Liver-directed therapies for liver metastases from neuroendocrine neoplasms:Can laser ablation play any role?

Aggressive cytoreduction can prolong survival in patients with unresectable liver metastases(LM)from neuroendocrine neoplasms(NEN),and minimally invasive,liver-directed therapies are gaining increasing interest.Catheter-based treatments are used in disseminated disease,whereas ablation techniques are usually indicated when the number of LM is limited.Although radiofrequency ablation(RFA)is by far the most used ablative technique,the goal of this opinion review is to explore the potential role of laser ablation(LA)in the treatment of LM from NEN.LA uses thinner needles than RFA,and this is an advantage when the tumors are in at-risk locations.Moreover,the multi-fiber technique enables the use of one to four laser fibers at once,and each fiber provides an almost spherical thermal lesion of 12-15 mm in diameter.Such a characteristic enables to tailor the size of each thermal lesion to the size of each tumor,sparing the liver parenchyma more than any other liver-directed therapy,and allowing for repeated treatments with low risk of liver failure.A recent retrospective study reporting the largest series of LM treated with LA documents both safety and effectiveness of LA,that can play a useful role in the multimodality approach to LM from NEN.

Prevention of metastasis to liver by using 5-FU intraperitoneal chemotherapy in nude mice inoculated with human colonic cancer cells

AIMS Using a new approach of regional adjuvant chemotherapy to prevent cancer cells hepatic metasta- sis after radical surgery of large bowel cancer. METHODS A model of liver with metastasis of hu- man colonic cancer (HCC) cells in nude mice was used to observe the effect in prevention of metastasis of HCC cells inoculated via spleen applied with early postoper- ative intraperitoneal (IP) chemotherapy using large dose of 5-FU. RESULTS The incidence of metastasis to liver was decreased by 40%,the mean number of metastatic liv- er nodules in each animal was reduced by 50.89% and the mean survival times of each animal was prolonged by 48.21% by using 5-FU 40 mg/NS 40 ml/kg IP for two consecutive days as compared with the controls. CONCLUSIONS IP is a new and more effective re- gional adjuvant chemotheraputic approach in the pre- vention of liver metastasis HCC cells after radical surgery of large bowel cancer.

The value of postoperative hepatic regional chemotherapy in prevention of recurrence after radical resection of primary liver cancer

INTRODUCTIONIn China,primary liver cancer (PLC) ranks secondin cancer mortality since the 1990s.In the field ofPLC treatment,surgical resection remains the best,which includes large PLC resection,small PLCresection,re-resection of subclinical recurrence,aswell as cytoreduction and sequential resection forunresectable PLC.However,recurrence

Targeted IL-24 gene therapy inhibits cancer recurrence after liver tumor resection by inducing tumor cell apoptosis in nude mice

BACKGROUND: Interleukin-24 (IL-24) is a novel candidate tumor suppressor that induces tumor cell apoptosis experimentally in a variety of human malignant cells including liver cancer cells. The present study was conducted to investigate the potential effect of recombinant adeno-associated virus (rAAV)-mediated IL-24 gene therapy on tumor recurrence and metastasis by inducing tumor cell apoptosis in a hepatocellular carcinoma (HCC) model in nude mice. METHODS: We established a recurrent and metastatic HCC model in nude mice and constructed an rAAV vector carrying alpha-fetoprotein (AFP) promoter for expressing the IL-24 gene (rAVV/AFP/IL-24). The vector was administered by regional injection (liver incisal margin). AFP was detected by radiation immunoassay. Histological evaluation of tumor recurrence and metastasis was performed for the liver and lung. The effect of tumor cell apoptosis was confirmed by TUNEL analysis. RESULTS: IL-24 gene therapy prevented tumor recurrence and metastasis, as evidenced by marked decreases in the number of metastatic tumor nodules and tumor volume in the liver and lung. At the same time, serum AFP concentration decreased markedly in the IL-24 group compared with the control or rAAV groups (P<0.05). IL-24 gene therapy inhibited tumor recurrence and metastasis as evidenced by the induction of tumor cell apoptosis. CONCLUSION: The results demonstrated that targeted IL-24 gene therapy was effective in the prevention of postoperative recurrence and metastasis in an HCC nude mice model by induction of tumor cells apoptosis with potential minimum tumor burden.

