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Annals of Surgical Oncology 8:449-457 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Effect of Sodium Thiosulfate on Cisplatin Removal With Complete Hepatic Venous Isolation and Extracorporeal Charcoal Hemoperfusion: A Pharmacokinetic Evaluation

Nobuya Kusunoki, MD, Yonson Ku, MD, PhD, Masahiro Tominaga, MD, Takeshi Iwasaki, MD, Takumi Fukumoto, MD, Sanshiro Muramatsu, MD, Takemi Sugimoto, MD, Shinobu Tsuchida, MD, Manabu Takamatsu, MD, Yasuyuki Suzuki, MD and Yoshikazu Kuroda, MD, PhD

From the First Department of Surgery, Kobe University, Faculty of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

Correspondence: Address correspondence and reprint requests to: Yonson Ku, MD, PhD, First Department of Surgery, Kobe University, Faculty of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Fax: 81-78-382-5939; E-mail: yonson{at}med.kobe-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Complete hepatic venous isolation and extracorporeal charcoal hemoperfusion (HVI·CHP) can limit systemic exposure to high-dose chemotherapeutic agents when given by hepatic arterial infusion (HAI). The purpose of this study was to determine if the concomitant use of sodium thiosulfate (STS) could further expand the advantages of pharmacologic delivery of HVI·CHP for cisplatin (CDDP) during HAI chemotherapy.

Methods: CDDP (4mg/kg) was administered over 20 minutes via HAI under conditions of HVI·CHP in 14 mongrel dogs. HVI·CHP was performed for 30 minutes after initiation of HAI. During CDDP infusion, 7 dogs each received 400 mg/kg STS (a 100-fold molar ratio to CDDP) over 20 minutes via the prefilter (STS group) circuit line, while the remaining 7 dogs (controls) received no STS. Blood samples were taken serially from the prefilter circuit line (hepatic venous blood), postfilter line, and the left carotid artery (systemic blood). The free and total CDDP concentrations in these samples were determined by flameless atomic absorption spectrophotometry.

Results: During 20 minutes HAI of CDDP, the mean CDDP extraction ratios (ER) by CHP filter were always higher in the STS group than in the control group, regardless of the form (free or total) of CDDP. The differences between the STS and control groups in the extraction ratios of free and total CDDP were significant at all time points measured (P < .05). Consequently, systemic exposure to CDDP, as assessed by area under the time-concentration curve of total CDDP, was significantly lower in the STS group than in the control group (P < .05).

Conclusions: These results indicated that concomitant STS infusion could further increase the effect of HVI·CHP on CDDP removal after HAI.

Key Words: Isolated hepatic chemoperfusion • Hepatic arterial infusion • Cisplatin • Sodium thiosulfate


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cisplatin (CDDP) is an antineoplastic agent with demonstrated activity against a variety of human cancers.1,2 A number of investigators have recently employed CDDP for hepatic arterial infusion (HAI) chemotherapy for the treatment of primary and metastatic liver tumors to take advantage of its steep dose-response relationship.3,4 However, CDDP has a relatively low hepatic extraction ratio;5 thus, high systemic drug concentrations with resultant systemic toxicity occur after HAI. This has prevented significant dose intensification of CDDP in HAI chemotherapy for liver tumors.

In order to solve this problem, we previously described a novel system of complete hepatic venous isolation and extracorporeal charcoal hemoperfusion (HVI·CHP) for the performance of high-dose HAI chemotherapy.6–8 Experimental studies demonstrated that the system can profoundly limit systemic exposure to various antineoplastic agents, including doxorubicin, mitomycin C, and CDDP.6,7,9 Accordingly, we serially conducted phase I and II studies of percutaneous isolated hepatic perfusion with HVI·CHP in patients with advanced hepatocellular carcinoma,8,10–12 and found this approach to be highly effective—producing long-term complete remission in a subset of patients. In addition, these clinical studies have demonstrated that toxicity caused by systemic drug exposure, as represented by myelosuppression for doxorubicin and nephrotoxicity for CDDP, limits the dose in the current venous isolation-filtration system. Although hepatotoxicity was the expected dose-limiting factor, intrahepatic doses of doxorubicin up to 150 mg/m2 and CDDP up to 200 mg/m2 were considered within the range of hepatic tissue tolerance.12

