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Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death. Because HCC is multicentric with time, excluding the few transplanted patients, sooner or later it becomes untreatable with loco-regional therapies and, until some years ago, it was not responsive to systemic therapies. In 2005 a randomized trial indicated the efficacy of a product containing stem cell differentiation stage factors (SCDSF) taken from zebrafish embryos during the stage in which the totipotent stem cells are differentiating into the pluripotent adult stem cells. In such a trial the patients, with “intermediate” and “advanced” HCC according to Barcelona Clinic Liver Cancer/American Association for the Study of Liver Diseases (BCLC/AASLD) guidelines, presented benefit in terms of performance status and objective tumoral response, with some cases (2.4%) of complete response, that is, sustained disappearance of the neoplastic areas or blood supply therein, accompanied by normalization of alpha-fetoprotein...

The chapter considers the principles, the techniques, the results of PEI for treating cirrhotic patients with HCC, and its current indications compared to those of RF, which is now considered the gold standard.

Norman Kneteman, Tito Livraghi, David Madoff, Eduardo de Santibanez, and Michael Kew Division of Transplantation, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada; Department of Interventional Radiology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; Division of Interventional Radiology, New York-Presbyterian/Weill Cornell Medical Center, New York, NY; General Surgery and Liver Transplant Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; and Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa

Hepatocellular carcinoma (HCC) represents the third cause of cancer-related death. Because HCC is multi-centric with time, excluding the few transplanted patients, sooner or later it becomes untreatable with loco-regional therapies and, until some years ago, it was not responsive to systemic therapies. In 2005 a randomized trial indicated the efficacy of a product containing stem cell differentiation stage factors (SCDSF) taken from zebra fish embryos during the stage in which the totipotent stem cells are differentiating into the pluripotent adult stem cells. In such a trial the patients, with "intermediate" and "advanced" HCC according to BCLC/AASLD guidelines, presented benefit in terms of performance status (PS) and objective tumoral response, with some cases (2.4%) of complete response (CR). The aim of this cohort study is to report the experience of a tertiary referral center on the evidence of cases of CR in patients with "advanced" stage HCC treated with SCDSF as supportive care. CR was regarded as sustained disappearance of the neoplastic areas or blood supply therein, accompanied by normalization of AFP levels. Out of 49 patients consecutively recruited and retrospectively evaluated, 38 had "advanced" stage and 11 "terminal" stage. In 5 patients with "advanced" stage a sustained CR was reported (13.1%). Improvement on PS was obtained in 17 patients (34.6%). No side effects occurred. SCDSF treatment confirmed its efficacy in patients with "advanced" HCC, in terms of PS and tumoral response.

Purpose: Recommendations of the Barcelona Clinic Liver Cancer (BCLC) therapeutic flow-chart, endorsed by the American Association for the Study of Liver Diseases (AASLD), are the most applied worldwide. Over recent years, however, several referral centers have questioned some of the BCLC treatment allocations and proposed alternative strategies. The present study plans to review and discuss these suggestions, with the aim to evaluate whether there are well-grounded reasons to reconsider some of the BCLC/AASLD recommendations. Methods: A search was made into the MEDLINE database, focusing on randomized controlled trials, meta-analysis reviews, case–control studies, concordant clinical trials on novel therapies and studies reporting the opinion of respected experts. Their results and conclusions were compared stage by stage with BCLC/AASLD recommendations. Results: I n stage 0 (very early, or single

PURPOSE: To retrospectively assess the local control and intermediate- and long-term survival of patients with liver metastases from breast cancer who have undergone percutaneous ultrasonography (US)-guided radiofrequency (RF) ablation. MATERIALS AND METHODS: This study was approved by the hospital ethics committee, and all patients provided written informed consent. RF ablation was used to treat 87 breast cancer liver metastases (mean diameter, 2.5 cm) in 52 female patients (median age, 55 years). Inclusion criteria were as follows: fewer than five tumors, maximum tumor diameter of 5 cm or smaller, and disease either confined to the liver or stable with medical therapy. Forty-five (90%) of 50 patients had previously undergone chemotherapy, hormonal therapy, or both, and had no response or an incomplete response to the treatment. Contrast material-enhanced computed tomography and US were performed to evaluate complications and technical success and to assess for local tumor progression during follow-up. The Kaplan-Meier method was used to assess survival, and results were compared between groups with a log-rank test. Cox regression analysis was used to assess independent prognostic factors that affected survival. RESULTS: Complete tumor necrosis was achieved in 97% of tumors. Two (4%) minor complications occurred. Median time to follow-up from diagnosis of liver metastasis and from RF ablation was 37.2 and 19.1 months, respectively. Local tumor progression occurred in 25% of patients. New intrahepatic metastases developed in 53% of patients. From the time of first RF ablation, overall median survival time and 5-year survival rate were 29.9 months and 27%, respectively. From the time the first liver metastasis was diagnosed, overall median survival time was 42 months, and the 5-year survival rate was 32%. Patients with tumors 2.5 cm in diameter or larger had a worse prognosis (hazard ratio, 2.1) than did patients with tumors smaller than 2.5 cm in diameter. CONCLUSION: Survival rates in selected patients with breast cancer liver metastases treated with RF ablation are comparable to those reported in the literature that were achieved with surgery or laser ablation

In the EASL and AASLD guidelines, hepatic resection (HR) is considered the first option for patients in stage 0 (very early HCC). This statement was not based on randomized controlled trials (RCTs) versus other therapies, but on the oncological assumption that HR is the better procedure for obtaining complete tumor ablation including a safety margin. Subsequently, three RCTs compared percutaneous radiofrequency ablation (RFA) versus HR in patients with early HCC. All failed to demonstrate better survival in favor of HR, even though the larger size of the early stage needs a larger area of necrosis. A recent study focused on stage 0 demonstrated a sustained local complete response after RFA comparable with that of HR. All these trials established that RFA is less invasive and associated with lower complication rates and lower costs. These data suggest that RFA can be considered the first option for operable patients with very early HCC. Other options (HR, PEI, selective TAE/TACE) can be used as salvage therapy for the few cases in which RFA is unsuccessful or unfeasible.

