|Year : 2020 | Volume
| Issue : 7 | Page : 1603-1610
Adjuvant cytokine-induced killer cells with minimally invasive therapies augmented therapeutic efficacy of unresectable hepatocellular carcinoma
Zhi-Mei Huang1, Chun-Xiao Lai2, Meng-Xuan Zuo1, Chao An1, Xiu-Chen Wang1, Jin-Hua Huang1, Eerdunbagena Ning3
1 Department of Minimal Invasive Intervention, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
2 Department of Gastroenterology, Clifford Hospital, Guangzhou, China
3 Department of Interventional Radiology, Haiku People's Hospital, Haikou, China
|Date of Submission||16-Nov-2019|
|Date of Decision||12-May-2020|
|Date of Acceptance||22-Sep-2020|
|Date of Web Publication||9-Feb-2021|
Department of Interventional Radiology, Haiku People's Hospital, 43, Renmin Road, Haikou City, 570208
Department of Minimal Invasive Intervention, Sun Yat-sen University Cancer Center. 651, Dongfeng East Road, Guangzhou, 510060
Source of Support: None, Conflict of Interest: None
Objective: To investigate the safety and therapeutic efficacy of adjuvant cytokine-induced killer (CIK) cells to minimally invasive therapies in unresectable hepatocellular carcinoma (u-HCC).
Materials and Methods: Hundred patients diagnosed with having u-HCC in our department from January 1, 2001, to July 31, 2018, were recruited. Forty-three patients received microwave ablation (MWA) and transcatheter arterial chemoembolization (TACE) together with autologous CIK cell treatment (TACE + MWA + CIK group), whereas 57 patients received TACE and MWA only (TACE + MWA group). Postprocedural complications and cumulative therapeutic effects were assessed in all patients. The disease control rate, median survival time (MST), and cumulative survival rate were compared between the cohorts using the Kaplan–Meier method and unpaired Student's t-tests.
Results: The overall response (complete response [CR] + partial response [PR]) rate was 74.42% (32/43) and 77.19% (44/57) for TACE + MWA + CIK and TACE + MWA groups, respectively (P = 0.243). Those of the TACE + MWA + CIK group had better rates of disease control (CR + PR + stable disease) in contrast to the TACE + MWA group (87.72% vs. 79.07%, respectively) but this failed to achieve statistical significance (P = 0.748). Based on the Kaplan–Meier survival graphs, those of the TACE + MWA + CIK groups possessed markedly increased overall survival (41 months vs. 24 months, P = 0.002) and progression-free survival (17 months vs. 10 months, P = 0.023) rates in compared to the TACE + MWA group. Survival rates were raised also TACE + MWA + CIK group than in TACE + MWA group (P = 0.002), with a MST of 6.13 ± 0.83 months and 11.61 ± 1.59 months in the TACE + MWA + CIK and TACE + MWA groups, respectively. Patients in the TACE + MWA + CIK group were not reported to have any severe complications.
Conclusion: CIK cell immunotherapy as an adjuvant to TACE and MWA enhanced long-term prognosis and improved quality of life in patients with u-HCC. This regimen may be recommended as a novel treatment regime in u-HCC patients.