The purpose of this pharmacokinetic study was to determine whether or not the combined use of sodium thiosulfate (STS) as the antidote with HVI·CHP could further expand the maximum tolerated dose of intrahepatic CDDP, while decreasing systemic toxicity. STS is known to be a strong nucleophile which reacts with CDDP to form a nontoxic covalent complex in human plasma.13–15


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Experimental Groups
Mongrel dogs of both sexes weighing 10.4 ± 1.2 kg (mean ± SEM) were divided into two groups. The first group consisted of seven dogs with STS infusion (STS group), and the second group contained seven dogs without STS infusion (control group). The use of animals in this study conformed to the ethical guidelines set by the Animal Experimental Committee of the Faculty of Medicine, Kobe University. Food was withheld for 12 hours preoperatively. At the end of the study, the dogs were euthanized with a lethal dose of potassium chloride.

Experimental Procedure
Anesthesia was induced by the intravenous administration of sodium pentobarbital (25 mg/kg) and pancuronium bromide (0.1 mg/kg). After endotracheal intubation, the dogs were mechanically ventilated throughout the experiment. A catheter (6F) was inserted into the right external jugular vein and lactated Ringer solution was administered at 30–40 ml/kg/hr during the procedure. An arterial line was placed into the right carotid artery for both blood pressure monitoring and blood sampling. Laparotomy was then performed with a midline incision from xiphoid to pubis. A catheter (3F) was introduced into the proper hepatic artery through the gastroduodenal artery. The bilateral femoral veins and the left external jugular vein were exposed through small cutdown incisions. A catheter (14F) was placed in the retrohepatic inferior vena cava through the right femoral vein to drain hepatic effluent. Another catheter (14F) was placed in the inferior vena cava below the renal veins through the left femoral vein. A return catheter (16F) was placed in the left external jugular vein. These two catheters were connected to an extracorporeal unit consisting of a capacitance pump (Biopump-50; Medtronic Bio-Medicus, Inc.; Eden Prairie, MN) and a CHP filter (DHP-1; Kuraray Co., Ltd.; Osaka, Japan) as diagrammed in Fig. 1. Once the system was established, blood was anticoagulated with an administration of heparin (100 units/kg). Following thoracotomy, HVI·CHP was achieved with concomitant vascular clamps placed at the suprahepatic and infrahepatic inferior vena cava. Subsequently, in both groups, a 20-minute hepatic arterial infusion of CDDP (Nippon Kayaku Co., Ltd., Osaka, Japan) at a dose of 4 mg/kg was initiated with a syringe infusion pump (Terufusion Model STC-523; Terumo Co., Ltd.; Tokyo, Japan), and HVI·CHP was maintained for 30 minutes after the initiation of CDDP infusion. In the STS group, STS (400 mg/kg, a 100-fold molar ratio to CDDP) was administered over 20 minutes via the prefilter circuit line concomitantly with CDDP infusion. STS was prepared at a concentration of 100 mg/ml.



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  		FIG. 1. Schematic drawing of the experimental model with hepatic venous isolation and charcoal hemoperfusion (HVI·CHP). Hepatic arterial infusion (HAI) of CDDP (4 mg/kg) is performed over 20 minutes in both groups. The blood samples were obtained at the inlet (A) and outlet (B) of the CHP filter in the extracorporeal circuit and the carotid artery (systemic blood). STS (400 mg/kg) was administered through the prefilter circuit line in the STS group.