The purpose of this study was to compare the efficacy of contrast-enhanced pulse inversion harmonic imaging with contrast-enhanced power Doppler sonography and helical CT to determine incomplete local treatment after radiofrequency ablation in patients with hepatocellular carcinoma.Thirty-five consecutive patients (24 men and 11 women; mean age, 64 years) with 43 hepatocellular carcinomas (3.6 +/- 1.1 cm) were treated using internally cooled radiofrequency ablation therapy. Therapeutic response was evaluated at 4 months with dual-phase contrast-enhanced helical CT, conventional power Doppler Sonography, and pulse inversion harmonic imaging using a sonographic contrast agent (SH-508). CT and sonographic studies were reviewed separately in random order by four radiologists at different consensus conferences. Sensitivity and specificity of the sonographic methods were determined using CT as a gold standard and results were compared using the McNemar test.CT examinations identified residual tumor in 12 lesions (27.9%). Although conventional contrast-enhanced power Doppler sonography identified residual viable tumor foci in four incompletely treated lesions (9.3%), contrast-enhanced pulse inversion harmonic imaging identified residual tumoral enhancement in 10 lesions (23.3%). Thus, the sensitivity of pulse inversion harmonic imaging (83.3%) was significantly greater (p0.05) for detecting residual nonablated tumor compared with conventional contrast-enhanced power Doppler sonography.Our study suggests that contrast-enhanced pulse inversion harmonic imaging may enable the detection of residual nonablated tumor in more cases than contrast-enhanced power Doppler sonography and may ultimately prove to be a useful adjunct for percutaneous ablation therapies. Nevertheless, contrast-enhanced axial imaging (CT or MR imaging) is currently the most sensitive test for managing thermal ablation for patients with hepatocellular carcinoma.

In the treatment of hepatocellular carcinoma, the range of indications for percutaneous ablation techniques is becoming wider than surgery and intra-arterial therapies. Indeed, whereas for some years only patients with up to three small lesions were treated, with the introduction of the single-session technique under general anesthesia, even patients with more advanced disease are now being treated. Although it is understood that partial resection assures the highest local control, the survival rates after surgery are roughly comparable with percutaneous ethanol injection (PEI). The explanation is due to a balance among advantages and disadvantages of the two therapies. PEI survival curves are better than curves of resected patients who present adverse prognostic factors, and this means that surgery needs a better selection of the patients. Indications for both therapies are reported. Single-session radiofrequency (RF) ablation seems to offer better results in terms of local control and safety than transarterial chemoembolisation (TACE) in multifocal tumours. An open question remains the choice between PEI and other new ablation procedures. In our department, we use RF, PEI and segmental TACE, according to the features of the disease. In the treatment of colorectal liver metastases, the initial survival curves of thermal ablation techniques are promising. However, they are size and site dependent, so partial resection remains the gold standard. An interesting indication seems to be the treatment of breast liver metastases in selected patients.

Objective: Percutaneous ethanol injection (PEI) has become one of the most widely used procedures for treating hepatocellular carcinoma (HCC) in patients with cirrhosis. PEI spread rapidly thanks to its ease of execution, safety, low resection cost, repeatability, therapeutic efficacy, and survival rates comparable to those of surgical resection. A new version of the procedure known as “single session” PEI, designed for treatment of large HCC under general anesthesia, was proposed in 1993. Materials and methods: In our study of 108 patients with HCC>5 cm in diameter, 24 patients (Group A), were treated for a single and encapsulated lesions measuring from 5–8.5 cm, 63 patients (Group B), had a single and infiltrating lesions measuring from 5–10 cm or multiple HCC; and 21 patients (Group C), had advanced disease. Results: In Group A, complete necrosis was achieved in 58.3% of lesions, in Group B complete necrosis was achieved only in encapsulated lesions. In infiltrating lesions of Group B and C, complete necrosis was never obtained. Survival of patients at 3 years with encapsulated HCC was 57%, in infiltrating or multiple HCC 42%, and in advanced HCC 0%. One death due to bleeding of esophageal varices occurred in a Child's C patient. Major complications included intraperitoneal hemorrhage, an important hepatic decompensation, a transitory renal insufficiency, and two infarction of adiacent segment. Conclusion: Single session PEI is as effective in inducing liver tumor necrosis as traditional PEI. Its advantage are shorter treatment time and the capability of treating larger and multiple HCC. The One-shot technique proved a more aggressive therapeutic modality than traditional PEI.

In the treatment of early and intermediate hepatocellular carcinoma the range of indications for percutaneous ablation techniques is becoming wider than surgery or intra-arterial therapies. Indeed, whereas for some years only patients with up to three small tumours were treated, with the introduction of the single-session technique performed under general anaesthesia, even patients with more advanced disease are now being treated. Although it is understood that partial resection assures the highest local control, the survival rates after surgery are roughly comparable with percutaneous ethanol injection (PEI). The explanation is due to a balance among advantages and disadvantages of the two therapies. PEI survival curves are better than curves of resected patients who present adverse prognostic factors, and this means that surgery needs a better selection of the patients. Indications for both of therapies are reported. An unanswered question remains the choice between PEI and other new ablation procedures. In our department we currently use radio-frequency ablation in the majority of patients but consider PEI and segmental transarterial chemoembolisation complementary, and use them according to the features of the disease and the response. Evaluation of therapeutic efficacy, technique and results of them are reported.