Keywords: Cytokine-induced killer cells, microwave ablation, therapeutic efficacy, transcatheter arterial chemoembolization, unresectable hepatocellular carcinoma
|How to cite this article:|
Huang ZM, Lai CX, Zuo MX, An C, Wang XC, Huang JH, Ning E. Adjuvant cytokine-induced killer cells with minimally invasive therapies augmented therapeutic efficacy of unresectable hepatocellular carcinoma. J Can Res Ther 2020;16:1603-10
|How to cite this URL:|
Huang ZM, Lai CX, Zuo MX, An C, Wang XC, Huang JH, Ning E. Adjuvant cytokine-induced killer cells with minimally invasive therapies augmented therapeutic efficacy of unresectable hepatocellular carcinoma. J Can Res Ther [serial online] 2020 [cited 2021 Jun 24];16:1603-10. Available from: https://www.cancerjournal.net/text.asp?2020/16/7/1603/308775
| > Introduction|| |
As the fourth most commonly occurring malignancy, hepatocellular carcinoma (HCC) is a primary cause of worldwide cancer-related death. Nevertheless, substantial advancement in early HCC therapy is of little significance given the large proportion of HCC patients who often present in the stages of inoperable disease. There is a lack of consensus guidelines for treating unresectable HCC (u-HCC). Studies have reported that transcatheter arterial chemoembolization (TACE) achieved favorable results both in the response rate and survival in advanced HCC., This therapy delivers chemotherapeutic agents directly into tumor-associated vessels, creating an effective high-dose toxic environment in the tumor while lowering systemic toxicity. TACE has proved to be an effective means of improving patients' overall survival (OS) time in the past 30 years. Data from recent studies suggested that TACE combined with local thermal ablation improved the prognosis and promoted longer survival of patients with u-HCC.,, The addition of thermal ablation therapy has been shown to augment the efficacy of TACE. Despite the discovery of these many modes of treatment, long-term survival of u-HCC is not favorable because of its high incidence of recurrence and distant metastases.,
Cytokine-induced killer (CIK) cells represent a promising therapeutic strategy in the ongoing battle against cancer, with its efficaciousness proven in a number of recent clinical trials. Studies had proved that CIK cells may increase OS in HCC patients. CIK cells are derived from intravascular mononuclear cells and through exposure to cytokines such as interferon-gamma (IFN-γ), interleukin (IL)-1, IL-2, and CD3 monoclonal antibody are triggered to evolve into cytotoxic T-lymphocytes CIK cells with high histocompatibility presented little cytotoxicity to normal cells, while demonstrating strong anti-tumor cytotoxicity. These cells have been applied for various tumor treatments. Previous clinical trials suggest that immunotherapy involving CIK cells resulted in higher recurrence-free survival (RFS) posthepatectomy. Data suggest that transfusion with CIK cells imparted an immune-enhancing effect in patients with HCC, an important factor in reducing recurrence rates.
Encouraged by these promising results, our study looks the effect of CIK immunotherapy when used to manage u-HCC patients who were first treated with TACE and microwave ablation (MWA). Studies regarding the benefits of such a regimen in u-HCC patients are few. Our previous study laid the foundation by showing that a combination of TACE, radiofrequency ablation (RFA), and CIK immunotherapy in HCC patients feasible and safe means of reducing metastatic rates and recurrence. In this study, the long-term efficacy, safety, and OS rates were evaluated in patients with u-HCC designated to either TACE + MWA + CIK or TACE + MWA treatment regimens to determine the effectiveness of adjuvant immunotherapy in improving overall and cancer-specific survival in u-HCC patients.
| > Materials and Methods|| |
This investigation was performed out through a retrospective analysis of existing patient databases extracted from the Sun Yat-sen University Cancer Center (Guangzhou, China) in a consecutive manner between the dates of January 1, 2001 to December 10, 2015. The eligibility criteria of the selected patients were as follows: (1) HCC diagnosed in accordance to the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver for HCC; (2) tumors large enough to bar adequate postresection functional liver volume or ≥3 tumor nodules of any size; (3) Patients who had a score of <1 in Eastern Co-operative Oncology Group performance status scoring and who had good existing liver function (Child-Pugh Class A or B); (4) No history of prior radiotherapy chemotherapy or surgery; (5) alanine transaminase (ALT) and aspartate aminotransferase (AST) <5 folds above the upper limit of normal, bilirubin levels <3 mg/dl, and no thrombus in the main portal vein. Patients were not eligible for this study if there were found to have intractable deranged coagulation profiles, bleeding tendency, current recruitment in other trials or if they had a history of other malignancies. A total of 100 patients with u-HCC were included for the further analysis. Of these, 43 received minimally invasive therapies and postoperative CIK cell immunotherapy (TACE + MWA + CIK group), whereas the other 57 cases were treated minimally invasive therapies only (TACE + MWA group).
A 5-Fr Yashiro catheter (Terumo, Tokyo, Japan) cannulating the right femoral artery with the Seldinger technique was used to carry out TACE. Tumor arterial supply was visualized by carrying out angiographies of the superior mesenteric artery, hepatic artery, and celiac trunk to determine the feasibility of super selective catheterization, which if was carried out, was done using a micro-catheter as far as possible. TACE was carried out with a mixture of 10–30 ml of Lipiodol (LaboratorieGuerbet, Aulnay-sous-Bois, France), 20–50 mg of Lobaplatin (Chang'an International Pharmaceutical, Hainan, China), and 40–60 mg of Epirubicin (Farmorubicin; Pharmacia, Tokyo, Japan) through fluoroscopy-guided slow injections. Complete filling of the target lesion or back-flow of the chemical agents was taken as the markers of adequate TACE. This was followed by the use of gelatin sponge particles to embolize the primary feeding artery in cases where the artery failed to demonstrate stagnant flow after complete dosage of the TACE solution. Follow-up imaging was performed in 3–4 weeks posttreatment, with repeat TACE performed on any residual hypervascular liver tumors. TACE treatment was stopped if the patient showed signs of insufficient liver function, severe life-threatening complications, or experienced disease progression.
In the case of residual hypovascular tumors, MWA was carried out in 3–4 weeks after TACE. Computed tomography (CT)-guided cannulation of the tumor with a microwave needle was performed, with the degree of radiowave deployment determined in accordance to the shape and size of the tumor. All procedures were done under anesthesia.
Briefly, based on the lesion location, patients were positioned either prone or supine. After local anesthesia, the needle (MTC-3C, Nanjing Qinghai Research Institute of Microwave Electric, China) was inserted into the tumor at an angle that was predetermined. CT scans were performed to confirm the correct location of the ablation electrode. Duration of ablation and power adjustments was done based on manufacturer instructions. A single session was limited to the treatment of five lesions, with the overlapping technique used to ensure that the entire tumor was eradicated.
To prepare the CIK cells, we collected 50 ml of peripheral blood which was then processed using previously described methods., The State Key Laboratory of Oncology in South China performed all CIK manufacturing with samples collected only after patients had received MWA and TACE. All patients received a minimum of four cycles of CIK cell immunotherapy, with 2 weeks between each cycle. Minimally invasive therapy was performed immediately after the blood collection if deemed necessary after reviewing magnetic resonance imaging (MRI)/CT images. CIK maintenance treatment was provided for the same patients unless they were diagnosed with disease progression.
All cases involved a minimum of one of each of MWA and TACE procedures in the follow-up study. Patients that required additional TACE or MWA therapy only received them if they had satisfactory Karnofsky Performance Score and adequate residual liver function. After TACE and MWA, patients in the TACE + MWA + CIK group received CIK cells fortnightly, with a median successive time of CIK cells therapy at six times (range, 4–14 times). A detailed procedure is shown in [Figure 1]. Those of the TACE + MWA group were not recipients of CIK cell therapy. Local therapy (such as 125I seed implantation, RFA, and so on) was performed in patients with newly diagnosed or existing lymph node, lung or any other sites of extra-hepatic metastasis. Supportive management was provided to those who progressed to develop infiltrative HCC or met any of the exclusion criteria during study recruitment.
|Figure 1: Method of preparation of CIK cells. Peripheral blood (50 ml) was collected from all patients in the TACE + MWA + CIK group. Secondly, isolation and culture of mononuclear cells were done with IFN-γ, IL-2, CD3McAb and IL-1α for 14 days. 1.1–1.5 × 1010 CIK cells were infused intravenously each treatment session which was carried out at 2 week intervals. CIK = Cytokine-induced killer, TACE = Transcatheter arterial chemoembolization, MWA = Microwave ablation, IFN-γ = Interferon-gamma, IL = Interleukin|
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Evaluation of clinical efficacy
Liver function and treatment response were evaluated in 3–4 weeks posttreatment using the following parameters: Prothrombin time (PT), ALT, AST, and alfa-fetoprotein (AFP). At 3 months after the allocated treatment, a contrast-enhanced CT/MRI or positron emission tomography-CT was performed to assess response based on the modified response evaluation criteria in solid tumors. In brief, the complete lack of tumor arterial enhancement was deemed to be complete response (CR). Tumors that shrunk ≥ 30% in diameter were defined as having partial response (PR). Tumors that grew a minimum of 20% of their largest diameter recorded since treatment started or the appearance of one or more new lesions were defined as having progressive disease (PD). Stable disease (SD) was cases that did not fulfil the criterion set out by PD, PR or CR. The National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3 (CTCAE v3.0, National Cancer Institute, Bethesda, Maryland, America) was used to determine the complications at 48 h and every 4 weeks after treatment. The primary safety endpoints were liver toxicity affecting PT, ALT, AST, bilirubin, and albumin.
Follow-up and statistical analysis
Long-term follow-up of all cases in this study was started from when HCC was first diagnosed lasting until the time of death or last follow-up. The deadline for all cases was July 31, 2018. All data were analyzed using the Statistical Package for the Social Sciences (SPSS) software (version 16.0, SPSS Inc., Chicago, IL, USA) for Windows/The Mann–Whitney U-test and Student's t-test were used to evaluate differences of intergroup continuous variables, whereas categorical variables were analyzed with the Pearson Chi-square test and Fisher's exact test. The survival curves of OS and progression-free survival (PFS) were constructed according to the Kaplan–Meier method with the log-rank test, with the life table used to determine 1-, 3-, 5-, and 10-year survival rates. All statistical tests were two-sided, and P < 0.05 was interpreted as having significance.
| > Results|| |
Patient clinical characteristics
Factors (such as age, gender, AFP level, presence of liver cirrhosis, HBsAg, and vascular invasion) that had the potential to influence treatment outcomes were distributed evenly across both cohorts [Table 1]. There were 13 females and 87 meals in this study that were of a median age of 50 years (range, 22–83 years). Both groups had higher numbers of those with hepatitis B virus infection and males. Eighty-four percent of the patients were of Child-Pugh Class A liver function. The median tumor diameter was 9 cm (range: 5–26 cm). The BCLC stage of the patients consisted of stage B (77%) and C (23%). Tumor burden and patient demographics were not significantly different across both groups.
|Table 1: Baseline characteristics of hepatocellular carcinoma patients in the transcatheter arterial chemoembolization + microwave ablation + cytokine-induced killer group and the transcatheter arterial chemoembolization + microwave ablation group (cases)|
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Both TACE + MWA or TACE + MWA + CIK groups were subjected to detailed examination. Overall response (CR + PR) rate was 74.42% (32/43) and 77.19% (44/57) for the TACE + MWA + CIK and TACE + MWA groups, respectively (P = 0.243). Those in the TACE + MWA + CIK group had better rates of disease control (CR + PR + SD) than in the TACE + MWA group (87.72% vs. 79.07%), but this was not statistically significant.(P = 0.748). [Table 2] depicts the relevant details. [Figure 2] shows the images of a 58-year-old female patient with a large HCC that was diagnosed based on a CT-scan done in view of serum a-fetoprotein (AFP) >121000 ng/mL (normal value, 25.0 ng/ml). Imaging demonstrates a large liver mass (arrow in A and B) with a maximal diameter of 145 mm × 89 mm. One month after the final MWA, MRI scanning detected no viable lesion (arrow in C and D), AFP decreased to 2.3 ng/ml. After 8 CIK infusion and 6 years of follow-up, MRI images showed no recurrence (arrow in E and F), and this patient had normal AFP levels.
|Figure 2: CT scan imaging of a 58-year-old female patient diagnosed with huge HCC. Baseline level of serum AFP was more than 121,000 ng/mL, (normal value, 25.0 ng/mL). Imaging depicts a giant mass in liver (arrow in a and b) with measuring 145 × 89 mm at its maximal diameter. One month after the last MWA, MRI scanning detected no viable lesion (arrow in c and d), AFP decrease to 2.3 ng/ml. After 8 cycles of CIK infusion and 6 years of follow-up, latest MRI images show no recurrence (arrow in e and f). AFP values were also normal in this patient. HCC = Hepatocellular carcinoma, AFP = A-fetoprotein, MWA = Microwave ablation, MRI = Magnetic resonance imaging, CIK = Cytokine-induced killer, CT = Computed tomography|
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|Table 2: Short-term response of hepatocellular carcinoma patients in the transcatheter arterial chemoembolization + microwave ablation + cytokine-induced killer group and the transcatheter arterial chemoembolization + microwave ablation group (cases)|
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OS rates were evaluated together with the PFS rate during follow-up. Patients were followed up for a median of 32 months (range, 1–163 months). Median survival time (MST) was 41 months in the TACE + MWA + CIK group (95% confidence interval [CI], 25.89–56.11 months) and 24 months in the TACE + MWA group (95% CI, 13.43–34.57 months). Those in the TACE + MWA + CIK group had markedly higher MSTs in contrast to those of the TACE + MWA group [[Table 2], P = 0.002]. Those of the TACE + MWA + CIK group had longer median PFS curves (12.0 months, 95% CI, 7.96–16.04 months) in contrast to the TACE + MWA group (10.0 months, 95% CI, 5.00–15.00 months), depicted in [Table 3]. The cumulative OS rate at 1-, 3-, 5- and 10-year was 81.4%, 59.9%, 39.2%, and 3.1%, respectively, in TACE + MWA + CIK group, and 70.2%, 29.8%, 13.5%, and 0.0%, respectively, in TACE + MWA group, depicted in [Table 3].