 
Cisplatin and STS Measurements
During HVI·CHP, blood samples were collected in heparinized tubes from the pre-CHP filter circuit line (hepatic venous blood), post-CHP filter line, and the left carotid artery (systemic blood) just before and 5, 10, 15, 20, and 30 minutes after the initiation of CDDP infusion. They were placed immediately on ice, centrifuged at 1000 g at 4°C for 10 minutes, and plasma was removed. STS concentrations in plasma samples and standards were determined by the methylene blue method with the absorbance measurement at 665 nm, as described previously.16 For CDDP measurement, approximately 1 ml of plasma was transferred immediately to an ultrafiltration YMT membrane cone (Centrifree micropartition device; Amicon, Inc.; Beverly, MA) and centrifuged at 1000 g at 4°C for 20 minutes; the ultrafiltrate fraction was used for determining the filterable CDDP concentration. The ultrafiltrates and plasma samples were analyzed directly by flameless atomic absorption spectrophotometry to determine the free and total CDDP concentrations, respectively, as described previously.17

The free CDDP concentrations, as measured by flameless atomic absorption spectrophotometry, consist of truly free CDDP (unchanged CDDP) and low molecular CDDP mass metabolites (Fig. 2).18 Therefore, in one dog in each group, we additionally determined the concentrations of unchanged CDDP in the ultrafiltrates of systemic blood by high-performance liquid chromatography (HPLC) using postcolumn derivatization.18,19 In brief, the system consisted of a Shimadzu HPLC system (Kyoto, Japan) in combination with a Hitachi NO.3013-N analytical column, two HPLC pumps (Shimadzu LC-9A, Kyoto, Japan), and two different sizes of PTFE tube for postcolumn derivatization. Samples (50 µl) of plasma ultrafiltrate were injected directly into the analytical column. The column was eluted with acetonitrile/10 mM sodium chloride (15:85 v/v) at a constant flow rate of 0.9 ml/min.



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  		FIG. 2. Diagram showing CDDP and its derivatives in the plasma. Total CDDP ({square}) and Free CDDP ({image}) determined by HPLC method. Unchanged CDDP ({image}) determined by atomic absorption spectrometry.

 
Flow Measurement and Pharmacokinetic Evaluation
Hepatic venous blood flow rate was monitored continuously with an electromagnetic flow probe (Bioprobe TX40; Medtronic Bio-Medicus, Inc.; Eden Prairie, MN) placed at the pre-CHP filter circuit line (Fig. 1). Based on the blood flow rate (Q) and CDDP concentrations in the hepatic vein (C), the amount of CDDP eliminated by the HVI·CHP system (µg) was calculated by using the following equation: Go


(1)

where Ci = the inlet concentration (µg/ml) at the sampling time of i; C’j = the outlet concentration (µg/ml) at sampling time j; and j is the sampling time immediately after sampling time i. Qij (ml/min) = the average blood flow rate between the time of i and j (= (Qi + Qj)/2). Tij (min) = the time interval between i and j.

The drug clearance fraction by HVI·CHP (%) was defined as the percent of drug removal amount compared to the amount of drug administered. The drug extraction ratio (ER) of the CHP filter at each sampling time was calculated as follows: ER (%) = (Ci - C’i)/Ci x 100, where Ci and C’i = the inlet and outlet concentrations, respectively, at sampling time i. The area under the time-concentration curve (AUC) was calculated by the trapezoidal method.

Statistical Analysis
All values are presented as the mean ± SEM. Statistical analysis was performed using unpaired Student’s t-test and P < .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Hemodynamic Effects of HVI·CHP
In both groups, the systolic and diastolic arterial pressure showed a slight decrease after the initiation of HVI·CHP. However, HAI of CDDP had no effect on the arterial pressure, and no significant difference was observed between the two groups throughout the experiment. Both groups also had similar hepatic venous flow rates ranging from 260 to 370 ml/min during HVI·CHP.

Plasma Profile of Free CDDP Concentrations
The time courses of free CDDP concentrations at the inlet and outlet of CHP filter and systemic blood are illustrated in Figs. 3 A, B, and C, respectively. The prefilter free CDDP concentrations increased gradually and reached a peak 15 minutes after the start of drug infusion in both groups: 4.73 ± 0.52 µg/ml and 4.82 ± 1.11 µg/ml in STS and control groups, respectively. There was no significant difference in prefilter concentrations between the two groups throughout the time course. On the other hand, the postfilter and systemic free CDDP concentrations reached a peak 20 to 30 minutes after the start of drug infusion in both groups. The peak values of postfilter and systemic blood were significantly lower than those at the inlet side of the CHP filter in each group (P < .01). Similar to the prefilter drug levels, both the postfilter and systemic free CDDP concentrations did not show significant differences between the two groups throughout the time course.



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  		FIG. 3. Time course of plasma free CDDP concentrations at inlet (A), outlet (B) of the CHP filter, and systemic blood (C). Data are the mean (SEM).

 
Plasma Profile of Total CDDP Concentrations
Figure 4 shows the time courses of total CDDP concentrations at the inlet and outlet of the CHP filter and in systemic blood. In both groups, the plasma profile of total CDDP concentrations at each blood sampling site was essentially analogous to that of free CDDP concentrations, and the peak concentrations of total CDDP at postfilter and systemic blood showed a significant reduction compared with those at the inlet side of the CHP filter in each group (P < .01).



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  		FIG. 4. Time course of plasma total CDDP concentrations at inlet (A), outlet (B) of the CHP filter, and systemic blood (C). Data are the mean (SEM). * P < .05, ** P < .01, STS vs. control group.

 
There was no significant difference in prefilter concentrations between the two groups throughout the time course. In contrast, the postfilter and systemic concentrations of total CDDP in the STS group were significantly lower than those of the control group at all time points measured (P < .05).

Plasma Profile of Systemic Concentrations of Platinum Species
Figure 5 shows the systemic concentrations of unchanged, free, and total CDDP in one dog in each group. In the STS-treated dog, the unchanged CDDP concentrations remained very low with a peak value of 0.08 µg/ml at 15 minutes after the start of CDDP infusion. However, the unchanged CDDP concentrations in the control dogs increased lineally and reached a peak of 0.58 µg/ml 15 minutes after the start of CDDP infusion. There were profound differences in the unchanged CDDP concentrations between the STS-treated and the control dogs at measurement time points from 10 to 30 minutes. On the other hand, there were minor differences in the free CDDP concentrations between the two dogs throughout the time course. Of note, in the 2STS-treated dog, the concentrations of total CDDP were almost comparable to those of free CDDP. In contrast, at all time points measured, the total CDDP concentrations in the control dog were markedly higher than those of free CDDP.



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  		FIG. 5. Time course of systemic concentrations of platinum species in one dog in each group: (A) unchanged CDDP, (B) free CDDP, (C) total CDDP.

 
Time Course of CDDP Extraction Ratio of The CHP Filter
Figure 6A shows changes in the ER of free CDDP. During a 20-minute CDDP infusion, the ER of free CDDP was always higher in the STS group than in the control group: the mean values at 5 and 20 minutes were 90.8% ± 1.9% and 63.4% ± 4.8% for the STS group, and 75.5% ± 5.6% and 24.7% ± 11.5% for the control group, respectively. The differences in the ER of free CDDP between STS and control groups were significant at all time points measured (P < .05).



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  		FIG. 6. Time course of CDDP extraction ratios by CHP filter: (A) free CDDP, (B) total CDDP. Data are the mean (SEM). * P < .05, STS vs. control group.

 
Figure 6B shows changes in the ER of total CDDP. Similar to the free CDDP, the ER of total CDDP was higher in the STS-treated group than in the control group. The differences in the ER of total CDDP between STS and control groups were also significant at all time points measured (P < .05).

The Area Under the Time-Concentration Curve (AUC) and Clearance Fraction of Plasma CDDP
Table 1 shows the AUC of plasma CDDP concentrations and CDDP clearance fraction during HVI·CHP. At all sites measured, there was no significant difference in the AUC of free CDDP concentrations between the two groups. However, the AUC of outlet and systemic total CDDP concentrations in the STS group were significantly lower than those in the control group (P < .05). The free and total CDDP clearance fractions by HVI·CHP were significantly higher in the STS group than in the control group (P < .05).


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  		TABLE 1. AUC of plasma CDDP and clearance fraction during a 30-min HVI · CHP
 
Plasma Profile of STS Concentrations
STS pharmacokinetic data in the STS group are shown in Table 2. Throughout the time course, the postfilter STS concentrations remained similar to the prefilter STS concentrations, indicating a very low affinity of STS to the CHP filter. The systemic STS concentrations increased gradually, and reached a peak value of 73.0 mg/dl 20 minutes after the start of STS infusion.


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  		TABLE 2. Time course of plasma STS concentrations during a 30-min HVI · CHP
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The HVI·CHP described here achieved the equivalent of a pharmacologic first-pass effect by binding CDDP that was not extracted by the liver. In agreement with previous studies using a swine model of HVI·CHP,20 our data showed that the filter extraction of CDDP was less efficient than that of doxorubicin or mitomycin C.6,8,9 It is well known that CDDP is highly protein-bound, thereby causing a rapid change in its molecular properties. We assume that this pharmacologic characteristic of CDDP primarily accounts for the less efficient binding by the CHP filter.

It should be noted, however, that despite an apparently lower ER, the clearance fraction of CDDP by a 30-minute HVI·CHP in the control group was almost comparable to that of doxorubicin or mitomycin C reported in our previous study6 and was somewhat greater than that predicted on the basis of ER alone. This was probably due to the fact that CDDP undergoes a lower rate of first-pass hepatic extraction compared with the other two drugs.5 As stated previously by us and others,6,20,21 the HVI·CHP theoretically offers greater pharmacologic advantage for a drug like CDDP with a low hepatic extraction ratio. It is most likely that the high CDDP concentrations in the hepatic effluent offset the low ER of the drug by the filter.

Our strategy of the combined use of STS with HVI·CHP lies in attempts to detoxicate the superfluous drug that is not extracted by the liver and the filter. A number of clinical studies have shown that the combination of intravenous STS with intra-arterial, intravenous, or intraperitoneal CDDP is beneficial to cancer chemotherapy, allowing for dose escalation of CDDP while decreasing nephrotoxicity.22–28 STS binds covalently with CDDP, resulting in a nontoxic soluble product. Thus in the STS-treated animals, the ultrafilterable platinum (free CDDP) consists of unchanged CDDP (biologically active form), its low molecular mass metabolites, and STS-CDDP complex (Fig. 2). In the present study, although the systemic concentrations of free CDDP did not significantly differ between the two groups, those of unchanged CDDP were profoundly reduced in the STS-treated dog, as demonstrated in Fig. 5A. Recently, some investigators have reported similar findings that, although the free CDDP levels were not significantly different between the control and STS-treated rats after intravenous infusion of CDDP at a dose of 5 mg/kg, the unchanged CDDP concentrations in the kidney and systemic plasma were markedly reduced by STS coadministration.18 They have also shown that more than 80% of the ultrafilterable platinum fraction consists of covalently bound platinum-STS in the STS-treated rats. These data altogether support our postulate that STS, when administered into the hepatic effluent, could effectively bind with unchanged CDDP before systemic circulation.

Of further note, our data showed that the systemic concentrations of free CDDP were almost comparable to those of total CDDP in the STS-treated dogs. In the control group, the systemic as well as the postfilter concentrations of free CDDP were approximately one half of those of total CDDP, indicating the remaining half of total CDDP to be protein-bound platinum. Previous in vitro studies have shown that STS, at a 100-fold molar ratio to CDDP, inhibited protein binding of unchanged CDDP in human plasma.29 Thus, it is most likely that, in the presence of STS, the unchanged CDDP may form STS-CDDP complex rather than react with plasma proteins. It could also be speculated that STS reacts not only with unchanged CDDP but also with protein-bound CDDP, thus leading to dissociation of CDDP from plasma-binding proteins. This hypothesis is supported by previous in vitro studies14 showing that approximately 10% of the protein-bound CDDP was reversed to the free CDDP when incubated with STS at a higher dosage than a 100-fold molar ratio.

We also found that combined use of STS with HVI·CHP was beneficial in increasing the ER of CDDP by the filter and in reducing systemic exposure to the drug. Irrespective of the form of CDDP, the STS group showed a higher value of the ER at all measured time points compared with the controls. Consequently, the drug clearance fractions of both free and total CDDP increased significantly in the STS group compared with the control group. Although we did not separately determine the ER of STS-CDDP complex, these data suggest that this platinum fraction exhibits a charcoal affinity comparable to that of unchanged CDDP. This would mainly account for the increasing effect of STS on CDDP elimination by the HVI·CHP demonstrated in this study.

The mechanisms for chemoprotective effect of STS are controversial. Previous studies have shown that STS is not a very potent neutralizing agent for CDDP and that the rate constant is very low in the plasma, although it is quite rapid in the renal tubules where STS is concentrated.22 Thus, some investigators have postulated that the kidney is the major site for inactivation of CDDP with STS.2 On the other hand, it has been shown that active, unchanged CDDP concentrations were rapidly reduced with concurrent STS infusion in a dose-dependent manner and that complete inactivation was obtained in the blood stream when STS was intravenously administered at doses of more than 400-fold molar ratios to CDDP.30 In this study, we administered STS at a 100-fold molar ratio into the isolated hepatic vein blood and found that this could achieve a significant increase of the clearance fraction of CDDP by HVI·CHP. This is in agreement with the previous postulate that STS reacts directly with CDDP to form an inactive complex in the blood stream if just enough STS is administered.14,29

It has been previously reported that STS distribution is limited to the extracellular fluid, as determined in dogs.13 This implies that STS will not react inside the cell with CDDP or its hydrolyzed derivatives which exert the antitumor activity. However, one potential concern is the possible reduction of antitumor effects caused by inactivation of CDDP by the excess of STS at hepatic reentry. Our data showed that adding STS to the liver outflow via the prefilter circuit line produced a gradual increase of STS with a peak plasma concentration of 73 mg/dl in the systemic circulation. Based on the hepatic blood flow rate and the peak systemic STS concentration, the maximal amount of STS reaching the liver was estimated to be around 270 mg/min in the STS group. During a 20-minute HAI, CDDP is administered at an infusion rate of 2 mg/min in dogs with 10 kg body weight. This implies that molar STS/CDDP ratios would be maintained at levels of <135 in the hepatic circulation during HAI of CDDP. Some investigators previously reported that effective protection against CDDP toxicity in human cells can be achieved by the concurrent presence of STS in the blood with molar ratios of >500, but not when a ratio of <100 is used.32 Taken together, we assume that antitumor efficacy of CDDP would be minimally affected by the STS co-infusion at a dose rate used in this study. However, further preclinical studies are needed to determine the optimal dose rate for STS when used concurrently with HVI·CHP. Several investigators have proposed another possible way to prevent this problem: a two-compartment system to provide a partition between the two agents.22,23,26–28 The delay of STS administration after CDDP infusion may be effective as a two-compartment approach for the HVI·CHP system.

Medical contraindications for STS administration include sodium-retaining conditions such as congestive heart failure, impaired renal function, and end-stage liver cirrhosis. In previous clinical trials, STS was administered as a chemoprotectant at bolus doses ranging from 0.8 g/m2 to 20 g/m215,22,26,31 Although transient increases in serum sodium level and blood pressure were noted with high-dose STS (>=16 g/m2), no evidence of serious toxicity was reported. These data indicate the dose rate used in this study to be well tolerated in human beings.

In conclusion, this study demonstrated that, in the canine model of HVI·CHP used, hepatic venous infusion of STS during HAI of CDDP is beneficial in reducing systemic exposure to unchanged CDDP that is not extracted by the liver and the filter. In addition, we found that STS co-infusion significantly reduced protein-bound CDDP, thereby increasing the clearance fraction of CDDP by the system. Thus, the combined use of STS infusion with HVI·CHP may further expand the maximum tolerated intrahepatic dose of CDDP when local toxicity is not a dose-limiting factor.


   Acknowledgments
 
Supported by grants-in-aid for scientific research (04670781 and 06454386) and the highly-advanced therapeutic technology developing program from the Ministry of Education, Science and Culture, Japan.

Received for publication August 23, 2000. Accepted for publication December 13, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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