In the treatment of early and intermediate hepatocellular carcinoma, the range of indications for percutaneous ablation techniques is becoming wider than surgery or intra-arterial therapies. Indeed, whereas for some years only patients with up to three small tumors were treated, with the introduction of the single-session percutaneous ethanol injection (PEI), performed under general anesthesia, even patients with more advanced disease are now being treated. Although it is understood that partial resection assures the highest local control, the survival rates after surgery are roughly comparable with PEI. The explanation for this is a balance among the advantages and disadvantages of the two therapies. PEI survival curves are better than curves for resected patients who present adverse prognostic factors, and this means that surgery needs a better selection of the patients. Indications for both therapies are reported. An open question remains the choice between PEI and other new ablation procedures. In our department we currently use radiofrequency ablation in the majority of patients but consider PEI and segmental transarterial chemoembolization complementary, and use them according to the features of the disease and the response.

The authors' purpose was to create larger and more regular liver lesions in vitro by testing a new hyperthermia approach that uses a bipolar saline-enhanced electrode for radiofrequency (RF) in the audible spectrum and a greater power supply.The authors' hyperthermia approach (group A, n = 23) was used in excised porcine livers, and the results were compared with those of a previously described monopolar saline-enhanced electrode procedure (group B, n = 23). In each set of experiments, RF in the audible spectrum current (50 Hz) was provided for 15 minutes with a similar ablation protocol. Electrical variables (impedance, current, voltage, power, and energy), temperatures in the lesions, volume size, regularity ratio of the lesion, and microscopic findings were measured.In group A, the mean volume size and the mean regularity ratio values were 144.8 cm3 +/- 59.8 and 0.78 +/- 0.1, respectively. In group B, the mean volume size and regularity ratio values were 62.1 cm3 +/- 36.4 and 0.62 +/- 0.1, respectively. The values in group B were thus significantly lower than those in group A (P.01). The lesions in group A were also more homogeneous. No significant differences were found in electrical variables.The new bipolar saline-enhanced electrode produced larger, more regular, and more homogeneous lesions ex vivo than the previously used monopolar saline-enhanced electrode method. Using a greater power supply increased the amount of coagulative necrosis.

BACKGROUND The objective of this study was to evaluate the indications for percutaneous ethanol injection (PEI) performed in a single session under general anesthesia for treating patients with cirrhosis and large (tumors > 5 cm) hepatocellular carcinoma (HCC), and relevant survival curves. METHODS Between November 1991 and November 1996, 108 patients were treated (a total of 128 procedures). They fell into 3 groups: 24 patients with single, encapsulated HCC measuring from 5-8.5 cm (Group A); 63 patients with single, infiltrating HCC measuring from 5-10 cm or multiple HCC (Group B); and 21 patients with advanced disease, either hepatic (Child's Class C) or neoplastic (symptomatic HCC or with portal thrombosis) type (Group C). The mean amount of ethanol injected was 62 mL. The average hospital stay was 3.8 days. The mean follow-up time was 40 months. RESULTS The 1-, 2-, 3-, and 4-year survival rates were: 72%, 65%, 57%, and 44%, respectively, for Group A; 73%, 60%, 42%, and 18%, respectively, for Group B; and 46%, 25%, and 0%, respectively, for Group C. Mortality was 0.7% (bleeding from esophageal varices in a Child's Class C patient). The rate of major complications was 4.6% (1 case of peritoneal hemorrhage, 1 case of severe liver failure, 1 case of transient renal insufficiency, 1 case of peritoneal seeding, and 2 cases of infarctions of a segment adjacent to the tumor). CONCLUSIONS Single session PEI has been proven to be a valid alternative in patients otherwise treated surgically or with transcatheter arterial chemoembolization who present with adverse prognostic factors or risks for these therapies, and may be an option for selected patients with advanced disease previously excluded from any therapy. Risk conditions are marked portal or pulmonary hypertension or esophageal varices at risk of bleeding, superficial tumors with severe coagulation disorders, hyperfibrinolysis, chronic renal insufficiency, and obstructive jaundice. Cancer 1998;83:48-57. © 1998 American Cancer Society.

Percutaneous ethanol injection (PEI) has become a widely used procedure in the treatment of hepatocellular carcinoma (HCC). However, the criteria for selecting patients are not standardized, and little information is available about the complications of the procedure.A questionnaire was sent to 11 experienced Italian centers. It investigated: the size and the number of HCC nodules suitable for treatment and the Child-Pugh risk class of the associated cirrhosis; the performance of the procedure; the number and characteristics of the patients treated; and, finally, any complications.Most of the centers performed PEI in single HCC nodules less than 5 cm in diameter or in multiple nodules if fewer than three, the larger being less than 3 cm. Patients in Child-Pugh's classes A, B, and C with single nodules were generally considered for PEI. A prothrombin time of less than 40% and a platelet count of less than 40,000/mm3 contraindicated PEI in most of the centers. PEI was generally performed on outpatients, using Chiba or spinal needles. One thousand and sixty-six patients (8118 sessions) were enrolled; 74% had a single HCC nodule and 26% multiple nodules. All except four had cirrhosis; 53% were in Child class A, 38% in class B, and 9% in class C. The mean number of sessions needed to destroy an HCC nodule was 6.7 (range, 2-14), with a mean alcohol injection volume of 5.0 ml per session (range, 2-20 ml). One death (0.09%) and 34 complications (3.2%) were reported. Among the complications we call attention to the hemorrhagic ones (eight cases) and tumoral seeding (seven cases). Severe pain experienced during the maneuver led to discontinuation of the procedure in 3.7% of the patients; 13.5% of the patients required analgesics and 24% had fever after PEI.Some procedural aspects of PEI treatment differ among the various centers a standardization is advisable. In the present survey PEI is a low-risk technique.