Double-bullet radioimmunotargeting therapy in 31 patients with primary liver cancer

AIM To observe the effect of a double bullet immunotargeting therapy with the merit of chemotherapy and internal radiotherapy for primary liver cancer. METHODS The polyclonal horse antibody against human AFP (anti AFPAb) and the monoclonal murine antibody against human AFP (anti AFPMcAb) were used as carriers, and 131 I and mitomycin C (MMC) as warheads, to form double bullet, ie, 131 I anti AFPMcAb MMC (double bullet 1) and 131 I anti AFPAb MMC (double bullet 2) prepared by the modified chloramine T method. The double bullet targeting therapy was administered by intravenous drip once a month in 31 patients (treatment group) with unresectable primary liver cancer. Among them 4, 17 and 10 patients were administered 1, 2 and 3 times, and the median value of radiation dose (MBq/case) were 193 5±37 74; 651 9±232 4, and 992 0±230 5 respectively. RESULTS The shrinkage of tumor, AFP decrease and 1 and 2 year survival rates were significantly higher than those of the control groups of transarterial infusion (TAI) or transarterial chemoembolization (TACE) at the same time (50 0%, 15/30 vs 30 0%, 9/30, P <0 05; 66 7%, 18/27 vs 28 0%, 7/25, P <0 01 and 50 0%, 34 0% vs 33 0%, 3 3%, P <0 01, respectively). Furthermore, the tumor progression rate (10%) in treatment group was significantly lower than that of control group (40 0%, P <0 01). CONCLUSION Double bullet target therapy has a better effect due to the synergistic effects of antibody, radioisotope, and anticancer agents, thus enhancing the tumor killing effect.

Adeno-associated virus mediated endostatin gene therapy in combination with topoisomerase inhibitor effectively controls liver tumor in mouse model

AIM:rAAV mediated endostatin gene therapy has been examined as a new method for treating cancer.However, a sustained and high protein delivery is required to achieve the desired therapeutic effects.We evaluated the impact of topoisomerase inhibitors in rAAV delivered endostatin gene therapy in a liver tumor model. METHODS:rAAV containing endostatin expression cassettes were transduced into hepatoma cell lines.To test whether the topoisomerase inhibitor pretreatment increased the expression of endostatin,Western blotting and ELISA were performed.The biologic activity of endostatin was confirmed by endothelial cell proliferation and tube formation assays. The anti-tumor effects of the rAAV-endostatin vector combined with a topoisomerase inhibitor,etoposide,were evaluated in a mouse liver tumor model. RESULTS:Topoisomerase inhibitors,including camptothecin and etoposide,were found to increase the endostatin exPression level in vitro.The over-expressed endostatin, as a result of pretreatment with a topoisomerase inhibitor, was also biologically active.In animal experiments,the combined therapy of topoisomerase inhibitor,etoposide with the rAAV-endostatin vector had the best tumor- suppressive effect and tumor foci were barely observed in livers of the treated mice.Pretreatment with an etoposide increased the level of endostatin in the liver and serum of rAAV-endostatin treated mice.Finally,the mice treated With rAAV-endostatin in combination with etoposide showed the longest survival among the experimental models. CONCLUSION:rAAV delivered endostatin gene therapy in combination with a topoisomerase inhibitor pretreatment is an effective modality for anticancer gene therapy.

Comprehensive treatment of advanced primary live cancer with intraperitoneal chemotherapy or in combination with other therapies:therapeutic observation of 72 cases

Objective： To evaluate the effect of intraperitoneal chemotherapy or in combination with other therapies in patients with advanced primary liver cancer. Methods： 72 patients with advanced primary liver cancer with no indication for surgery received intraperitoneal chemotherapy in combination with other therapies including transcatheter arterial chemoembolization （TACE）, radiofrequency catheter ablation （RFA）, percutaneous ethanol injection therapy （PELT） and radiotherapy. Of them, 29 cases were complicated with hilar or retroperitoneal multiple lymph node metastases, 14 with portal vein embolus, 15 with intrapedtoneal and diaphragmatic metastases, 6 with chylous ascites, one with cancerous ascites, and 7 with suspected cancerous ascites （referring to large amounts of ascites without hypoproteinemia while exfoliative cytology of the ascites was positive）. The mean maximum tumor size was 8.2 cm in diameter. Liver function at the initial treatment was Child A in 53 cases, and Child B in 19 cases. I ntrapedtoneal chemotherapy was performed in all these patients. The intraperitoneal chemotherapy protocols included： 5-FU 0.5-0.75 g/d for 10-15 consecutive days, with a total dosage of 5-12.5 g, and at the last day of chemotherapy 10 mg mitomycin （MMC） or 100 mg carboplatin was injected. For 7 cases of cholangiocarcinoma, Gemzar 800-1000 mg was administered additionally. A majority of all these patients received another one or two therapy methods followed by intraperitoneal chemotherapy. TACE was performed in the patients with multiple tumors or nodule more than 5 cm in diameter in the liver, RFA or PElT with nodule fewer than 4 in number and 5 cm or less than 5 cm in diameter and radiotherapy, only for metastases, with metastatic lymph nodes, localized metastasis within the abdominal cavity or portal vein embolus. Interval time between two methods was one month or so. Two months after the sequential therapy, repeated treatment would be given if general medical condition and liver function were perfect at that time. Results： The median survival time of the group was 13.97 ± 6.27 months. The 1- and 2-year survival rates were 59.7% and 30.6% respectively. The mean survival time of the patients with liver function Child A was 15.91 ± 5.49 months, and that of the patients with Child B was 8.55 ± 5.09 months. The difference was statistically significant （P 〈 0.05）. Conclusion： Intraperitoneal chemotherapy or in combination with other therapies in patients with advanced primary liver cancer with metastases to abdominal cavity is an effective method. It can prolong the survival time and improve life quality for a certain percentage of patients with advanced pnmary liver cancer.

A comparative study of different interventional therapies for primary liver cancer

IM To compare the therapeutic effect of three types of interventional management for pimary liver cancer.METHODS 468 patients with primary liver cancer were randomly allocated to three groups: 138 cases with chemotherapy alone using mitomycin C, adriamycin and 5FU (group A); 158 with chemoembolization using lipiodol (group B); and 172 with chemoembolization using lipiodol and gelfoam (group C). All patients were angiographically and sonographically followed up.RESULTS ① 675% patients in group C had the AFP value decreased by more than 50%, which was much higher than 433% ingroup B and 322% in group A; ② The tumor size reduced by ≥50% in 203% of group A, 412% of group B and 448% of group C. There was obvious difference between groups A and group B or C (P<001); ③ The oneyear and threeyear survival rates were 205%±36% and 19%±24% for group A, 513%±44% and 101%±49% for group B, and 630%±24% and 139%±50% for group C respectively. There was obvious difference among the three groups (P<005); ④ The mean survival time for patients in groups A, B and C were 96 months, 161 months and 179 months, respectively.CONCLUSION Chemoembolization with lipiodol and gelfoam is the most effective therapy for primary liver cancer in this study. The position of the embolization should be the far and middle sections of the hepatic artery, and the proximal section should be reserved as the route of the next intraarterial chemoembolization.

Application of interventional therapy via hepatic artery in pancreatic neuroendocrine neoplasms liver metastases

Pancreatic neuroendocrine neoplasm(PNEN)is the second most common malignant tumor of the pancreas.It has the characteristic of high metastases rate,and the liver is the most common site for metastasis.Metastasis affects prognosis and survival seriously.A number of earlier studies have shown that the interventional therapy via hepatic artery could reduce hepatic tumor burden and hormone secretion safely and rapidly,significantly improve objective response rate(ORR),and enhance the efficacy and prolong the survival time when combined with system therapy.The interventional therapy via hepatic artery plays an important role in the treatment of PNEN liver metastases.Interventional therapy via hepatic artery could possibly increase ORR,prolong progression-free survival,and even overall survival for appropriate patients.

Clinical observation of 125 I labeled anti alpha fetoprotein antibody radioimmunotherapy in hepatocellular carcinoma *

AIM To observe the therapeutic effects and toxic side reactions of 125 I labeled hourse anti human AFP polyclonal antibodies in immuno targeting therapy against hepatocellular carcinoma (HCC).

Progress in research of liver surgery in China

INTRODUCTIONLiver surgery,was started in the late 1950s in Chinaand has developed rapidly in the past 40 years.The study on the diagnosis and treatment of primaryliver cancer in China underwent four stages:①Inthe 1950s,the anatomical study of the liver lay asolid foundation for liver resection.①In

Clinical research advances in primary liver cancer

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Combined therapy with transcatheter arterial chemoembolization and percutaneous microwave coagulation for small hepatocellular carcinoma

AIM:To assess the efficacy of combined transcatheter arterial chemoembolization(TACE)and percutaneous microwave coagulation therapy(PMCT)for small hepatocellular carcinoma(HCC). METHODS:Thirty-five patients with a total of 41 HCC nodules(≤3 cm in diameter)were treated with TACE followed by computed tomograghy(CT)-guided percutaneous microwave coagulation therapy(PMCT) within 1-3 wk. RESULTS:By biopsies and enhanced CT scans, complete necrosis of the tumor and 3-5 mm of the surrounding non-cancerous area were observed in 34 foci.In seven foci,incomplete necrosis of the surrounding parenchyma was observed.Serum alpha- fetoprotein(AFP)levels returned to normal 10 d after treatment in 25 patients who originally had high serum AFP levels.The follow-up period was 6-31 mo,and all patients remained alive.One patient had a recurrence in the subsegments of the liver,and another patient had a recurrence near the original lesion. CONCLUSION:Combined therapy with TACE and PMCT is a safe and effective treatment without severe complications for small HCC.

Liver transplantation for hepatocellular carcinoma:an update

BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment. DATA SOURCES: PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles. RESULTS: Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease. CONCLUSIONS: Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate biomarkers of tumor biology.

Liver-first approach of colorectal cancer with synchronous hepatic metastases: A reverse strategy

Recently, there has been a change in the strategy of how synchronous colorectal hepatic metastases are attributed to the development of more valuable protocols of chemotherapy and radiotherapy for neoadjuvant treatment of colorectal neoplasms and their hepatic metastases. There is a consensus that patients with synchronous colorectal hepatic metastases have lower survival than those with metachronous colorectal hepatic metastases. Currently, controversy remains concerning the best approach is sequence in a patient with colorectal cancer and synchronous hepatic metastases resection. To obtain a better patient selection, the authors have suggested the initial realization of systemic chemotherapy in the circumstance of patients with colorectal tumor stage Ⅳ, since these patients have a systemic disease. The rationale behind this liver-first strategy is initially the control of synchronous hepatic metastases of colorectal carcinoma, which can optimize a potentially curative hepatic resection and longstanding survival. The liver-first strategy procedure is indicated for patients with colorectal hepatic metastases who require downstaging therapy to make a curative liver resection possible. Thus, the liver-first strategy is considered an option in cases of rectal carcinoma in the early stage and with limited or advanced synchronous colorectal hepatic metastases or in case of patients with asymptomatic colorectal carcinoma, but with extensive liver metastases. Patients undergoing systemic chemotherapy and with progression of neoplastic disease should not undergo hepatic resection, because it does not change the prognosis and may even make it worse. To date, there have been no randomized controlled trials on surgical approach of colorectal synchronous hepatic metastases, despite the relatively high number of available manuscripts on this subject. All of these published studies are observational, usually retrospective, and often non-comparative. The patient selection criteria for the liver-first strategy should be individualized, and the approach of these patients should be performed by a multidisciplinary team so its benefits will be fully realized.

Reduction of tumorigenicity of SMMC-7721 hepatoma cells by vascular endothelial growth factor antisense gene therapy

AIM: To test the hypothesis to block VEGF expression of SMMC-7721 hepatoma cells may inhibit tumor growth using the rat hepatoma model. METHODS: Amplify the 200 VEGF cDNA fragment and insert it into human U6 gene cassette in the reverse orientation transcribing small antisense RNA which could specifically interact with VEGF165, and VEGF121 mRNA. Construct the retroviral vector containing this antisense VEGF U6 cassette and package the replication-deficient recombinant retrovirus. SMMC-7721 cells were transduced with these virus and positive clones were selected with G418. PCR and Southern blot analysis were performed to determine if U6 cassette integrated into the genomic DNA of positive clone. Transfected tumor cells were evaluated for RNA expression by ribonuclease protection assays. The VEGF protein in the supernatant of parental tumor cells and genetically modified tumor cells was determined with ELISA. In vitro and in vivo growth properties of antisense VEGF cell clone in nude mice were analyzed. RESULTS: Restriction enzyme digestion and PCR sequencing verified that the antisense VEGF RNA retroviral vector was successfully constructed.After G418 selection, resistant SMMC-7721 cell clone was picked up. PCR and Southern blot analysis suggested that U6 cassette was integrated into the cell genomic DNA. Stable SMMC-7721 cell clone transduced with U6 antisense RNA cassette could express 200 bp small antisense VEGF RNA and secrete reduced levels of VEGF in culture condition. Production of VEGF by antisense transgene-expressing cells was 65+/-10 ng/L per 10(6) cells, 42045 ng/L per 10(6) cells in sense group and 485+/-30 ng/L per 10(6) cells in the negative control group, (P【 0.05). The antisense-VEGF cell clone appeared phenotypically indistinguishable from SMMC-7721 cells and SMMC-7721 cells transfected sense VEGF. The growth rate of the antisense-VEGF cell clone was the same as the control cells. When S.C. was implanted into nude mice, growth of antisense-VEGF cell lines was greatly inhibited compared with control cells. CONCLUSION: Expression of antisense VEGF RNA in SMMC-7721 cells could decrease the tumorigenicity, and antisense-VEGF gene therapy may be an adjuvant treatment for hepatoma.

Source of blood supply of liver cavernous hemangioma and sclerosis and embolization treatment

AIM To investigate the source of blood supply of carvenous hemangioma of liver (CHL) and provide a feasibile treatment for CHL via hepatic artery. METHODS Ⅰ. Origin of blood supply of CHL: portovenography, hepatic arteriography and portal vein staining were performed in 5 patients. Two casts of hepatic blood vessels from resected specimen were observed. Ⅱ. Clinical data: Among 75 patients (30 males, 45 females, aged 25～57 years with a mean of 37 4). 56 were of solitary type (44 on the right lobe, 12 on the left with 4 having intraparenchymatoma) and 19 were of multiple type (9 on the right, 2 the left, 8 whole liver). Twenty two patients were treated by sclerosis, 50 by embolization via hepatic artery and 3 were excised. RESULTS In 5 cases with portography, the contrast medium did not enter the tumor, the tumor appeared as low denty area and the intrahepatic branches of portal vein were pushed aside. In 5 cases with portal vein staining, the normal liver parenchyma was stained deep blue, and the tumor was not stained. The tumor area appeared as a round vacant cavity in 2 specimen casts. In 72 patients treated with sclerosis a or embolization via hepatic artery or through interventional method, the tumors diminished by 10%～30% in diameter and no tumors grew larger. CONCLUSION The blood supply of CHL originates from the hepatic artery. Tumors treated with sclerosis and emblization decreased in size or got fiberized.

