The Role of Carbon Ion Therapy in the Changing Oncology Landscape-A Narrative Review of the Literature and the Decade of Carbon Ion Experience at the Italian National Center for Oncological Hadrontherapy.

BACKGROUND: Currently, 13 Asian and European facilities deliver carbon ion radiotherapy (CIRT) for preclinical and clinical activity, and, to date, 55 clinical studies including CIRT for adult and paediatric solid neoplasms have been registered. The National Center for Oncological Hadrontherapy (CNAO) is the only Italian facility able to accelerate both protons and carbon ions for oncological treatment and research. METHODS: To summarise and critically evaluate state-of-the-art knowledge on the application of carbon ion radiotherapy in oncological settings, the authors conducted a literature search till December 2022 in the following electronic databases: PubMed, Web of Science, MEDLINE, Google Scholar, and Cochrane. The results of 68 studies are reported using a narrative approach, highlighting CNAO's clinical activity over the last 10 years of CIRT. RESULTS: The ballistic and radiobiological hallmarks of CIRT make it an effective option in several rare, radioresistant, and difficult-to-treat tumours. CNAO has made a significant contribution to the advancement of knowledge on CIRT delivery in selected tumour types. CONCLUSIONS: After an initial ramp-up period, CNAO has progressively honed its clinical, technical, and dosimetric skills. Growing engagement with national and international networks and research groups for complex cancers has led to increasingly targeted patient selection for CIRT and lowered barriers to facility access.

Biomedical Research Programs at Present and Future High-Energy Particle Accelerators.

Biomedical applications at high-energy particle accelerators have always been an important section of the applied nuclear physics research. Several new facilities are now under constructions or undergoing major upgrades. While the main goal of these facilities is often basic research in nuclear physics, they acknowledge the importance of including biomedical research programs and of interacting with other medical accelerator facilities providing patient treatments. To harmonize the programs, avoid duplications, and foster collaboration and synergism, the International Biophysics Collaboration is providing a platform to several accelerator centers with interest in biomedical research. In this paper, we summarize the programs of various facilities in the running, upgrade, or construction phase.

[The Italian National Center for Oncological Adrotherapy (CNAO): status and perspectives]. / Il Centro Nazionale di Adroterapia Oncologica (CNAO): stato e prospettive.

SUMMARY: A complex particle accelerator has been built at the Italian National Centre for Oncological Adrotherapy in Pavia, called synchrotron, which is able to decompose atoms and create beams of particles to be directed to tumour cells in order to destroy them. It is the hadrontherapy, a very advanced radiation therapy for the treatment of X-ray resistant or inoperable tumours. In particular, the CNAO synchrotron in Pavia is the only one in Italy capable of extracting carbon ions from the atom, which are the most powerful particles capable of destroying the DNA of cancer cells while preserving the surrounding healthy tissues. Hadrontherapy has been recently included by the Italian Ministry of Health into the essential levels of assistance, recognizing its scientific validity. All Italian citizens can access treatments within the National Health System, according to defined modalities. More than 50 patients are treated at CNAO every day and to date more than 2300 cancer patients from all over Italy have been able to benefit from hadrontherapy. The article will illustrate the technological innovation of the centre in Pavia and will focus on the most interesting research and development projects.

Online proton therapy monitoring: clinical test of a Silicon-photodetector-based in-beam PET.

Particle therapy exploits the energy deposition pattern of hadron beams. The narrow Bragg Peak at the end of range is a major advantage but range uncertainties can cause severe damage and require online verification to maximise the effectiveness in clinics. In-beam Positron Emission Tomography (PET) is a non-invasive, promising in-vivo technique, which consists in the measurement of the ß+ activity induced by beam-tissue interactions during treatment, and presents the highest correlation of the measured activity distribution with the deposited dose, since it is not much influenced by biological washout. Here we report the first clinical results obtained with a state-of-the-art in-beam PET scanner, with on-the-fly reconstruction of the activity distribution during irradiation. An automated time-resolved quantitative analysis was tested on a lacrimal gland carcinoma case, monitored during two consecutive treatment sessions. The 3D activity map was reconstructed every 10 s, with an average delay between beam delivery and image availability of about 6 s. The correlation coefficient of 3D activity maps for the two sessions (above 0.9 after 120 s) and the range agreement (within 1 mm) prove the suitability of in-beam PET for online range verification during treatment, a crucial step towards adaptive strategies in particle therapy.

Simple and Quick Method to Obtain a Decellularized, Functional Liver Bioscaffold.

The development of new approaches for organ transplantation has become crucial in the last years. In particular, organ engineering, involving the preparation of acellular matrices that provide a natural habitat for reseeding with an appropriate population of cells, is an attractive although technically demanding approach. We here describe a method that allows for the derivation of functional in vitro hepatic organoids and that does not require a previous selection of all the parenchymal hepatocytes and non-parenchymal cells, namely, Kupffer cells, liver endothelial cells, and hepatic stellate cells. The procedure also replaces the costly standard collagenase perfusion step with a trypsin-based enzymatic digestion that results in high-yield decellularization. A combination of physical and chemical treatments through deep immersion and intraluminal infusion of two different consecutive solutions is used: (1) deionized water (DI) and (2) DI + Triton X 1% + ammonium hydroxide (NH4OH) 0.1%. This ensures the isolation of the hepatic constructs that reliably maintain original architecture and ECM components while completely removing cellular DNA and RNA. The procedure is fast, simple, and cheap and warrants an optimal organoid functionality that may find applications in both toxicological and transplantation studies.

Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter restropective study of 1,006 nodules.

BACKGROUND & AIMS: The use of contrast enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis was questioned because of the risk of a false positive diagnosis in cases of cholangiocarcinoma. The American College of Radiology has recently released a scheme (CEUS Liver Imaging Reporting and Data System [LI-RADS®]) to classify lesions at risk of HCC investigated by CEUS. The aim of the present study was to validate this LI-RADS scheme for the diagnosis of HCC. METHODS: A total of 1,006 nodules from 848 patients with chronic liver disease at risk of HCC were collected in five Italian centers and retrospectively analyzed. Nodules were classified as LR-5, (HCC) if ≥1 cm with arterial phase hyperenhancement, and late washout (onset ≥60 s after contrast injection) of mild degree. Rim enhancement and/or early and/or marked washout qualified lesions as LR-M (malignant, but not specific for HCC). Other combinations qualified lesions at intermediate risk for HCC (LR-3) or probable HCC (LR-4). Diagnostic reference standard was CT/MRI diagnosis of HCC (n = 506) or histology (n = 500). RESULTS: The median nodule size was 2 cm. Of 1,006 nodules, 820 (81%) were HCC, 40 (4%) were cholangiocarcinoma, 116 (11%) regenerative nodules (±dysplastic). The LR-5 category (52% of all nodules) was 98.5% predictive of HCC, with no risk of misdiagnosis for pure cholangiocarcinoma. Sensitivity for HCC was 62%. All LR-M nodules were malignant and the majority of non-hepatocellular origin. Over 75% of cholangiocarcinomas were LR-M. The LR-3 category included 203 lesions (HCC 96 [47%]) and the LR-4 202 (HCC 173 [87%]). CONCLUSIONS: The CEUS LI-RADS class LR-5 is highly specific for HCC, enabling its use for a confident non-invasive diagnosis. LAY SUMMARY: This is a retrospective study of approximately 1,000 focal lesions at risk for hepatocellular carcinoma (HCC). Herein, we demonstrate that the refined definition of the typical contrast enhanced ultrasound pattern of HCC introduced by the Liver Imaging Reporting and Data System (LI-RADS®) practically abolishes the risk of misdiagnosis of other malignant entities (e.g. cholangiocarcinoma) for HCC with negligible reduction in sensitivity. These data support the use of contrast enhanced ultrasound to diagnose HCC in cirrhosis.

The Prognosis of Patients with Liver Metastases from Colorectal Cancer still Depends on Anatomical Presentation more than on Treatments.

BACKGROUND: The best management of liver metastases from colorectal cancer is still debated and little is known about the true impact of treatments on survival. MATERIALS AND METHODS: The study involved 122 patients (77 males), aged 64.0 ± 11.0 years (range: 27.8-86.1) at diagnosis of liver metastatization (synchronous in 59). All underwent chemotherapy and at least one procedure of radiofrequency ablation; 53 also had partial hepatic resections. Demographics, tumor characteristics and survival outcomes from liver metastatization were analyzed with univariate and multivariate techniques. This analysis was performed also taking into account relative survival as the best estimate of specific survival. RESULTS: The analysis with observed survival selected the categorized number of involved lymph nodes in the colorectal specimens as the only statistically significant predictor, while the analysis with relative survival also showed site of the primary tumor (above the sigmoid colon or otherwise) and number of liver metastases as significant factors. The standardized mortality ratio was 9.673 (95% CI: 7.668-11.663) and a total of 201.85 years of life were lost in comparison with the survival of the reference population. CONCLUSIONS: The computation of relative survival ­ better than observed survival ­ selected a more adequate number of predictors, making investigation of even limited series of patients with confounding factors reliable. The finding that prognosis was mainly dependent on the anatomical presentation of the primary tumor and of liver metastases ­ instead of treatments ­ could explain the still contrasting opinions on the role of the available therapies in this field.

The National Centre for Oncological Hadrontherapy (CNAO): Status and perspectives.

The National Centre for Oncological Hadrontherapy (CNAO, sited in Pavia, Italy) completed at the end of 2013 the clinical trial phase achieving the CE label from the notified body of the Italian Health Ministry and obtained the authorisation to treat patients within the national health system. Nowadays more than 400 patients completed the treatments, two thirds of them with carbon ions, and recently started the treatment of pathologies located within moving organs. For the first time in the world carbon ions delivered with active scanning, coupled with breathing synchronisation and rescanning modalities have been applied to treat patients affected by tumours of the liver and by pancreatic cancers. The path to reach the final CE label required a wide-ranging experimental activity that went through dosimetry measurements of the hadron beams, in-vitro and in-vivo radiobiology essays and treatments of 150 patients, all enrolled in one of the 23 clinical trials approved by the Ethical Committee of CNAO and then authorized by the Italian Ministry of Health. The results of the trials were very positive in terms of safety and reliability of the procedures. The follow-up period is still short, but preliminary good results are observed in particular in terms of limited toxicity, that on the whole is less than expected. The paper gives a status report on the experimental phase that completed the CE certification process and then outlines the ongoing activities with also indications on the future trends and the most interesting R&D programmes pursued at CNAO.

Expression of pERK and VEGFR-2 in advanced hepatocellular carcinoma and resistance to sorafenib treatment.

BACKGROUND & AIMS: The study aimed to evaluate the tissue expression of molecules involved in intracellular signalling pathways as predictors of response to sorafenib in advanced hepatocellular carcinoma (HCC). METHODS: We considered 77 patients enrolled into three prospective trials of sorafenib treatment for whom pretreatment tumour tissue was available. The tissue expression of ß-catenin, glutamine synthetase (GS), phosphorylated extracellular signal regulated kinase (pERK), phosphorylated v-akt murine thymoma viral oncogene homolog (pAKT) and vascular endothelial growth factor receptor-2 (VEGFR-2) was analysed by immunostaining. Stains were scored semiquantitatively and compared with a reference group of 56 untreated HCCs. RESULTS: Overall, the expression of antigens was comparable between treated and untreated patients. Shorter progression-free survival (PFS) and overall survival (OS) were associated with increased pERK staining (≥ 2+ scores) (PFS: 75th percentile 4.4 vs 8.4 months; P = 0.01; OS: 75th percentile 7.0 vs 15.0 months; P = 0.005) and VEGFR-2 staining (≥ 2+ scores) (PFS: 75th percentile 3.8 vs 7.0 months; P = 0.039; OS: 75th percentile 6.3 vs 15.0 months; P = 0.004). At multivariate analysis, both pERK and VEGFR-2 staining maintained an independent effect on OS (HR 2.09; 95% CI, 1.13-3.86, P = 0.019 and HR 2.28; 95% CI, 1.13-4.61, P = 0.021 respectively). No effect was observed for the other tested biomarkers. CONCLUSIONS: Elevated tissue expression of pERK and VEGFR-2 was predictive of poor outcome in advanced HCC treated with sorafenib.

Portal hypertensive gastropathy in cirrhotics without varices: a case-control study.

OBJECTIVE: Information is lacking on portal hypertensive gastropathy (PHG) in cirrhotics without varices; our aim it is to evaluate whether clinical and sonographic parameters are associated with PHG and may provide information suitable for the management of these patients. PATIENTS AND METHODS: After endoscopic selection of 145 cirrhotics without varices, 75 with PHG and 70 without PHG, clinical and sonographic characteristics were assessed. RESULTS: Forty portosystemic shunts were present in 27 patients. The mean Child-Pugh score was 6.3±1.4 and 5.6±0.5 in patients with severe and mild PHG, respectively (P=0.004). The mean portal vein diameter was 10.4±1.7 and 11.6±2.0 mm in cirrhotics without and with PHG, respectively (P=0.0002). CONCLUSION: A link between the presence of PHG and a more advanced phase of cirrhosis was found. Duplex Doppler sonography was confirmed to be a valuable diagnostic method in monitoring cirrhosis. Management of these patients cannot be performed on the basis of a single diagnostic method, and a multimodal diagnostic approach is required.

The challenge of extraabdominal desmoid tumour management in patients with Gardner's syndrome: radiofrequency ablation, a promising option.

Desmoid tumours are benign, myofibroblastic stromal neoplasms common in Gardner's syndrome, which is a subtype of familial adenomatous polyposis characterized by colonic polyps, osteomas, thyroid cancer, epidermoid cysts, fibromas and sebaceous cysts. The primary treatment is surgery, followed by adjuvant radiotherapy, but the local recurrence rate is high, and wide resection can result in debilitating loss of function. We report the case of a 39-year-old man with Gardner's syndrome who had already undergone a total prophylactic colectomy. He developed desmoid tumours localized in the mesenteric root, abdominal wall and dorsal region, which were treated from 2003 through 2013 with several surgical procedures and percutaneous radiofrequency ablation. In 2008 and 2013, RFA was applied under ultrasonographic guidance to two desmoid tumours localized in the dorsal thoracic wall. The outcomes were low-grade pain and one case of superficial skin necrosis, but so far there has been no recurrence of desmoid tumours in these locations. Surgical resection remains the first-line therapy for patients with desmoid tumours, but wide resection may lead to a poor quality of life. Radiofrequency ablation is less invasive and expensive and is a possible therapeutic option for desmoid tumours in patients with Gardner's syndrome.

Fiber-optic chirped FBG for distributed thermal monitoring of ex-vivo radiofrequency ablation of liver.

A linearly chirped fiber Bragg grating (LCFBG) has been used as a temperature sensor for online monitoring of radiofrequency thermal ablation (RFTA). The LCFBG acts as a distributed sensor, with spatial resolution of 75 µm. A white-light setup that records the LCFBG spectrum estimates the temperature profile in real time. Three RFTA experiments have been performed ex-vivo on porcine liver measuring the radial temperature distribution during the heating process. The analysis of thermal maps quantifies the spatial heat distribution along the measurement axis and determines the ablation efficiency.

Fiber-optic combined FPI/FBG sensors for monitoring of radiofrequency thermal ablation of liver tumors: ex vivo experiments.

We present a biocompatible, all-glass, 0.2 mm diameter, fiber-optic probe that combines an extrinsic Fabry-Perot interferometry and a proximal fiber Bragg grating sensor; the probe enables dual pressure and temperature measurement on an active 4 mm length, with 40 Pa and 0.2°C nominal accuracy. The sensing system has been applied to monitor online the radiofrequency thermal ablation of tumors in liver tissue. Preliminary experiments have been performed in a reference chamber with uniform heating; further experiments have been carried out on ex vivo porcine liver, which allowed the measurement of a steep temperature gradient and monitoring of the local pressure increase during the ablation procedure.

Radiofrequency ablation of pancreatic neuroendocrine tumors: a pilot study of feasibility, efficacy, and safety.

OBJECTIVE: This study aimed to assess the feasibility, safety, and efficacy of radiofrequency ablation (RFA) of pancreatic neuroendocrine tumors (PNETs). METHODS: We performed RFA on 10 patients (7 women) aged 38 to 75 years with histologically diagnosed PNETs (secreting in 3 cases) who could not or would not undergo surgical resection. Tumor nodules (diameter, 0.9-2.9 cm; mean [SD], 1.6 [0.5] cm) were located in the head (n = 7) or body (n = 3) of the pancreas. Ultrasound-guided RFA was performed percutaneously (n = 7), endoscopically (n = 1), or intraoperatively (n = 2) using commercially available equipment. Complete ablation was defined as absence of enhancing tissue at the tumor site on contrast-enhanced imaging studies and normalization of previously elevated serum hormone levels. RESULTS: Complete ablation was achieved with 1 (n = 9) or 2 (n = 1) RFA procedures. All neuroendocrine syndromes regressed within 24 hours of treatment. No recurrences were observed during follow-up (range, 12-60 months; median [SD], 34 [14] months). No deaths occurred. Major complications included acute pancreatitis in 3 patients, 2 of whom developed pancreatic fluid collections that were successfully managed with ultrasound-guided drainage and endoscopy. CONCLUSIONS: Radiofrequency ablation is a feasible, safe, and effective option for patients with small PNETs who cannot or do not want to undergo surgical resection.

Proton beam radiotherapy: report of the first ten patients treated at the "Centro Nazionale di Adroterapia Oncologica (CNAO)" for skull base and spine tumours.

PURPOSE: The Italian National Centre for Oncological Hadrontherapy (Centro Nazionale di Adroterapia Oncologica, CNAO), equipped with a proton and ion synchrotron, started clinical activity in September 2011. The clinical and technical characteristics of the first ten proton beam radiotherapy treatments are reported. MATERIALS AND METHODS: Ten patients, six males and four females (age range 27-73 years, median 55.5), were treated with proton beam radiotherapy. After one to two surgical procedures, seven patients received a histological diagnosis of chordoma (of the skull base in three cases, the cervical spine in one case and the sacrum in three cases) and three of low-grade chondrosarcoma (skull base). Prescribed doses were 74 GyE for chordoma and 70 GyE for chondrosarcoma at 2 GyE/fraction delivered 5 days per week. RESULTS: Treatment was well tolerated without toxicity-related interruptions. The maximal acute toxicity was grade 2, with oropharyngeal mucositis, nausea and vomiting for the skull base tumours, and grade 2 dermatitis for the sacral tumours. After 6-12 months of follow-up, no patient developed tumour progression. CONCLUSIONS: The analysis of the first ten patients treated with proton therapy at CNAO showed that this treatment was feasible and safe. Currently, patient accrual into these as well as other approved protocols is continuing, and a longer follow-up period is needed to assess tumour control and late toxicity.

Proton beam radiotherapy: report of the first patient treated at the Centro Nazionale di Adroterapia Oncologica (CNAO) [National Center of Oncologic Hadron Therapy].

Proton beam radiotherapy, an innovative treatment modality, allows delivery of high radiation doses to the target while sparing surrounding healthy structures. The Centro Nazionale di Adroterapia Oncologica (CNAO), equipped with a synchrotron and capable of using both protons and ions, initiated its clinical activity in September 2011. The first treatment of a skull base tumor with protons is reported here. The case of a 26-year-old man with an intracranial low-grade chondrosarcoma of the right petroclival junction is discussed with emphasis on technical and clinical details. Two previous surgical interventions had achieved partial removal of the tumor and the patient was treated with protons for residual disease. The prescribed dose was 70 GyE in 35 fractions of 2 GyE. Treatment was completed with minimal acute toxicity consisting of grade 1 alopecia and nausea. Nine months after treatment the disease is locally controlled. Use of high-energy protons at CNAO is a safe and effective means of treating a tumor located near critical normal structures.

Histologic changes in type A chronic atrophic gastritis indicating increased risk of neuroendocrine tumor development: the predictive role of dysplastic and severely hyperplastic enterochromaffin-like cell lesions.

The role of putative preneoplastic enterochromaffin-like cell lesions, either hyperplastic or dysplastic, in the genesis of type 1 enterochromaffin-like cell neuroendocrine tumors associated with type A chronic atrophic gastritis, their actual neoplastic risk, and their precise histogenetic mechanism deserve further clarification by specific histopathologic studies coupled with patient follow-up. A total of 100 patients with severe type A chronic atrophic gastritis, enterochromaffin-like cell hyperplasia, and antral G-cell hyperplasia were endoscopically and histologically followed up for a median of 90.1 months (total of 9118 person-months). Preneoplastic enterochromaffin-like cell lesions and newly developed neuroendocrine tumors were investigated histologically and histochemically, in parallel with enterochromaffin-like cell lesions found in nontumor mucosa of another 32 well-characterized and previously reported type 1 neuroendocrine tumors. Both neuroendocrine and nonneuroendocrine mucosa changes were analyzed and statistically evaluated. During follow-up, 7 of 100 patients developed neuroendocrine tumors: 5 were in a group of 20 cases with previous enterochromaffin-like cell dysplasia and 2 were among 80 cases showing only enterochromaffin-like cell hyperplasia throughout the study (hazard ratio, 20.7; P < .001). The severity of enterochromaffin-like cell hyperplasia at first biopsy, with special reference to linear hyperplasia with 6 chains or more per linear millimeter, also increased the risk of neuroendocrine tumor development during follow-up (hazard ratio, 13.0; P < .001). Enterochromaffin-like cell microinvasive dysplastic lesions arising at the epithelial renewal zone level, in connection with immature proliferating mucous-neck cells, were found to be linked to early intramucosal neuroendocrine tumor histogenesis. Both enterochromaffin-like cell dysplasia and severe hyperplasia indicate increased risk of neuroendocrine tumor development in type A chronic atrophic gastritis with hypergastrinemia/G-cell hyperplasia.

Patterns of appearance and risk of misdiagnosis of intrahepatic cholangiocarcinoma in cirrhosis at contrast enhanced ultrasound.

AIM: Primary aim was to validate the percentage of intrahepatic cholangiocarcinomas (ICC) which have a contrast vascular pattern at contrast enhanced ultrasound (CEUS) at risk of misdiagnosis with hepatocellular carcinoma (HCC) and, secondary aim, to verify if any characteristics in the CEUS pattern helps to identify ICC. METHODS: All ICC on cirrhosis seen in three Italian centres (Bologna, Milan and Pavia) between 2003 and 2011, in which CEUS and at least another imaging technique (CT or MRI) had been performed, were retrospectively identified. Those patients with ICC size comparable to the early HCC stage (Milan criteria, considered as small ICC) were enrolled for this study. The enhancement pattern at CEUS was analysed and compared with CT or MRI. RESULTS: A total of 25 small ICC made this study group. CEUS was at risk of misdiagnosis of ICC for HCC in a significantly higher number of cases than in CT (performed in 24 ICC) (52% vs. 4.2%, P = 0.009) and MRI (11 ICC) (52% vs. 9.1%, P = 0.02). A different contrast pattern among all techniques was found in 6 of 10 ICC lesions submitted to the three imaging methods. In the arterial phase, ICC lacked global hyperenhacement in approximately 50% of cases at CEUS and the degree of intensity of wash-out in the late phase was marked in 24% of nodules. CONCLUSIONS: CEUS misdiagnosed as HCC a significantly higher number of ICC lesions in cirrhotic patients than CT and MRI. However, some CEUS contrast features can help suspect ICC, especially in some cases with inconclusive CT or MRI.

Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: a long-term cohort study.

UNLABELLED: In most patients with cirrhosis, successful percutaneous ablation or surgical resection of hepatocellular carcinoma (HCC) is followed by recurrence. Radiofrequency ablation (RFA) has proven effective for treating HCC nodules, but its repeatability in managing recurrences and the impact of this approach on survival has not been evaluated. To this end, we retrospectively analyzed a prospective series of 706 patients with cirrhosis (Child-Pugh class ≤ B7) who underwent RFA for 859 HCC ≤ 35 mm in diameter (1-2 per patient). The results of RFA were classified as complete responses (CRs) or treatment failures. CRs were obtained in 849 nodules (98.8%) and 696 patients (98.5%). During follow-up (median, 29 months), 465 (66.8%) of the 696 patients with CRs experienced a first recurrence at an incidence rate of 41 per 100 person-years (local recurrence 6.2; nonlocal 35). Cumulative incidences of first recurrence at 3 and 5 years were 70.8% and 81.7%, respectively. RFA was repeated in 323 (69.4%) of the 465 patients with first recurrence, restoring disease-free status in 318 (98.4%) cases. Subsequently, RFA was repeated in 147 (65.9%) of the 223 patients who developed a second recurrence after CR of the first, restoring disease-free status in 145 (98.6%) cases. Overall, there were 877 episodes of recurrence (1-8 per patient); 577 (65.8%) of these underwent RFA that achieved CRs in 557 (96.5%) cases. No procedure-related deaths occurred in 1,921 RFA sessions. Estimated 3- and 5-year overall and disease-free (after repeated RFAs) survival rates were 67.0% and 40.1% and 68.0 and 38.0%, respectively. CONCLUSION: RFA is safe and effective for managing HCC in patients with cirrhosis, and its high repeatability makes it particularly valuable for controlling intrahepatic recurrences.