|Table 3: Survival analysis of hepatocellular carcinoma patients in the transcatheter arterial chemoembolization + microwave ablation + cytokine-induced killer group and the transcatheter arterial chemoembolization + microwave ablation group (cases)|
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The TACE + MWA + CIK had higher OS rates in contrast to the TACE + MWA group, based on survival curves [[Figure 3]a, P = 0.002], a finding that was proved significant based on the log-rank tests. In addition, those in the TACE + MWA + CIK group had much longer PFS than their TACE + MWA counterparts [[Figure 3]b, P = 0.023]. The 1-, 3-, and 5-year PFS was 48.8%, 21.9%, and 15.6% in the TACE + MWA + CIK group, and 29.2%, 8.3%, and 0.0% in the TACE + MWA group [Table 3].
|Figure 3: (a) The OS curve in unresectable HCC patients. The graph depicts cumulative survival rates of HCC patients in the TACE + MWA + CIK group and the TACE + MWA group. Data were analyzed with the Kaplan–Meier method (P = 0.002 between groups). (b) The PFS curve in HCC patients. The graph shows the PFS rates of patients with HCC in the TACE + MWA + CIK group and the TACE + MWA group. Data were analyzed with the Kaplan–Meier method (P = 0.023 between groups). OS = Overall survival, HCC = Hepatocellular carcinoma, CIK = Cytokine-induced killer, TACE = Transcatheter arterial chemoembolization, MWA = Microwave ablation, PFS = Progression-free survival|
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There were no records of any procedure-related mortality, Grade 3–4 liver toxicity or any other major complications after the TACE and MWA procedures in both cohorts. The most common minor adverse effect in both groups were postablation syndrome including fever/malaise (92/100, 92%) and mild-to-moderate pain (82/100, 82.0%), asymptomatic self-limiting pleural effusions (5/100, 5%), and postembolization syndrome (including vomiting, nausea, fever, and mild-to-moderate right upper quadrant pain) (84/100, 84.0%). There were no significant differences between the overall frequency of treatment-related adverse effects between the TACE + MWA and TACE + MWA + CIK groups based on the CTCAE, version 3.0. Those of the TACE + MWA + CIK group demonstrated no signs of autoimmune conditions, hepatic failure, or infection.
| > Discussion|| |
HCC represents the sixth most commonly diagnosed malignancy worldwide and is the fourth highest in cancer-related mortality. Several therapeutic regimens have been explored, given its poor prognosis. TACE is a commonly used method to stem tumor growth and development in patients with u-HCC and is the recommended standard treatment in tumors that are more than 5 cm in diameter. However, only TACE for HCC therapy often is unable to achieve satisfactory prognosis. Studies have reported that 10%–20% of HCC patients post-TACE experience complete tumor necrosis and had a MST 16 − 20 months. Strategies to improve the outcomes of large HCC have been subject to intense research. TACE combined MWA has been suggested to be a first-line u-HCC therapy. Liu et al. had proved that this combination appeared to be an efficient and promising therapy for the management of large-sized u-HCC. At the same time, TACE could act as adjuvant treatment to decrease heat dispersion when combined with thermal ablation to obtain better prognosis. MWA also represents one of the most promising therapy of HCC that imparts larger ablation zone and faster temperature increase compared to other thermal modalities and maintaining consistent popularity in u-HCC., TACE in combination with MWA appears to improve survival of u-HCC that has previously been known to have a high incidence of recurrence and distant metastases.
