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Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

Studies suggest that retinoic acid (RA) can augment the antitumor effects of interferon-based therapy in patients with advanced renal cell carcinoma (RC); however, this benefit has not been achieved convincingly using oral formulations of 13-cis RA and all-trans RA. Liposome-encapsulated all-trans RA (ATRA-IV) has improved pharmacokinetics with increased and prolonged ATRA serum levels compared with oral retinoids.

METHODS

Cohorts of 3–6 patients with progressive metastatic RC received a dose of 3 MU interferon α2b per day subcutaneously, which was escalated weekly to 5 MU and then to 10 MU, plus ATRA-IV beginning at a dose of 90 mg/m2 intravenously three times per week (Monday, Wednesday, and Friday), with a planned escalation to a maximum of 140 mg/m2.

RESULTS

Two of the initial five patients experienced Grade 3 leukopenia while receiving 3 MU interferon and 90 mg/m2 ATRA-IV. Therefore, the trial was amended to begin ATRA-IV at a dose of 15 mg/m2 three times per week with a planned escalation by 15 mg/m2 per cohort plus interferon-α at a dose of 3 MU subcutaneously 5 days per week (Monday through Friday), which was escalated weekly to 5 MU and then to 10 MU. Twelve patients were treated on the revised schedule. Toxicity was mild and included Grade 2 anemia (n = 7 patients), leukopenia (n = 2 patients), nausea (n = 2 patients), fatigue (n = 2 patients), fever (n = 2 patients), hepatic toxicity (n = 1 patient), edema (n = 1 patient), neurocortical toxicity (n = 1 patient), headache (n = 1 patient), and infection (n = 1 patient). One patient developed hyperthyroidism, and one patient required admission for bacteremia from a line infection. Dose limiting toxicity was Grade 3 hepatic toxicity, which was observed at a dose of 30 mg/m2 ATRA-IV in 2 of 6 patients. Only 2 of 12 patients agreed to a dose escalation up to 10 MU interferon-α. Of 12 patients who were evaluable for response, 2 patients (17%) had a partial response in bone and lung, including 1 partial response of > 91 weeks' duration, at a dose of 15 mg/m2 ATRA-IV three times per week and 5 MU interferon-α. Five additional patients experienced stable disease, two of whom had disease progression in bone only.

CONCLUSIONS

The acceptable toxicity profile and preliminary efficacy results suggest that this regimen warrants further evaluation. ATRA-IV (15 mg/m2 TIW) and interferon-α (3 MU Monday through Friday escalated weekly to 5 MU and to 7 MU) are recommended for further study in patients with advanced RC. Cancer 2002;95:1220–7. © 2002 American Cancer Society.

DOI 10.1002/cncr.10809

Renal cell carcinoma (RC) is a frequent cause of cancer morbidity and mortality, with over 10,000 deaths per year in the United States.1 This fact reflects a lack of effective chemotherapeutic or biologic treatment modalities for patients who develop metastatic disease. Recent preclinical and clinical data suggest that retinoids may play a role in inhibiting RC growth. Although we reported previously that retinoic acid (RA) alone inhibited the growth of only one of 12 RC cell lines,2 and no major responses were observed in 25 patients with advanced RC who were treated with 13-cis RA,3 we did show that RA can augment significantly the growth-inhibitory effects of interferon-α (IFN-α) in vitro2, 4 and the antitumor effects of IFN-α in patients with RC.5 Furthermore, our analysis of retinoid receptor expression in RC lines showed that, whereas RA receptor β (RARβ) could not be detected or induced by 13-cis RA treatment in 11 RA-resistant RC cell lines, retinoid-sensitive SK-RC-06 cells basally expressed RARβ transcripts, and RARβ mRNA expression was up-regulated by 13-cis RA treatment.2 Moreover, an analysis of sequential tumor biopsies from patients who were treated with 13-cis RA and IFN-α demonstrated a significant increase in the intensity of RARβ mRNA expression in RC cells only in patients who achieved a major clinical response.6 Taken together, these data suggest that RC cells, which are responsive to retinoid therapy (as indicated by an increase in RARβ expression), are also growth inhibited. Nevertheless, the vast majority of RCs both in vitro and in vivo are resistant to growth inhibition mediated by retinoids.

The physiologically relevant form of retinoids, retinol, normally undergoes intracellular esterification. Although the precise functions of these retinyl esters in cells are not understood fully, it is believed that retinyl esters are stored within the cells to ensure that the cells have enough retinyl esters to convert to bioactive retinoids for several days, even if the retinol source is interrupted. Recent studies have shown that the metabolism of retinol to retinyl esters is reduced greatly in various types of human carcinoma cell lines, such as carcinomas of the oral cavity, skin, and breast, compared with normal human cultured epithelial cell strains from these same human tissues.7–9 This finding suggests that human carcinoma cells are retinoid deficient relative to normal epithelial cells. We recently reported10 that 1) there is also a major reduction in retinol and retinyl ester content in RCs both in vitro and in vivo relative to autologous normal kidney; 2) with the exception of retinoid-sensitive SK-RC-06 cells, most retinoid-resistant RC cell lines do not metabolize RA very rapidly, consistent with other studies showing that the rapid metabolism of RA to polar RA metabolites correlates with sensitivity to growth inhibition by RA;11–14 and 3) the addition of IFN to RA results in increased growth inhibition, greater esterification of retinol, and higher levels of retinyl esters in RC cell lines, suggesting that the increase in intracellular retinoid content contributes to growth inhibition.

A major limitation of retinoid therapy is that the pharmacokinetics of oral all-trans RA (ATRA) show that the clearance of ATRA changes substantially during therapy, with the bioavailability diminishing over time. Thus, the ineffectiveness of ATRA may be related in part to the failure of drug delivery associated with an enhanced mechanism of ATRA clearance, which occurs within a few days of beginning ATRA treatment.15, 16 Oral 13-cis RA achieves higher serum levels and, thus, may be more effective than oral ATRA. However, it is believed that ATRA is the more biologically active retinoid; therefore, 13-cis RA may function as a prodrug. Liposome-encapsulated ATRA (ATRA-IV; formally known as ATRAGEN) may be a more potent retinoid. The liposomal delivery system improves the activity of ATRA by altering its pharmacologic profile, changing the drug's pharmacokinetics and tissue distribution. In vitro, liposomal ATRA has a greater antiproliferative effect on neoplastic cells than free ATRA,17, 18 inhibiting the proliferation of lymphoma cells in a dose dependent manner through the induction of apoptosis.19 In vivo, liposomes bypass the mechanism of increased drug clearance that evolves in the livers of patients who are treated with the oral formulation. Microsomes isolated from the rat liver metabolize liposomal ATRA to a significantly lower extent than free ATRA.20, 21 Thus, liposomal ATRA is not metabolized as rapidly as free RA, resulting in increased ATRA concentrations in the serum and in cells. Based on previous studies showing that ATRA-IV was well tolerated as a single agent, we performed a dose-finding study to investigate the combination of ATRA-IV with IFN in the treatment of patients with advanced RC.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patient Selection

Between December 1998 and April 2000, 17 patients with advanced RC were entered onto this trial, which was approved by the Institutional Review Board at Weill Medical College of Cornell University. All patients gave informed consent and had bidimensionally measurable disease, Karnofsky performance status (KPS) ≥ 60%, age > 18 years, estimated life expectancy > 12 weeks, white blood cell count ≥ 3000 cells/μL, platelet count ≥ 100,000 cells/μL, serum bilirubin ≤ 1.5 mg/dL, and serum creatinine ≤ 2 mg/dL or creatinine clearance ≥ 50 mL per minute. Patients were excluded if they had active brain metastases, prior therapy with IFN or a retinoid, or more than one chemotherapy and/or biologic response-modifier treatment or radiation therapy within 4 weeks of starting on the study. Patients also were excluded if they had another underlying, uncontrolled medical or psychiatric condition; prior deep vein thrombosis or pulmonary embolus; or a poorly controlled thyroid or retinal condition. Before therapy, each patient was evaluated with a history and physical examination, chest radiography, electrocardiogram, automated complete blood count, screening blood chemistry (including cholesterol and triglycerides), thyroid function tests, urinalysis, and appropriate imaging of sites of disease. A negative pregnancy test and birth control counseling were required in women of childbearing age.

Treatment Plan

Patients were instructed to self-administer recombinant IFN-α2b (Intron A) using a multidose pen. ATRA-IV was obtained from Antigenics, Inc., and was supplied as a lyophilized powder in bottles requiring reconstitution with 50 mL of 0.9% sodium chloride for a final concentration of 2 mg/mL of ATRA. The maximum tolerated dose (MTD) of ATRA-IV administered every other day was determined previously at 140 mg/m2.22 Therefore, the initial starting dose of ATRA-IV was 90 mg/m2 intravenously three times per week, which was escalated to 115 mg/m2 and then to 140 mg/m2 in cohorts of 3 patients. However, