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Comment on “Does Thermal Ablation Increase or Decrease the Risk of Tumor Local Recurrence?”
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Purpose: Radiofrequency ablation (RFA) is widely accepted as a curative treatment for small hepatocellular carcinoma (HCC). However, insufficient RFA (IRFA) can lead to rapid local recurrence. The underlying mechanisms remain poorly understood. This study aimed to elucidate the role and regulatory mechanisms of autophagy in the recurrence of HCC after IRFA.
Materials and methods: SMMC7721 and Huh7 cells were exposed to sublethal heat stress to stimulate the transition zone of IRFA treatment. The levels of autophagy were measured by western blot, immunofluorescence and transmission electron microscopy. Functional assays, such as CCK-8, EdU incorporation and flow cytometry, were performed to determine the role of heat-induced autophagy. The involved signaling pathways were explored by western blot. Finally, the antitumor effects of chloroquine (CQ) on heat-treated HCC cells were evaluated via an in vivo xenograft tumor model.
Results: Sublethal heat stress induced autophagy in a temperature- and time-dependent manner in HCC cells. Furthermore, the inhibition of autophagy by CQ or siRNA targeting the autophagy-related genes Beclin-1 and Atg5 enhanced heat-induced apoptosis. The combination of CQ and heat treatment significantly suppressed tumor growth both in vitro and in vivo. Mechanistically, we reported for the first time that the ATP-AMPK-mTOR signaling pathway was involved in heat-induced autophagy.
Conclusions: Heat stress induced protective autophagy against heat-induced apoptosis in HCC via the ATP-AMPK-mTOR axis, suggesting that targeting autophagy may be a promising strategy for improving the efficacy of RFA treatment for HCC.
Irreversible electroporation (IRE) has recently gained in popularity as an ablative technique, however little is known about its oncological long-term outcomes. To determine the long-time survival of animals treated with a high dose of IRE and which histological changes it induces in tumoral tissue, IRE ablation was performed in forty-six athymic-nude mice with KM12C tumors implanted in the liver by applying electric current with different voltages (2000 V/cm, 1000 V/cm). The tumors were allowed to continue to grow until the animals reached the end-point criteria. Histology was harvested and the extent of tumor necrosis was semi-quantitatively assessed. IRE treatment with the 2000 V/cm protocol significantly prolonged median mouse survival from 74.3 ± 6.9 days in the sham group to 112.5 ± 15.2 days in the 2000 V/cm group. No differences were observed between the mean survival of the 1000 V/cm and the sham group (83.2 ± 16.4 days, p = 0.62). Histology revealed 63.05% ± 23.12 of tumor necrosis in animals of the 2000 V/cm group as compared to 17.50% ± 2.50 in the 1000 V/cm group and 25.6% ± 22.1 in the Sham group (p = 0.001). IRE prolonged the survival of animals treated with the highest electric field (2000 V/cm). The animals in this group showed significantly higher rate of tumoral necrosis.
To elucidate if a nonpositive <1-cm resection margin has any effect on hepatic recurrence in patients undergoing liver resection for colorectal liver metastases.
Six hundred and nine patients underwent 663 liver resections. Patients with positive margin were excluded from the analysis. Two groups were studied: group A, <1-cm resection margin and group B, > or =1-cm resection margin.
A total of 545 liver resections in 523 patients were carried out with nonpositive resection margins. With a median follow-up of 25 months, the 5-year cumulative hepatic recurrence reached 54% in group A (n = 206) and 41% in group B (n = 339). Factors associated with hepatic recurrence were synchronic metastases (P = 0.0015), bilobar (P < 0.001), two or more metastases (P < 0.001), margin <1 cm (P = 0.0123) and extrahepatic disease (P = 0.0037). A strong correlation between resection margin and number of metastases was confirmed (P < 0.001). At multivariate analysis only two factors were independent predictors of hepatic recurrence: multinodular disease in the liver specimen [> or =4 metastases hazard ratio (HR) = 3.45; 95% confidence interval (CI): 2.2-5.38; P < 0.001] and extrahepatic disease at hepatectomy (HR = 1.58; 95% CI: 1.58-3.32).
Subcentimeter nonpositive resection margins do not directly influence hepatic recurrence in patients undergoing hepatectomy for colorectal liver metastases.
Objective:
To determine the impact of radiofrequency (RF) and microwave (MW) energy compared to direct cautery on metatstatic colon cancer growth.
Background:
Hepatic ablation with MW and RF energy creates a temperature gradient around a target site with temperatures known to create tissue injury and cell death. In contrast, direct heat application (cautery) vaporizes tissue with a higher site temperature but reduced heat gradient on surrounding tissue. We hypothesize that different energy devices create variable zones of sublethal injury that may promote tumor recurrence. To test this hypothesis we applied MW, RF, and cautery to normal murine liver with a concomitant metastatic colon cancer challenge.
Methods:
C57/Bl6 mice received hepatic thermal injury with MW, RF, or cautery to create a superficial 3-mm lesion immediately after intrasplenic injection of 50K MC38 colon cancer cells. Thermal imaging recorded tissue temperature during ablation and for 10 seconds after energy cessation. Hepatic tumor location and volume was determined at day 7.