Hence, new strategies which were to aim at achieving the better outcomes have inspired extensive preclinical and clinical research. Lee et al. demonstrated an improvement in HCC patients' overall and cancer-specific survival after receiving adjuvant CIK immunotherapy. This investigation aims to determine the efficacy of this treatment in combination with TACE + MWA in patients with u-HCC against those who only received TACE + MWA. Those in the group treated with CIK immunotherapy were noted to have better disease control as compared with those who did not receive immunotherapy (87.72% vs. 79.07%). At the final analysis, the TACE + MWA + CIK group had longer MSTs in contrast to the TACE + MWA group (41 vs. 24 months), as well as longer PFS (12 vs. 10 months). The data revealed that CIK induced a remarkable rate of tumor eradication with increased survival rates when used in combination with TACE and MWA in patients with u-HCC. Our study reported no Grade 3/4 serious adverse event those receiving CIK, a testament to the safety of this treatment modality.
Currently, there is still a lack of standardized clinical therapy for u-HCC to prevent relapse and metastasis. There is an urgent need for effective strategies to reduce tumor burden and lengthen survival times. Studies have supported the benefits of CIK-based immunotherapies in reducing distant and local intrahepatic recurrence, thus consequently improving RFS., The safety of CIK cells in cancer management has also been demonstrated in a number of various malignancies. Adjuvant CIK therapy to the use of RFA and TACE was able to achieve microscopic clearance in residual HCC, thereby halting metastasis and recurrence. These studies are convincing proof toward the application of CIK cells in cancer treatment. Similarly, we have shown in the current study that patients with u-HCC also benefit from TACE + MWA + CIK treatment. Those of this group had higher rates of 1-, 3-, 5- and 10-year OS as well as the 1-, 3- and 5-year PFS in contrast to patients who only received TACE and MWA.
A majority of study participants in TACE + MWA + CIK received six to eight cycles of CIK cell treatment and obtained satisfying PFS extension. A number of these patients had recurrence, but none developed florid disease. There were four cases of those who received CIK for 3 years who developed florid disease relapse 6 months after suddenly stopping CIK cells administration. These patients demonstrated multiple liver tumors and portal vein tumor thrombosis but did not develop extra-hepatic metastasis. [Figure 4] shows the images of a 45-year-old male HCC patient who developed florid disease relapse upon cessation of CIK cells administration. This 45-year-old male HCC patient received CIK cells infusion more than 5 years and maintained CR [Figure 4]a. However, 6 months after suddenly stopping CIK cells administration, MRI scanning detected portal vein tumor thrombosis [arrow in [Figure 4]b and [Figure 4]c], without any extrahepatic metastasis. The most likely reason for his relapse was disrupted immune homeostasis. Despite these positive outcomes, some studies have demonstrated the failure of CIK cell immunotherapy to reduce late recurrence (>2 years). Both late and distant intrahepatic recurrence were related to new tumor development and not due to existing tumor cell metastasis.
|Figure 4: The images of a 45-year-old male HCC patient with florid disease upon sudden cessation of CIK cell treatment. This 45-year-old male HCC patient received CIK cells infusion for more than 5 years and maintained CR (a). However, 6 months after sudden CIK cells treatment, MRI scanning detected portal vein tumor thrombosis (arrow in b and c), but no extra-hepatic metastasis. MRI = Magnetic resonance imaging, CIK = Cytokine-induced killer, HCC = Hepatocellular carcinoma, CR = Complete response|
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This analysis was done on a single study center in a retrospective manner. Further, larger-scale studies on this subject are necessary to provide a stronger evidence pool. The lack of histological diagnosis in our patient cohort is another shortcoming of this study.
This study conclusively demonstrates that the addition of CIK to TACE and MWA in the management of u-HCC patients imparted higher survival benefits compared to those treated with TACE and MWA alone. CIK proves to be a feasible adjuvant therapeutic strategy that is safe and effective in improving prognosis and extending the survival in an otherwise bleak scenario.
This research was supported by the National Science Foundation of China (grant number 81172165), National Science Foundation of China (grant number 81371652), the National High Technology Research and Development Program of China (863 Program, grant number 2012AA022700), the Project on the Integration of Industry, Education and Research of Guangdong Province (grant number 2012B091000145) and the Science and Technology Planning Project of Guangdong Province, China (grant number 2014A020212532).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]