|Year : 2020 | Volume
| Issue : 5 | Page : 1038-1050
Predictive effects of a combined indicator in patients with hepatocellular carcinoma after thermal ablation
Qi Yang1, Xiao-ling Yu1, Ying Wang2, Zhi-gang Cheng1, Zhi-yu Han1, Fang-yi Liu1, Tong-gang Qian3, Jie Yu1, Ping Liang1
1 Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
2 Department of Ultrasound, The Second Affiliated Hospital of Qiqihar Medical College, Qiqihar, China
3 Department of Ultrasound, Zunhua People's Hospital, Hebei Province, Zunhua 064200, China
|Date of Submission||04-Dec-2019|
|Date of Decision||02-Mar-2020|
|Date of Acceptance||06-Apr-2020|
|Date of Web Publication||29-Sep-2020|
Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853
Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853
Department of Ultrasound, Zunhua People's Hospital, Hebei Province, Zunhua 064200
Source of Support: None, Conflict of Interest: None
Aim: This study aimed to investigate the predictive power of the combination of Systemic Immune-Inflammation Index (SII) and albumin-bilirubin (ALBI) grade in prognosis outcomes of early-stage hepatocellular carcinoma (HCC) after thermal ablation.
Materials and Methods: This retrospective study was reviewed and approved by our institutional review board, and written informed consent was obtained from each patient. According to the Milan criteria, a total of 405 treatment-naïve patients with clinicopathologically confirmed HCC were enrolled who subsequently underwent thermal ablation from 2011 to 2016. The outcomes of overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were statistically analyzed.
Results: The median follow-up time of this study was 45.1 months (range, 1.3–83.2 months). After thermal ablation in patients with SII-ALBI Grades 1, 2, and 3, the cumulative 5-year OS rates were 81.7%, 63.2%, and 26.9%; the 5-year CSS rates were 82.4%, 67.5%, and 26.9%; and the 5-year RFS rates were 49.3%, 44.6%, and 25.3%, respectively (all P < 0.001). On multivariate Cox regression analyses, SII-ALBI was independently associated with the three outcomes after adjustment for various confounders (all P < 0.05). In addition, SII-ALBI played a predictive role in OS, CSS, and RFS for patients with negative alpha-fetoprotein (AFP) (P < 0.05). Compared with SII and ALBI, the AUCs for the prediction of OS and CSS using SII-ALBI were superior to single indicator (bothP < 0.05).
Conclusion: Elevated preablation SII-ALBI is associated with shorter OS, CSS, and RFS in patients with early-stage HCC. Our indicator showed the potential to be a supplement tool for patients with negative AFP during follow-up.
Keywords: Albumin-bilirubin grade, hepatocellular carcinoma, prognosis, Systemic Immune-Inflammation Index, thermal ablation, ultrasound
|How to cite this article:|
Yang Q, Yu Xl, Wang Y, Cheng Zg, Han Zy, Liu Fy, Qian Tg, Yu J, Liang P. Predictive effects of a combined indicator in patients with hepatocellular carcinoma after thermal ablation. J Can Res Ther 2020;16:1038-50
|How to cite this URL:|
Yang Q, Yu Xl, Wang Y, Cheng Zg, Han Zy, Liu Fy, Qian Tg, Yu J, Liang P. Predictive effects of a combined indicator in patients with hepatocellular carcinoma after thermal ablation. J Can Res Ther [serial online] 2020 [cited 2021 May 17];16:1038-50. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1038/296424
| > Introduction|| |
Hepatocellular carcinoma (HCC) is a common liver malignancy worldwide. The various treatment modalities include liver resection, liver transplantation, and local thermal ablation therapy., Local ablation therapy has been recommended as a nonsurgical treatment for hepatic tumors. It is generally accepted that the prognostic factors in HCC patients undergoing ablation therapy mainly depend on tumor factors (tumor size, number, stage, differentiation, alpha-fetoprotein [AFP] level, and vascular invasion).,,
Apart from the biological indicators of tumors, liver functional reserve and systemic inflammatory responses have also been used to predict the prognosis of HCC. Previous studies have shown that evaluation of liver functional reserve contributes to the efficacy of HCC subsequent therapy., Although Child–Pugh status  was the most frequently used tool, which used five variables to evaluate the prognostic performance in HCC patients, it was highly subjective. Therefore, Johnson et al. proposed a novel grading system incorporating both albumin and bilirubin (ALBI) to assess liver function and predict prognosis in patients with liver dysfunction or HCC. While several studies have analyzed the performance of ALBI grade on the survival of HCC patients after various treatments,,, so far, few have done thermal ablation.
In addition, the role of inflammation-based scores in predicting the prognosis of HCC has been actively explored. Inflammatory response plays a vital role in tumor progression including initiation, malignant conversion, promotion, invasion, and metastasis. Several types of inflammation cells include innate immune cells and adaptive immune cells, which can promote cancer development and progression., Therefore, several prognostic scores such as lymphocyte count, platelet-lymphocyte ratio, and neutrophil-lymphocyte ratio , have been developed to predict the inflammatory response, which is being associated with poor prognosis and high recurrence in different types of cancer, including HCC., However, these indicators did not comprehensively reflect the balance of host inflammation and immune status. Thus, a new and simple noninvasive index, Systemic Immune-Inflammation Index (SII), based on lymphocyte, neutrophil, and platelet counts was first described by Hu et al. in HCC patients.
To the best of our knowledge, no report has demonstrated the predictive value of the combination of SII and ALBI for patients with HCC after thermal ablation and liver resection. Thus, we combined SII score and ALBI grade, named SII–ALBI grade, which can reflect the local and systemic role, to investigate prognostic value for HCC patients after thermal ablation and then compare the predictive power of SII–ALBI, ALBI, and SII.
| > Materials and Methods|| |
This retrospective study was conducted at a single institution. A total of 405 consecutive HCC patients who underwent thermal ablation including percutaneous microwave ablation (MWA) and radiofrequency ablation (RFA) at our institution between January 2011 and May 2016 were enrolled and reviewed. The inclusion criteria included (1) meeting the Milan criteria and confirmed positive to HCC by histologic examination, (2) Child–Pugh Grade A or B, (3) platelet count >40,000/mm 3, and (4) no vascular or bile duct invasion. The exclusion criteria included (1) treatment by surgery, transarterial chemoembolization or other treatment before thermal ablation; (2) Grade C Child–Pugh classification of liver function; and (3) missing outcomes of liver function including ALBI and/or blood routine counts including platelet, neutrophil, and lymphocyte. This study was reviewed and approved by the institutional review board, and all patients signed informed consent prior to treatment.
All cases of newly diagnosed HCC at our institution were discussed at weekly multidisciplinary meetings for the determination of treatment strategy after a definite diagnosis. The patients finally decided whether they were willing to undergo MWA or RFA after the meeting.
Finally, a total of 319 patients were treated with a MWA system (KY-2000, Kangyou Medical Instruments, Nanjing, China) with a frequency of 2450 MHz, which was capable of producing maximum power of 100 Watts (W). This system had 21G thermocouple needles that could be percutaneously inserted into the tumor to measure temperature in real time during ablation. In addition, 86 patients were treated with a RF system (WB991029, Celon Lab Power, Olympus, Hamburg, Germany) with a maximum power 250 W (rated frequency, 470 ± 10 kHz), which could be connected to up to three electrodes with exposed tips of 20–40 mm. Before MWA or RFA, ultrasound (US)-guided biopsies were performed with an 18G cutting needle. All treatments were performed under intravenous anesthesia. For tumors ≤2.0 cm, one antenna or electrode was sufficient, while multiple electrodes or antennas were required for tumors >2.0 cm. In general, the distance between the two antennas or electrodes was 1.0–2.0 cm. A power output of 40–60 W was routinely used during MWA/RFA. Extended emission of microwave or radiofrequency was applied until reaching the desired ranged if the heat-generated hyperechoic microbubbles did not fully cover the target tumor. All procedures were performed by three interventional radiologists (PL, YJ, and CZG, with 20, 12, and 15 years of experience in performing thermal ablation, respectively).
The evaluation of tumors was conducted by conventional US and dynamic contrast enhanced US/computed tomography (CT)/magnetic resonance imaging (MRI) at 1, 3, and 6 months after initial treatment and then at every 6 months. If new lesions were detected in surveillance US or an elevated serum level of AFP >20 ng/mL, tumor recurrence was suspected and further be confirmed by CEUS/CT/MRI. Follow-up was terminated at death or last visit. The primary endpoint of in this study was overall survival (OS) and cancer-specific survival (CSS). OS was defined as the time interval from the thermal ablation to the full cause of death or last follow-up, whereas CSS was the time interval from the thermal ablation to death from advanced liver cancer or last follow-up. The secondary endpoint was recurrence-free survival (RFS).
Calculation formulas for systemic immune-inflammation-albumin-bilirubin
SII was calculated on the basis of blood routine counts, including neutrophil (N), platelet (P), and lymphocyte (L) counts, within 7 days before thermal ablation. The formula was as follows: SII = N × P/L. ALBI was defined as previously described. The equation was as follows: (log10 bilirubin × 0.66) + (−0.085 × albumin). Here, the units of bilirubin and albumin were mol/L and g/L, respectively. After applying the cutoff values proposed by Johnson et al. and Hu et al. for ALBI and SII, respectively, the combination of SII–ALBI was assigned grades as follows: Grade 1, both SII ≤330 × 109 and ALBI ≤−2.60; Grade 2, either SII 330 ×109 or ALBI ≤−2.60; and Grade 3, SII >330 × 109 and ALBI >−2.60.
The OS and CSS rates were calculated using the Kaplan–Meier method, and the log-rank test was used to compare differences among different groups. Categorical variables were analyzed by Chi-square or Fisher's exact tests. Unidirectional ordinal category data were analyzed by Mann–Whitney U-tests. We calculated hazard ratios (HRs) for lower OS, CSS, and RFS by Cox regression, progressively adjusted for age, gender, tumor size/number, type of hepatitis, AFP/alanine transaminase (ALT) level, Child–Pugh grade, and the degree of differentiation Receiver operating characteristic (ROC) curves were used to compare the differences in the area under the curves (AUCs). Statistical analysis was performed using IBM SPSS software (version 23.0; SPSS Inc., Chicago, IL, USA), R software (Version 3.4.1; www.R-project.org), and GraphPad Prism (version 5.0; USA). Stratified analyses were conducted according to SII–ALBI grade, SII score, and ALBI grade. P<0.05 was considered statistically significant.
| > Results|| |
Recruitment pathway for patients in this study is shown in [Figure 1]. A total of 405 patients with 562 index tumors including 324 men and 81 women were enrolled according to the inclusion and exclusion criteria. Their median age was 57 years (range, 27–83 years), and the mean tumor size was 2.6 cm (range, 0.9–5.0 cm). In this study, 78.8% of the patients (319/405) underwent percutaneous MWA. SII–ALBI Grades 1, 2, and 3 were identified in 150, 223, and 32 cases, respectively. One hundred and sixty-eight tumors were located in the location adjacent to important organs such as the gall bladder, gastrointestinal organs, and large vessels. The characteristics of all patients in this study are summarized in [Table 1].
Overall survival and cancer-specific survival
The median follow-up time was 45.1 months (range, 1.3–83.2 months). A total of 85 patients had died with the following causes of death: HCC progression (74 patients); liver failure (five patients); renal failure (three patients); and respiratory failure, heart failure, and cerebral hemorrhage (one patient each). For all patients, the OS rates at 1-, 3-, and 5-year were 96.0%, 86.5%, and 70.0%, respectively. For patients with SII–ALBI Grade 1, the 1-, 3-, and 5-year OS rates were 99.3%, 94.9%, and 81.7%, respectively. The corresponding OS rates for Grade 2 were 95.9%, 84.7%, and 63.2%, respectively. For patients with SII–ALBI Grade 3, the OS rates were 78.1%, 51.3%, and 26.9%, respectively [all the P < 0.001, [Figure 2]a.
|Figure 2: OS, CSS, and RFS rates for patients with HCC after thermal ablation. (a) Patients with SII–ALBI Grade 3 had significantly lower OS rates than those of patients with Grade 1 or 2; (b) patients with SII–ALBI Grade 3 had significantly lower CSS rates than those of patients with Grade 1 or 2; (c) patients with SII–ALBI Grade 3 had significantly lower RFS rates than those of patients with Grade 1 or 2. **P < 0.001. SII = Systemic Immune-Inflammation Index, ALBI = Albumin-bilirubin, HCC = Hepatocellular carcinoma, OS = Overall survival, CSS = Cancer-specific survival, RFS = Recurrence-free survival|
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In this study, 74 patents had died from HCC. The median follow-up time was 41.8 months (range, 1.3–83.2 months). For all patients, the CSS rates at 1-, 3-, and 5-year were 96.0%, 88.6%, and 73.0%, respectively. Similarly, the CSS of patients in the SII-ALBI Grade 3 group were shorter than that of in the SII-ALBI Grade 2 group (P < 0.001, HR = 3.759, 95% confidence interval [CI] 1.622–8.710) and 1 group (P < 0.001, HR = 9.355, 95% CI 3.227–27.000) [Figure 2]b and [Appendix 1.1].
Prognostic factors related to overall survival, cancer-specific survival, and recurrence-free survival
[Table 2] shows the results of multivariate Cox regression for effects of SII–ALBI on the three outcomes. The lower OS, CSS, and RFS rates were associated with higher SII–ALBI grade in crude model; nearly all these relationships remained statistically significant after adjusting for various baseline parameters (all P < 0.01). On analyses, adjusted various baseline factors including age, gender, tumor size/number, type of hepatitis, AFP/ALT level, Child–Pugh grade, the degree of differentiation, and the HR for lower OS and CSS rates at SII–ALBI Grades 2 and 3 were 2.6 (95% CI 1.4–4.7) and 9.6 (95% CI 4.7–19.7); 2.7 (1.4–4.9) and 11.9 (5.7–25.0), respectively. Consistently, the RFS rate was also grade-dependent related to the SII-ALBI grade according to the multivariate analysis.
|Table 2: Multivariate Cox regression for effect of Systemic Immune-Inflammation Index-albumin-bilirubin on overall survival, cancer-specific survival, and recurrence-free survival|
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Stratified analysis to assess the diagnostic accuracy
As shown in [Table 3], in the SII–ALBI Grade 1 group, the OS and CSS rates were higher than those of in the SII–ALBI Grades 2–3 group among all subgroups expect for well-differentiation subgroup. In particular, the stratified analysis results showed that SII–ALBI still retained its predictive power for patients with negative AFP [Figure 3]. As shown in [Figure 3], for patients with negative AFP levels, the 5-year OS rates of SII–ALBI Grades 1, 2, and 3 were 81.4%, 71.8%, and 33.1%, respectively (all the P < 0.001). For patients with positive AFP levels, the corresponding 5-year OS rates were 81.4%, 41.4%, and 0.0% for Grade 1, 2 and 3, respectively (all the P < 0.001). Similarly, SII–ALBI grade can predict CSS and RFS rates in patients with negative AFP [Figure 3].
|Table 3: Stratified analysis of the overall survival, cancer-specific survival, and recurrence-free survival rates of different systemic Immune-Inflammation Index-albumin-bilirubin grades|
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|Figure 3: The OS, CSS, and RFS rates for patients with HCC after thermal ablation according to AFP level. (a) The OS rate for patients with AFP ≤20 ng/mL; (b) the OS rate for patients with AFP >20 ng/mL; (c) the CSS rate for patients with AFP ≤20 ng/mL; (d) the CSS rate for patients with AFP >20 ng/mL; (e) the RFS rate for patients with AFP ≤20 ng/mL; (f) the RFS rate for patients with AFP >20 ng/mL, *P < 0.05, **P < 0.001. AFP = Alpha fetoprotein; SII = Systemic Immune-Inflammation Index, ALBI = Albumin-bilirubin, OS = Overall survival, CSS = Cancer-specific survival, RFS = Recurrence-free survival|
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Comparison of the predictive power of three different indicators
To compare the differences in the predictive prognostic values among the three indexes in treatment-naïve patients with HCC, we performed ROC analysis and compared the AUCs [Figure 4]. The AUCs for the prediction of OS and CSS rates using SII–ALBI were higher (OS: AUC, 0.666, 95% CI, 0.601–0.731; CSS: AUC, 0.670, 95% CI, 0.612–0.728) than those for ALBI (OS: AUC, 0.593, 95% CI, 0.525–0.660, P = 0.0019; CSS: AUC, 0.596, 95% CI, 0.537–0.655; P = 0.002) and SII (OS: AUC, 0.614, 95% CI, 0.543–0.685, P = 0.0492; CSS: AUC, 0.617, 95% CI, 0.560–0.675, P = 0.0479;). Unfortunately, the AUCs for the prediction of RFS rate were not significantly difference among the three indicators (P > 0.05). Interestingly, we found that the full model of SII and ALBI was not significantly associated with RFS rate [Table E1], while SII–ALBI Grade was significantly related with RFS rate [Table 2] and [Figure 2]. According to the results of subgroup analysis, the results also showed that SII–ALBI was superior to those of ALBI and SII for the power of predicting the prognosis in different clinicopathological subgroups, which both indicated that SII–ALBI was the better factor among indices (SII and ALBI) for predicting OS in patients with HCC [Figure E1]. In conclusion, SII-ALBI is a stronger predictor compared with SII and ALBI for predicting prognosis in patients with HCC.
|Figure 4: Comparison of ROC curves between three different indicators. (a) The AUC value for predicting OS; (b) the AUC value for predicting CSS; (c) the AUC value for predicting RFS. SII = Systemic Immune-Inflammation Index, ALBI = Albumin-bilirubin, OS = Overall survival, CSS = Cancer-specific survival, RFS = Recurrence-freed survival|
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| > Discussion|| |
In this study, the SII–ALBI Grade showed more better predictive power for OS, CSS, and RFS rates after thermal ablation, which suggested that this simple preoperative indicator could provide timely and effective reference for the management of HCC patients and evaluation of their outcomes. Second, for patients with negative AFP, our indicator can be as a complementary means to further evaluate efficacy during the follow-up. Third, SII–ALBI grade had higher discriminatory abilities than SII or ALBI alone in predicting the risk of death in HCC patients, although the predictive performance for recurrence was similar. In general, the predictive performance of SII–ALBI grade was superior to single indicator (SII and ALBI).
MWA and RFA have been the two main methods of thermal ablation because of their minimal invasiveness and reliable effectiveness and have been suggested as the optional treatment for early-stage HCC patients. The treatment for HCC requires the optimal selection of therapies based on different factors such as tumor stage, differentiation, liver functional reserve, and inflammatory response.,,, Previous studies have reported that preoperative liver function is one of the main factors affecting postoperative survival in patients with HCC, particularly those with cirrhosis, which tend to experience liver failure and finally death., Evaluation of the preoperative liver functional reserve may contribute to predict the occurrence of postoperative complications and death. In addition, accumulating evidence indicates that inflammation and cancer are closely linked.,,, Previous research reported that neutrophils enhanced circulating tumor cell adhesion in distant sites through the activation of endothelial and parenchymal cells, which accelerated the progression of metastasis. Platelets enhanced metastasis by promoting adhesion or preventing cell death. Lymphocytes, via inhibiting tumor cell proliferation and migration and inducing cytotoxic cell death, assist cancer immune surveillance and tumor defense. As an integrated indicator based on peripheral neutrophil, lymphocyte, and platelet counts, SII tended to be associated with progression, recurrence, and prognosis in HCC.,
Our study indicated that a higher SII–ALBI grade was linked to a shorter survival and high recurrence. The results showed that the 5-year OS of SII-ALBI Grade 3 was the lowest, at 26.9%. Multivariate analysis revealed that limited liver functional reserve and poor inflammatory response were associated with shorter OS and CSS after thermal ablation, which further verified that the novel combination of SII and ALBI, a more objective, easily calculated, and acquired indicator, could improve the clinical management of HCC patients who undergo thermal ablation. Especially for patients with SII–ALBI Grade 3, it may be essential to expand ablation boundary during the treatment with more rigorous and tight postoperative follow-up.
Another advantage was that SII–ALBI could still play a predictive role in patients with AFP ≤20 ng/mL. Although AFP, as a tumor marker for HCC, is often used to monitor for tumor recurrence and predict survival according to the previous study,, it does not reflect the biological characteristics of the tumors, and the negative rate of AFP was up to 40%. Therefore, our study analyzed the predictive prognostic performance of SII–ALBI in the AFP ≤20 ng/mL subgroup. The results showed that SII–ALBI could retain its predictive role for patients with AFP ≤20 ng/mL patients, which indicated that SII–ALBI may be a supplement tool in the follow-up of patients with negative AFP values and thus contribute to decreased rate of missed diagnosis and avoid delay clinical decision, especially for false-negative patients. For patients with AFP >20 ng/mL, the SII–ALBI Grade also plays a good predictive role in the risk of death but fail to predict the recurrence, which may be caused by the unbalanced data. Because patients with positive AFP would be easily recognized by clinicians, misdiagnoses of these recurrent cases would probably be avoided in practice.
Last but not the least, SII–ALBI showed more remarkable and comprehensive predictive performance than those of SII and ALBI in our study. When a single indicator was used to predict prognosis, it is possible to neglect some high-risk patients. In our study, 57 patients were considered as low-risk patients with ALBI but as high-risk patients with SII. Inversely, 166 patients were considered as high-risk patients with ALBI but as low-risk patients with SII [Figure E2]. All these indicated that some patients would be neglected by clinic doctors during follow-up when a single indicator was used to predict prognosis (SII or ALBI), which was avoided by the SII–ALBI grade.
However, our study had several limitations. The first was that this study was conducted only at a single institution and in a retrospective cohort; thus, selection bias was unavoidable. Second, the study had limited population size, with unbalanced distribution of the patient population among different SII-ALBI grades. Last, our index was not compared with other classical prognostic indicators, such as Child–Pugh score and BCLC staging, which was attributed to the fact that our patients were primarily early-stage HCC patients (97.0%). Therefore, large, multi-institutional, randomized controlled trials are needed to provide more convincing evidence.
| > Conclusion|| |
The SII–ALBI was negatively related with the prognosis of HCC patients after thermal ablation. It also played a predictive role in AFP-negative patients with HCC. In addition, the predictive value of the SII–ALBI was superior to that of SII or ALBI. SII–ALBI has a high potential to be an ideal tool for future assessment of HCC prognosis due to its low cost, simple detection, and reproducibility.
We thank the participants of our institute for their valuable contributions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > Appendix|| |
| > Results|| |
1.1 Cancer-specified survival
The 1-, 3- and 5- year CSS rates for patients with SII-ALBI grade 1 were 99.3%, 97.7%, and 82.4%, respectively. The corresponding CSS rates for grade 2 were 96.4%, 88.5%, and 67.5%, respectively. For patients with SII-ALBI grade 3, the CSS rates were 75.0%, 51.3%, and 26.9%, respectively (P<0.001). Patients with ALBI≤-2.60 and >-2.60 had 1-, 3- and 5- year CSS rates of 99.5%, 95.0%, and 76.6% and 92.4%, 82.5% and 63.5%, respectively (P<0.001). For patients with SII>330 and ≤330, the 1-, 3- and 5- year CSS rates were 97.8%, 93.1%, and 76.6% and 90.9%, 75.3%, and 46.4%, respectively (P<0.001).
1.2 Factors associated with recurrence-free survival
During the follow-up period, 140 patients had tumor recurrence and metastasis. The cumulative RFS rates at 1-, 3- and 5- year were 81.8%, 59.0% and 45.0%, respectively. Stratified according to SII-ALBI grade, patients with SII-ALBI grade 1 had 1-, 3- and 5- year RFS rates of 85.9%, 65.5%, and 49.3%, respectively; in grade 2 and 3, the corresponding rates were 80.8%, 56.5%, and 44.6% and 68.5%, 44.2% and 25.3%, respectively (grade 1 vs grade 3, P<0.001). Stratified according to ALBI grade, patients with ALBI≤-2.60 versus those with ALBI>-2.60 had 1-, 3- and 5- years RFS rates of 84.9% vs 78.5%, 64.0% vs 53.6%, and 50.0% vs 39.1%, respectively (P=0.048, [Figure E3]). Patients with SII≤330 versus those with SII>330 had 1-, 3- and 5- years RFS rates of 82.9% vs 77.7%, 60.2% vs 54.8%, and 45.7% vs 42.8%, respectively (P=0.197).
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]