Results:
Cautery demonstrated the highest maximum tissue temperatures (129°C) with more rapid return to baseline compared to MW or RF energy. All mice had metastasis at the ablation site. Mean tumor volume was significantly greater in the MW (95.3 mm; P = 0.007) and RF (55.7 mm; P = 0.015) than cautery (7.13 mm). There was no difference in volume between MW and RF energy (P = 0.2).
Conclusions:
Hepatic thermal ablation promotes colon cancer metastasis at the injury site. MV and RF energy result in greater metastatic volume than cautery. These data suggest that the method of energy delivery promotes local metastasis.
Radiofrequency ablation (RFA) is considered to be a potentially curative therapy for hepatocellular carcinoma (HCC). However, insufficient RFA (IRFA) can promote rapid progression of the residual tumor. The mechanisms underlying IRFA-induced tumor promotion remain poorly understood. In the present study, we have established a subcutaneous xenograft mouse model and monitored the location and extent of IRFA by dual monitoring with ultrasonography and a thermal imager. For the first time, we provide evidence of the activation of autophagic pathways in mice exposed to IRFA. We show that autophagy plays an important role in relapse and proliferation after IRFA and that hydroxychloroquine (HCQ) can suppress these effects. Our findings indicate that autophagy is involved in experimental IRFA and that inhibition of autophagy may be a novel approach in the treatment of local recurrences of HCC after IRFA in the clinic.
Resection is the gold standard in the treatment of liver metastases from colorectal cancer. An internal cooled radiofrequency electrode was described to achieve tissue coagulation to a greater margin width. The aim of this study is to determinate if a RF-assisted transection device (RFAT) has any effect on local hepatic recurrence (LHER) compared to conventional technologies. A study population of 103 patients who had undergone a hepatic surgical resection was retrospectively analysed. Patients were classified into two groups according to the device used: a RF-assisted device (RFAT group; n = 45) and standard conventional devices (control group; n = 58). LHER was defined as any growing or enhancing tumour in the margin of hepatic resection during follow-up. Cox proportional models were constructed and variables were eliminated only if p > 0.20 to protect against residual confounding. To assess the stability of Cox's regression model and its internal validity, a bootstrap investigation was also performed. Baseline and operative characteristics were similar in both groups. With a mean follow-up of 28.5 months (range 2–106), in patients with positive margins, we demonstrated 0% of LHER in RFAT vs. 27% in control group (p = 0.032). In the multivariate analysis five factors demonstrated significant influence on the final model of LHER: RFAT group, size of the largest metastases, number of resected metastases, positive margin and usage of Pringle-manoeuvre. This study suggests that parenchymal transection using a RFAT able to create deep thermal lesions may reduce LHER especially in case of margin invasion during transection.
The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO(2) in about 10 mm diameter tumours grown s.c. in the leg of rats was 3.7 +/- 0.3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO(2) measured within 10-15 min after heating for 30 min at 42.5 degrees C was about three-fold greater than that in the control tumours. About 62% of pO(2) values measured in control tumours were <5 mm Hg. After heating at 42.5 degrees C for 30 min, 37% of pO(2) values were <5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.
The purpose of this study was to examine the effects of radiofrequency ablation (RFA) on tumor growth and growth factor expression in a murine model.
Surgical excision remains the only potentially curative therapy for hepatic malignancies. Tumor growth in the remaining liver may be accelerated after resection. The mechanism of this enhanced tumor growth remains unexplained, although growth factors that are released after hepatic resection (which facilitate liver regeneration) may play a role in residual tumor growth. RFA has become a viable alternative for patients who are not candidates for a curative resection. The effect of RFA on tumor growth and growth factor expression has not been studied.
Hepatic tumors were established by direct injection with CT-26, a murine adenocarcinoma. Tumors were treated by either partial hepatic resection (PH) or RFA. Hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) expression was measured at selected time intervals post-treatment. Tumor growth was measured by reinjection of CT-26 into the residual liver after treatment. Nine days after reinjection, tumor volume was calculated and compared with nontreated controls.
HGF and bFGF expression was significantly higher at baseline in the CT-26 tumor-bearing mice when compared with non-tumor-bearing controls (P = 0.00001 and P = 9 x 10, respectively). There was an increase in HGF and bFGF expression at 24 hours (P = 0.005, and P = 0.001) in the PH group. In the RFA group, there was a decrease in HGF and bFGF expression at 24 and 72 hours (P = 0.001 and P = 0.002). Tumor growth comparisons revealed an increase in tumor growth in the hepatectomy group (P = 0.006) but not the RFA group (P = 0.2).
Baseline growth factor expression in tumor-bearing mice is exponentially higher when compared with non-tumor-bearing controls. HGF and bFGF expression are increased posthepatectomy, and decreased post-RFA. Partial hepatectomy results in an increase in tumor growth in the residual liver. RFA did not increase tumor growth after treatment. While hepatectomy is the only curative option for patients with hepatic malignancies, it may accelerate growth of microscopic residual disease.
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ISSN: 0003-4932/16/XXXX-0001
DOI: 10.1097/SLA.0000000000003874