“Wait and see” policy for early hepatocellular carcinomaGiampiero Francica, Ilario de Sio, Maurizio Pompili, Tito LivraghiPII: S0168-8278(13)00367-XDOI: http://dx.doi.org/10.1016/j.jhep.2013.04.039Reference: JHEPAT 4739To appear in: Journal of HepatologyReceived Date: 18 March 2013Revised Date: 25 April 2013Accepted Date: 26 April 2013Please cite this article as: Francica, G., Sio, I.d., Pompili, M., Livraghi, T., “Wait and see” policy for earlyhepatocellular carcinoma, Journal of Hepatology (2013), doi: http://dx.doi.org/10.1016/j.jhep.2013.04.039This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, andreview of the resulting proof before it is published in its final form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

PURPOSE: To define indications for percutaneous ethanol injection (PEI) in patients with hepatocellular carcinoma (HCC) and cirrhosis. MATERIALS AND METHODS: Survival rates were determined in 746 patients who had undergone PEI (567 men, 179 women; mean age, 64.3 years; mean follow-up, 36 months). RESULTS: In patients with Child A (n = 293), B (n = 149), or C (n = 20) cirrhosis and single HCCs 5 cm or smaller, the 3-5 year survival rate was 47%-79%, 29%-63%, and 0%-12%, respectively. In patients with Child A cirrhosis, it was 36%-68% for multiple HCCs (n = 121), 30%-53% for single HCCs larger than 5 cm (n = 28), and 0%-16% for advanced HCC (n = 16). Treatment was associated with a 1.7% rate of severe complications and a 0.1% mortality rate. CONCLUSION: PEI proved safe, effective, and repeatable and had a low cost. Survival after PEI was comparable to that after surgery, probably because of a balancing between greater radicality of surgery and absence of early mortality and liver damage of PEI.

Background/Aims: This retrospective study was undertaken to obtain information relevant to the therapeutic strategy in single hepatocellular carcinoma associated with Child's A and B cirrhosis. Methods: From a total of 1108 consecutive patients with hepatocellular carcinoma, 391 patients with single, small (≤5 cm) hepatocellular carcinoma (260 in Child A class and 131 in Child B class) were observed: 120 were treated by surgical resection, 155 by percutaneous ethanol injection and 116 were untreated. The end point of the study was 3-year survival. The log rank test was used to compare survival among the different groups. Results: In the Child A group the cumulative 3-year survival was 79% for surgery, 71% for percutaneous ethanol injection and 26% for no treatment ( p p p p Conclusions: Surgery and percutaneous ethanol injection improve survival in single hepatocellular carcinoma associated with Child A and B cirrhosis compared to untreated patients in the same Child class. A controlled study to identify factors affecting the choice of treatment is justified.

Radiofrequency ablation (RFA), usually performed under percutaneous ultrasound guidance, is considered the gold standard among minimally invasive therapies. On the strength of some recent randomized trials, its indications include operable patients with small hepatocellular carcinoma and inoperable patients with more advanced disease also in combination with other therapies. RFA has lower complication rates and costs less than surgery.

Recommendations of the Barcelona Clinic Liver Cancer (BCLC) therapeutic flow-chart, endorsed by the American Association for the Study of Liver Diseases (AASLD), are the most applied worldwide. Over recent years, however, several referral centers have questioned some of the BCLC treatment allocations and proposed alternative strategies. The present study plans to review and discuss these suggestions, with the aim to evaluate whether there are well-grounded reasons to reconsider some of the BCLC/AASLD recommendations.A search was made into the MEDLINE database, focusing on randomized controlled trials, meta-analysis reviews, case-control studies, concordant clinical trials on novel therapies and studies reporting the opinion of respected experts. Their results and conclusions were compared stage by stage with BCLC/AASLD recommendations.In stage 0 (very early, or single2 cm, or carcinoma in situ, Child A) radiofrequency should replace resection. In stage A (early, or single or three nodules up to 3 cm, Child A-B) radiofrequency and resection should expand their indications. In stage B (intermediate, or multinodular, Child A-B) resection and transplantation should expand their indications, while intra-arterial therapies are changing from conventional to selective treatments. In stage C (advanced, portal invasion or extrahepatic disease, Child A-B) systemic therapies should offer previously unknown promising options.In our opinion, so much evidence leads to suggest it is time to reconsider several BCLC/AASLD recommendations. Some treatments are comparable in results but vary in costs, local availability, or complication rates.

In 207 cirrhotic patient carriers of hepatocellular carcinoma (HCC), percutaneous ethanol injection (PEI) was administered with ultrasound guidance. The patients were classified as Child's Class A, 136; B, 54; and C, 17. Their mean age was 63.5 years, and the male-female ratio was 3.5:1. There was a single HCC less than 5 cm in diameter in 162 patients; 45 had more than one HCC. The follow-up ranged from 5 to 71 months (mean, 25 months). No noteworthy complications occurred during or after 2485 treatments. The 1-year, 2-year, and 3-year survival percentages (by the Kaplan-Meier method) for the patients with one HCC were 90%, 80%, and 63%, respectively. The corresponding percentages by Child's class were 97%, 92%, and 76% for Class A; 88%, 68%, and 42% for B; and 40%, 0%, and 0% for C. The 1-year, 2-year, and 3-year survival rates for patients with more than one HCC were 90%, 67%, and 31%, respectively. These results were similar to those found by others and showed that PEI was a safe, reproducible, easy-to-do, and low-cost therapeutic technique. In terms of survival, these PEI results were better than the published results of no treatment and equivalent to those of surgery. In uncontrolled series, bias can play an important role. Therefore, additional trials would be useful. Cancer 1992; 69: 925–929.

Ten patients with fatty liver changes were subjected to liver biopsies. In seven, ultrasonography showed focal hypoechogenicity within a “bright” liver, generally interpreted as focal sparing. Three patients had hyperechoic areas surrounded by “normal” parenchyma usually felt to represent local fat accumulation without diffuse involvement. Morphometric analysis was used to determine the total area occupied by fat (area density) and the number of lipid droplets (numerical density) per microscopic field in lesional and perilesional specimens. Compared with respective perilesional values, hypoechoic lesional numerical densities were significantly lower in 6 of 7 patients; the three hyperechoic samples had significantly higher values. In most cases, lesional and perilesional area densities were not significantly different. These hypoechoic focal lesions are believed to be merely areas in which a similar quantity of fat is contained in fewer droplets, and focal hyperechogenicity is believed to result from a larger number of fat-filled vacuoles with respect to that of the surrounding parenchyma. Variation in the number of solid-liquid interfaces causes the ultrasonic contrast between these lesions and the similarly fatty liver parenchyma surrounding them.

OBJECTIVE. The purpose of this study was to assess, with contrast-enhanced CT or MRI as the reference imaging technique, the diagnostic performance of low-mechanical-index contrast-enhanced sonography in detecting local tumor progression after percutaneous radiofrequency ablation of renal tumors. Materials AND METHODS. Twenty-nine patients with 30 renal tumors (18 men, 11 women; mean age, 73 years; range, 53–83 years) underwent percutaneous radiofrequency ablation at a single center between March 1998 and January 2007. The imaging follow-up schedule was both contrast-enhanced sonography and CT or MRI 4 months after completion of treatment and every 4 months for the first year. Thereafter, the follow-up schedule was contrast-enhanced sonography every 4 months with CT or MRI every 8 months. The chi square test with Yates correction was used to evaluate positive and negative predictive values and accuracy. RESULTS. One patient was scheduled to undergo surgical resection, and another patient was lost to follow-up. Twenty-seven patients with 28 renal tumors participated in follow-up. The concordance between contrast-enhanced sonographic and CT or MRI findings was 100% for 27 of 28 tumors (96.4%) that had a hypervascular pattern before treatment. In the case of the tumor that was hypovascular at imaging performed before percutaneous radiofrequency ablation, local tumor progression was missed at contrast-enhanced sonography. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of contrast-enhanced sonography were 96.6%, 100%, 100%, 95.8%, and 98.1%. CONCLUSION. Contrast-enhanced sonography is an effective alternative to CT and MRI in the follow-up of renal tumors managed with percutaneous radiofrequency ablation.

Two thousand and ninety-one ultrasound-guided fine-needle biopsies were performed in 1946 patients to diagnose focal liver lesions. The diagnostic accuracy of fine-needle biopsies is very high (only one false positive was observed), both for aspiration biopsy (93.4%) and for cutting biopsy (95.1%). The difference is not statistically significant. In cases of hepatocellular carcinoma (but not in cases of metastasis or hepatic lymphoma), double biopsy (aspiration and cutting) showed higher diagnostic sensitivity than single methods. A certain number of benign focal liver lesions were also diagnosed. In the present series, no case of death following liver puncture was observed. Intraperitoneal hemorrhage was the most common complication. The risk with a cutting needle being higher than with an aspirative needle.

Percutaneous ethanol injection (PEI) under ultrasound guidance is a new therapeutic possibility for patients with small hepatocellular carcinoma (HCC). In our series, 35 patients with a total of 50 tumors were treated (tumor size 0.8-5.0 cm). No significant complications occurred after 502 sessions of ethanol injection. Thirty patients presented complete remission, as no evidence of residual HCC was revealed during the follow-up (mean 16 months). Five patients with lesions larger than 3.5 cm presented only partial remission. The survival curves at 1, 2, and 3 years (Kaplan Meier method) were 100%, 100%, and 80%, respectively. In comparison with the survival curves of untreated and surgically treated patients, PEI seems to be the better treatment for operable HCC smaller than 3 cm, and for lesions smaller than 5 cm in patients with high surgical risk.

If liver transplantation is not feasible, partial resection is considered the treatment of choice for hepatocellular carcinoma (HCC) in patients with cirrhosis. However, in some centers the first-line treatment for small, single, operable HCC is now radiofrequency ablation (RFA). In the current study, 218 patients with single HCC ≤ 2.0 cm (very early or T1 stage) underwent RFA. We assessed 2 primary end points that could be easily compared with those reported for resective surgery: (1) the rate of sustained, local, complete response and (2) the rate of treatment-related complications. The secondary end point was 5-year survival in the 100 patients whose tumors had been considered potentially operable. After a median follow-up of 31 months, sustained complete response was observed in 216 patients (97.2%). In the remaining 6, percutaneous ethanol injection, selective intraarterial chemoembolization, or resection were used as salvage therapy. Perioperative mortality, major complication, and 5-year survival rates were 0%, 1.8%, and 68.5%, respectively. Conclusion: Compared with resection, RFA is less invasive and associated with lower complication rate and lower costs. RFA is also just as effective for ensuring local control of stage T1 HCC, and it is associated with similar survival rates (as recently demonstrated by 2 randomized trials). These data indicate that RFA can be considered the treatment of choice for patients with single HCC ≤ 2.0 cm, even when surgical resection is possible. Other approaches can be used as salvage therapy for the few cases in which RFA is unsuccessful or unfeasible. (HEPATOLOGY 2007.)

Percutaneous ethanol injection (PEI) was presented in 1986 [1]. Since long-term results of this therapy are now available, some considerations and conclusions can be drawn.

Radiofrequency ablation (RFA) is currently indicated for the treatment of primary and metastatic hepatic malignancies. Real-time ultrasound (US) is generally used during the procedure to guide electrode placement, but for evaluating the results of treatment, contrast-enhanced computed tomography and magnetic resonance imaging have traditionally been considered more effective. This view has changed, however, with the recent development of contrast-enhanced ultrasound (CEUS) (eg, using sulfur hexafluoride microbubbles), which can provide valuable information on the effects of RFA more rapidly and economically than computed tomography or magnetic resonance imaging without exposing the patient to ionizing radiation. In our center, CEUS is performed in patients with liver tumors before and immediately after RFA, in selected cases during the procedure as well, and in the follow-up. Between January 2003 and June 2005, we performed CEUS on 350 patients scheduled for RFA of primary or metastatic liver tumors. In 14 (13.4%) of the 96 patients whose disease was metastatic, CEUS revealed lesions that had been missed on the conventional US examination. In most of these cases, the result was a more complete treatment performed under CEUS guidance. In the remaining 2 (14%) of 14, the results of the examination allowed us to avoid subjecting the patient to useless treatment. In our experience, the use of CEUS also improved the management and follow-up of patients undergoing interstitial therapy.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and it represents more than 5% of all cancers (1). It usually coexists with underlying chronic liver disease, and according to the stage, one disease will prevail over the other. The stage of HCC at the time of diagnosis is very important to decide the type of treatment—possibly curative when the diagnosis is early, palliative or no treatment when the diagnosis is late.