Role of stereotactic body radiation therapy for hepatocellular carcinoma

The integration of new technologies has raised an interest in liver tumor radiotherapy,with literature evolving to support its efficacy.These advances,particularly stereotactic body radiation therapy(SBRT),have been critical in improving local control or potential cure in liver lesions not amenable to first-line surgical resection or radiofrequency ablation.Active investigation of SBRT,particularly for hepatocellular carcinoma(HCC),has recently started,yielding promising local control rates.In addition,data suggest a possibility that SBRT can be an alternative option for HCC unfit for other local therapies.However,information on optimal treatment indications,doses,and methods remains limited.In HCC,significant differences in patient characteristics and treatment availability exist by country.In addition,the prognosis of HCC is greatly influenced by underlying liver dysfunction and treatment itself in addition to tumor stage.Since they are closely linked to treatment approach,it is important to understand these differences in interpreting outcomes from various reports.Further studies are required to validate and maximize the efficacy of SBRT by a large,multi-institutional setting.

Hepatic arterial infusion chemotherapy and embolization in the treatment of primary hepatic carcinoma

AIM To study the effects of hepatic arterial infusion chemotherapy (HAI) or embolization (HAE) in the treatment of primary hepatic carcinoma (PHC) and the factors influencing the effects. METHODS Follow up information in 188 patients (166 males and 22 females) with PHC treated with HAI ( n =82) or HAE ( n =106) were analyzed retrospectively. RESULTS The overall therapeutic effects were as follows: symptomatic relief in 59 6%; tumor shrinkage in 55%, blood AFP decrease in 37 8% and the overall survival rates of 1/2, 1, 2 and 3 years after treatment being 75 4%, 46%, 23 5% and 14 7%, respectively. The mean survival time was 12 2 months and the longest survival period was 50 months after treatment. In the HAI group the 1/2, 1, 2 and 3 years survival rates were 61 0%, 25 4%, 4 5% and 0%, respectively, the mean survival time being 7 7 months; in the HAE group the survival rates were 86 8%, 61 7%, 37 8% and 26 1%, respectively, the mean survival time being 15 7 months. Eighteen patients received secondary surgery. Seven factors influencing the therapeutic effects were analyzed. CONCLUSION Those cases of PHC with or without mild liver cirrhosis, stages Ⅰ and Ⅱ, single tumor, tumor size less than 10cm in diameter, no cancerous thrombus within the portal vein or hepatic arterio venous fistula, and HAE treatment time more than 3 times had better therapeutic effects than the contrast cases. To overcome these influencing factors and to adopt the comprehensive therapy would improve the effects of HAI or HAE in the treatment of PHC.

Indications of external radiotherapy for hepatocellular carcinoma from updated clinical guidelines: Diverse global viewpoints

The etiology and disease patterns of hepatocellular carcinoma(HCC)significantly vary among regions. Modern standard treatments commonly require multidisciplinary approaches, including applications of up-to date medicine and advanced procedures, and necessitate the support of socioeconomic systems. For these reasons, a number of clinical guidelines for HCC from different associations and regions have been presented. External beam radiation therapy was contraindicated for HCC until a few decades ago, but with the development of new technologies, its application has rapidly increased as selective irradiation for tumorous lesions became possible. Most of the guidelines had been opposed or indifferent to radiotherapy in the past, but several guidelines have introduced indications and recommendations for radiotherapy in their updated versions. This review will discuss the characteristics of important guidelines and their contents regarding radiotherapy and will also provide guidance to physicians who are considering applications of locoregional modalities that include radiotherapy.