells. Thermal enhancement ratio as calculated at 10% survival was 2.02. The difference in radiosensitivity between two treatment modes manifested as a difference in the α components and the almost same β components, which α value was considerably higher in the cells of combined radiation and hyperthermia as compared with irradiating cells (1.07 Gy-1vs 0.44 Gy-1). Survival fraction showed 1 logarithm increase after an 8-hour interval between heat and irradiation, whereas DNA-PKcs activity did not show any recovery. The cells were exposed to heat 5 min only, DNA-PKcs activity was inhibited at the nadir, even though the exposure time was lengthened. Whereas the ability of DNA DSB rejoining was inhibited with the increase of the length of hyperthermic time. The repair kinetics of DNA DSB rejoining after treatment with Wortmannin is different from the hyperthermic group due to the striking high slow rejoining component.
CONCLUSION: Determination with the cell extracts and the peptide phosphorylation assay, DNA-PKcs activity was inactivated by heat treatment at 45.5 °C, and could not restore. Cell survival is not associated with the DNA-PKcs inactivity after heat. DNA-PKcs is not a unique factor affecting the DNA DSB repair. This suggests that DNA-PKcs do not play a crucial role in the enhancement of cellular radiosensitivity by hyperthermia.
Collapse
Affiliation(s)
- Zhao-Chong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | | | | | | | | | | |
Collapse
|
|
16
|
Lu MD, Chen JW, Xie XY, Liu L, Huang XQ, Liang LJ, Huang JF. Hepatocellular carcinoma: US-guided percutaneous microwave coagulation therapy. Radiology 2001; 221:167-72. [PMID: 11568335 DOI: 10.1148/radiol.2211001783] [Citation(s) in RCA: 160] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE To evaluate the use of percutaneous microwave coagulation therapy for hepatocellular carcinoma, particularly with tumor nodules larger than 2 cm in diameter. MATERIALS AND METHODS Fifty patients with 107 hepatocellular carcinoma nodules (mean diameter, 2.7 cm +/- 1.5 [SD]; range, 0.8-6.4 cm) were treated with percutaneous microwave coagulation therapy. Single electrode insertion was used in 46 nodules (43.0%) 2 cm or smaller, whereas multiple electrode insertion was applied in 61 (57.0%) nodules larger than 2 cm. RESULTS At 1 month after therapy, technical success for tumors 2 cm or smaller and those larger than 2 cm was achieved in 45 (98%) and 56 (92%) nodules, respectively. After follow-up of 9 months or longer, local recurrence was found in one nodule (2%) sized 1.8 cm and in five nodules (8%) larger than 2 cm. At the end of the study, 26 (52%) of 50 patients were free of disease, and disease-free survival rates at 1 and 2 years were 55% and 41%, respectively. Overall survival rates at 1, 2, and 3 years were 96%, 83%, and 73%, respectively. CONCLUSION Percutaneous microwave coagulation therapy is an effective and safe therapeutic modality for hepatocellular carcinoma. A multiple electrode insertion technique can enhance the effectiveness of this therapy in tumors 6 cm or smaller.
Collapse
Affiliation(s)
- M D Lu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Sun Yat-sen University of Medical Sciences, 2 Zhongshan Rd, Guangzhou, People's Republic of China.
| | | | | | | | | | | | | |
Collapse
|
|
17
|
Tang ZY. Hepatocellular carcinoma--cause, treatment and metastasis. World J Gastroenterol 2001; 7:445-54. [PMID: 11819809 PMCID: PMC4688653 DOI: 10.3748/wjg.v7.i4.445] [Citation(s) in RCA: 302] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2001] [Revised: 07/20/2001] [Accepted: 07/27/2001] [Indexed: 02/06/2023] Open
Abstract
In the recent decades, the incidence of hepatocellular carcinoma (HCC) has been found to be increasing in males in some countries. In China, HCC ranked second of cancer mortality since 1990s. Hepatitis B and C viruses (HBV and HCV) and dietary aflatoxin intake remain the major causative factors of HCC. Surgery plays a major role in the treatment of HCC, particularly for small HCC. Down-staging unresectable huge HCC to smaller HCC and followed by resection will probably be a new approach for further study. Liver transplantation is indicated for small HCC, however, some issues remain to be solved. Different modes of regional cancer therapy for HCC have been tried. Systemic chemotherapy has been disappointing in the past but the future can be promising. Biotherapy, such as cytokines, differentiation inducers, anti-angiogenic agents, gene therapy and tumor vaccine will probably play a role, particularly in the prevention of tumor recurrence. HCC invasiveness is currently the major target of study. Tremendous works have been done at the molecular level, which will provide clues for biomarker of HCC progression as well as targets for intervention.
Collapse
Affiliation(s)
- Z Y Tang
- Liver Cancer Institute of Fudan University, 136 Yixueyuan Road, Zhongshan Hospital, Shanghai 200032, China.
| |
Collapse
|
|
18
|
Dawson LA, McGinn CJ, Normolle D, Ten Haken RK, Walker S, Ensminger W, Lawrence TS. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol 2000; 18:2210-8. [PMID: 10829040 DOI: 10.1200/jco.2000.18.11.2210] [Citation(s) in RCA: 320] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE To evaluate the response, time to progression, survival, and impact of radiation (RT) dose on survival in patients with intrahepatic malignancies treated on a phase I trial of escalated focal liver RT. PATIENTS AND METHODS From April 1996 to January 1998, 43 patients with unresectable intrahepatic hepatobiliary cancer (HB; 27 patients) and colorectal liver metastases (LM; 16 patients) were treated with high-dose conformal RT. The median tumor size was 10 x 10 x 8 cm. The median RT dose was 58.5 Gy (range, 28.5 to 90 Gy), 1.5 Gy twice daily, with concurrent continuous-infusion hepatic arterial fluorodeoxyuridine (0.2 mg/kg/d) during the first 4 weeks of RT. RESULTS The response rate in 25 assessable patients was 68% (16 partial and one complete response). With a median potential follow-up period of 26.5 months, the median times to progression for all tumors, LM, and HB were 6, 8, and 3 months, respectively. The median survival times of all patients, patients with LM, and patients with HB were 16, 18, and 11 months, respectively. On multivariate analyses, escalated RT dose was independently associated with improved progression-free and overall survival. The median survival of patients treated with 70 Gy or more has not yet been reached (16.4+ months), compared with 11.6 months in patients treated with lower RT doses (P =.0003). CONCLUSION The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies.
Collapse
Affiliation(s)
- L A Dawson
- Departments of Radiation Oncology, Internal Medicine, and Pharmacology, University of Michigan, Ann Arbor 48109-0010, USA.
| | | | | | | | | | | | | |
Collapse
|