Percutaneous ethanol injection therapy (PEIT) is one of the most widely used local procedures to treat hepatocellular carcinoma (HCC). Local-regional therapies are specific ablation modalities that introduce a damaging agent directly into the neoplastic tissue percuta-neously. These techniques are capable of destroying the tissue chemically, such as with sterile ethanol acetic acid, or thermally by laser, microwave, or radiofrequency (1–3). Percutaneous ethanol injection therapy was the first method to be proposed (4). It was conceived independently at the University of Chiba in Japan and at the Vimercate Hospital in Milan, Italy.

The best treatment policy for some patients with hepatocellular carcinoma (HCC) and compensated cirrhosis is still controversial. The aim of this study was to evaluate the long-term survival and related prognostic factors of patients with early and intermediate HCC (Liver Unit of Barcelona classification) treated in a radiologic referral center by a multimodal image-guided tailored therapy (MIGTT), applied over time, choosing the procedure patient by patient according to the presentation of the disease. Between May 1996 and May 2003, 374 patients (210 with early and 164 with intermediate HCC) were treated with MIGTT. Radiofrequency ablation was considered the first choice; ethanol injection was preferred for nodules at risk for radiofrequency; and selective chemoembolization was preferred for nodules not recognizable at ultrasound examination, those not retreatable after an unsuccessful ablation technique, or for satellites. The rate of perioperative mortality and major complications was 0.2% and 4.5%, respectively. The 1-, 3-, and 5-year survival rates were 90%, 69%, and 49% and 83%, 43%, and 28% for patients with early and intermediate HCC, respectively. At the univariate analysis, the indicators of a poor prognosis were Child's class B, portal hypertension, abnormal bilirubin, infiltrating tumor, and abnormal serum alpha-fetoprotein (AFP) level. In conclusion, within the limits of historical comparisons, in early HCC, MIGTT should be considered an appropriate option for unresectable patients or for resectable patients presenting with adverse prognostic factors. In intermediate HCC, the 3-year survival rate obtained with MIGTT was better than the best survival rate reported with conventional chemoembolization; however, the benefit for patients presenting with poor prognostic factors remains unclear. (Liver Transpl 2004;10:S98–S106.)

At detection or over time, hepatocellular carcinoma (HCC) is multicentric in origin, against a background of chronic hepatic disease at different stages. Orthotopic liver transplantation (OLT) is the only therapy able to definitely cure both diseases. When OLT is not feasible, all other options can be only palliative. Owing to the multicentricity, surgical resection may be one possible option at the initial detection in selected patients, whereas percutaneous interventional techniques (percutaneous ethanol injection [PEI], radiofrequency ablation [RFA], selected transcatheter arterial chemoembolization [TACE]) are the options more often used. The range of their indications is becoming wider. Although it is understood that partial resection assures the greatest local control, the survival rates after surgery are roughly comparable with those obtained with PEI. The explanation for this result reflects a balance among the advantages and disadvantages of the two therapies. PEI survival curves are better than curves of resected patients who present with adverse prognostic factors, and this means that a better selection of the patients for surgery is needed. An open question remains the choice among percutaneous techniques. In our department we currently use RFA in most patients but consider PEI and selected TACE complementary, and use them according to the features of the disease and the response.

The field of image-guided tumor ablation requires standardization of terms and reporting criteria to facilitate effective communication of ideas and appropriate comparison between treatments with different technologies, such as chemical ablation (ethanol or acetic acid) and thermal therapies, such as radiofrequency, laser, microwave, ultrasound, and cryoablation. On the basis of this premise, a working committee was established with the goal of producing a proposal on such standardization. The intent of the Working Group is to provide a framework that will facilitate the clearest communication between investigators and will provide the greatest flexibility in comparisons between the many new, exciting, and emerging technologies. The members of the Working Group now propose a vehicle for reporting the various aspects of image-guided ablation therapy, including classifications of therapies and procedures, appropriate descriptors of image guidance, and terms to define imaging and pathologic findings. Methods for standardizing the reporting of follow-up findings and complications and other important aspects that require attention when reporting clinical results are addressed. It is the group's hope and intention that adherence to the recommendations of this proposal will facilitate achievement of the group's main objective: improved precision and communication in this field that lead to more accurate comparison of technologies and results and ultimately to improved patient outcomes.

BACKGROUND Some surgeons have advocated delaying resection of liver metastases to allow additional metastases which may be present, but are undetected, to be identified. This “test-of-time” approach can limit the number of resections performed on patients who ultimately will develop additional metastases. The current study evaluated the potential role and possible advantages of performing radiofrequency (RF) ablation during the interval between diagnosis and hepatic metastasectomy as part of a test-of-time management approach. METHODS Eighty-eight consecutive patients with 134 colorectal carcinoma liver metastases were potential candidates for hepatic metastasectomy. They were treated with percutaneous RF ablation using single (101 treatments) or triple-probe cluster (22 treatments) 18-gauge internally cooled electrodes. Treatment was performed under conscious sedation (22 of 119 treatments), anesthesia (14 of 119 treatments), or general anesthesia (83 of 119 treatments). At the time of the initial RF ablation procedure, 49 of 88 patients (56%) were found to have 1 metastasis, 32 of 88 patients (36%) had 2 metastases, and 7 of 88 patients (8%) had 3 metastases. Metastases ranged from 0.6 to 4.0 cm in greatest dimension (mean, 2.1 cm). Follow-up with serial computed tomography scans scans ranged from 18 to 75 months (median, 33 months) after the initial RF ablation. RESULTS A total of 119 RF ablations were performed. Complete necrosis was obtained in 53 of 88 patients (60%) and in 85 of 134 lesions (63%). During follow-up of these 53 patients, 16 (30%) remained free of disease and 37 (70%) developed new lesions. New lesions were intrahepatic in 26 of 37 patients (70%), extrahepatic in 4 patients (11%), and both intrahepatic and extrahepatic in 7 patients (19%). Of 26 patients whose new lesions were intrahepatic only, 15 (58%) were retreated with RF and 7 were free of disease at the time of last follow-up (median follow-up, 28 months). Ten additional patients with only intrahepatic new lesions were deemed untreatable and 1 patient underwent resection. Overall, among the 53 patients in whom complete tumor necrosis was achieved after RF ablation therapy, 52 (98%) were spared surgical resection: 23 (44%) because they have remained free of disease and 29 (56%) because they developed disease progression. Among all 88 patients, 21 (24%) underwent resection after RF ablation (8 were free of disease at the time of last follow-up), 23 (26%) remained free of disease after successful RF ablation, and 56 (64%) developed untreatable disease progression (44 after RF alone, 12 after RF and surgery). Lesions in 35 of 88 patients (40%) demonstrated local tumor recurrence on follow-up imaging studies. Twenty of these 35 patients (57%) underwent surgical resection, whereas the remaining 15 patients (43%) developed additional, untreatable metastases. New lesions were intrahepatic in 9 of 15 patients (60%), extrahepatic in 1 of 15 patients (7%), and both intrahepatic and extrahepatic in 5 of 15 patients (33%). No patient who had been treated with RF ablation became unresectable due to the growth of metastases and there was no evidence of needle track seeding in any patient after RF ablation. Overall, among the 35 patients in whom complete tumor necrosis was not achieved after RF ablation therapy, 15 (43%) were spared surgical resection. CONCLUSIONS The results of the current study suggest that current RF ablation techniques, when used as part of a test-of-time management approach, can decrease the number of resections performed. The approach results in complete tumor necrosis in some patients and provide an interval for others who ultimately will develop new intrahepatic and/or extrahepatic metastases to do so. Cancer 2003;97:3027–35. © 2003 American Cancer Society. DOI 10.1002/cncr.11426

To report complications encountered by members of a collaborative group who performed radio-frequency (RF) ablation in patients with focal liver cancer.Members of 41 Italian centers that were part of a collaborative group used a percutaneous internally cooled RF ablation technique and a standardized protocol for follow-up. They completed a questionnaire regarding number of deaths, presumed cause of death, and likelihood of its relationship to the RF procedure; number and types of major complications; and types of minor complications and side effects. Enrollment included 2,320 patients with 3,554 lesions (size, 3.1 cm +/- 1.1 [SD] in diameter): 1,610 had hepatocellular carcinoma with chronic liver disease; 693 had metastases, predominantly from colorectal cancer (n = 501); and 17 had cholangiocellular carcinoma. Number and characteristics of complications (ie, deaths and major and minor complications) attributed to the procedure were reported. Data were subsequently analyzed with analysis of variance to determine whether the major complication rate was related to tumor size, number of ablation sessions, or electrode type (single or cluster).In total, 3,554 lesions were treated. Six deaths (0.3%) were noted, including two caused by multiorgan failure following intestinal perforation; one case each of septic shock following Staphylococcus aureus-caused peritonitis, massive hemorrhage following tumor rupture, liver failure following stenosis of right bile duct; and one case of sudden death of unknown cause 3 days after the procedure. Fifty (2.2%) patients had additional major complications. The most frequent of these were peritoneal hemorrhage, neoplastic seeding, intrahepatic abscesses, and intestinal perforation. An increased number of RF sessions were related to a higher rate of major complications (P.01), whereas the number of complications was not significantly different when tumor size or electrode type were compared. Minor complications were observed in less than 5% of patients.Results of this study confirm that RF ablation is a relatively low-risk procedure for the treatment of focal liver tumors.

Objective: Radiofrequency (RF) has been demonstrated as a relatively safe procedure in the treatment of hepatocellular carcinoma (HCC). Methods: A 60-year-old man with liver cirrhosis presented with a large, infiltrating HCC close to the right colon. The patient was treated with internally cooled RF. Results: On the 8th day post-ablation, a complication of right colon perforation was diagnosed. Conclusion: RF can induce untoward thermal damage, and may not be indicated in large infiltrating lesions abutting the gastrointestinal tract.

In the treatment of early and intermediate hepatocellular carcinoma the range of indications for percutaneous ablation techniques is becoming wider than surgery or intra-arterial therapies. Indeed, whereas for some years only patients with up to three small tumors were treated, with the introduction of the single-session technique performed under general anesthesia, even patients with more advanced disease are now being treated. Although it is understood that partial resection assures the highest local control, the survival rates after surgery are roughly comparable with percutaneous ethanol injection. The explanation is due to a balance among advantages and disadvantages of the two therapies. Percutaneous ethanol injection survival curves are better than curves of resected patients who present adverse prognostic factors, and this means that surgery needs a better selection of the patients. Indications for both of these therapies are reported. An open question remains about the choice between percutaneous ethanol injection and other new ablation procedures. In our department we currently use radiofrequency ablation in the majority of patients but consider percutaneous ethanol injection and segmental transarterial chemoembolization complementary, and use them according to the features of the disease and the response. Evaluation of their therapeutic efficacy, techniques and results are reported.

Radiofrequency (RF) ablation resulted in a higher complete necrosis than percutaneous ethanol injection (PEI), above all in infiltrating lesions, and requires fewer treatment sessions in the treatment of small size tumors. We achieved 90% of complete necrosis in hepatocellular carcinoma (HCC)

Tumor ablation by using radio-frequency energy has begun to receive increased attention as an effective minimally invasive approach for the treatment of patients with a variety of primary and secondary malignant neoplasms. To date, these techniques have been used to treat tumors located in the brain, musculoskeletal system, thyroid and parathyroid glands, pancreas, kidney, lung, and breast; however, liver tumor ablation has received the greatest attention and has been the subject of a large number of published reports. In this article, the authors review the technical developments and early laboratory results obtained with radio-frequency ablation techniques, describe some of the early clinical applications of these techniques, and conclude with a discussion of challenges and opportunities for the future.

OBJECTIVE: Percutaneous ethanol injection may prolong the survival of patients with small hepatocellular carcinoma associated with cirrhosis. The aim was to identify prognostic factors of survival and of local recurrence, as well as separate new lesions. METHODS: We performed Cox regression analysis in 115 consecutive patients with hepatocellular carcinoma (81 Child-Pugh class A, 34 Child-Pugh class B) treated by percutaneous ethanol injection. The validity of the model was tested by comparing predicted and observed survival in 105 independent patients from an external series. RESULTS: Overall survival rates were 89%, 63%, and 43% at 1, 2, and 3 yr, respectively. The 1-, 2-, and 3-yr survival rates were 96%, 78%, and 63%, respectively, for Child-Pugh class A patients and were 73%, 35%, 12%, respectively, for Child-Pugh class B. The albumin level was the only independent variable significantly associated with survival (p < 0.0001). The 3-yr rate of appearance of separate new lesions and local recurrence were 41% and 23%, respectively. The survival predicted by the model agreed with that observed in the independent patients. CONCLUSIONS: Survival of patients with hepatocellular carcinoma treated by percutaneous ethanol injection is related to baseline albumin level. The high rate of recurrence (both local and distant) points out the palliative role of this therapy.

Six existing minimally invasive techniques for the treatment of primary and secondary malignant hepatic tumors--radio-frequency ablation, microwave ablation, laser ablation, cryoablation, ethanol ablation, and chemoembolization--are reviewed and debated by noted authorities from six institutions from around the world. All of the authors currently believe that surgery remains the treatment of choice for patients with resectable hepatic tumors. However, the clinical results of each of the minimally invasive techniques presented have exceeded those obtained with conventional chemotherapy or radiation therapy. Thus, for nonsurgical patients, these techniques are becoming standard independent or adjuvant therapies. In addition, with continued improvement in technology and increasing clinical experience, one or more of these minimally invasive techniques may soon challenge surgical resection as the treatment of choice for patients with limited hepatic tumor.

Percutaneous ethanol injection (PEI) is performed under ultrasound guidance, with multiple sessions in the out-patient department or with the “single-session” technique under general anesthesia, according to the size and number of the lesions. In our patients, with Child A (293), B (149), or C (20) cirrhosis and single hepatocellular carcinoma (HCC) lesions of 5 cm or smaller, the 1-, 3-, and 5-year survival rates were 98%, 79%, and 47%, 93%, 63%, and 29%, and 64%, 12%, and 0%, respectively. In our 108 patients with larger HCC, 1-, and 3-year survival rates were 72% and 57% in single, encapsulated tumors, 73% and 42% in single infiltrating or multiple encapsulated tumors, and 46% and 0% in symptomatic or with advanced portal thrombosis tumors. PEI proved to be a safe, effective, repeatable, easy, and low-cost therapy for HCC. Survival after PEI was comparable to that after surgical resection, probably because of the balance between the greater complete ablation rate of surgery compared to the absence of early mortality and liver damage using PEI. On the basis of the PEI rationale, other ablation techniques were proposed using radio frequency, laser, or acetic acid methods, and their initial results are promising.

In this study we discuss and evaluate the use of percutaneous ethanol injection for the treatment of hepatocellular carcinoma in cirrhosis.Percutaneous ethanol injection was performed under ultrasound guidance, with multiple sessions at an outpatient department or with "single-session" technique under general anesthesia, according to the size and number of the lesions.In our patients with Child A (293), B (149), or C (20) cirrhosis and single hepatocellular carcinoma 5 cm or smaller, the 1-, 3- and 5-year survival rates were 98, 79 and 47%, 93, 63 and 29%, and 64, 12 and 0%, respectively. In our 108 patients with larger hepatocellular carcinoma, 1- and 3-year survival rates were: 72 and 57% in single, encapsulated tumors, 73 and 42% in single infiltrating or multiple encapsulated tumors, and 46 and 0% in symptomatic or with advanced portal thrombosis tumors.Percutaneous ethanol injection proved to be a safe, effective, repeatable, easy and low-cost therapy for hepatocellular carcinoma. Survival after percutaneous ethanol injection was comparable to that after surgical resection, probably because of a balancing between greater complete ablation rate of surgery versus absence of early mortality and liver damage of percutaneous ethanol injection. On the basis of the percutaneous ethanol injection rationale, other ablation techniques were proposed using radiofrequency, laser or acetic acid. Their initial results are promising.

Percutaneous ethanol injection (PEI) under ultrasonography guidance has been widely tried in not advanced hepatocellular carcinoma (HCC). Ten years after the introduction of PEI, some conclusions of its indications can be drawn. In our series, 210 cirrhotic patients were treated; 141 with multisession PEI in an outpatient clinic, 57 with "single session" PEI under general anesthesia, and 12 with both. The 1-, 3-, and 5-year survival rates (by Kaplan-Meier method) were 953%, 65%, and 41% for Child class A patients with single HCC < or = 5 cm, and 88%, 47%, and 33% for patients with multiple HCC up to five lesions < or = 5 cm. In these patients the local recurrence rate was 15% and the new lesion rate at the 5-year follow-up was 74%. One death due to hemorrhage from esophageal varices in a Child class C patient treated by single session PEI occurred. The large number of cirrhotic patients demand for effective, safe, repeatable, low-cost treatment that can be offered at many centers. PEI meets all these requirements. PEI is proposed as the treatment of choice for the mentioned patients, excluding candidates for liver transplantation and surgical resection according to the predictive adverse factors currently in use. "Single session" technique widened the indications of traditional PEI to larger lesions.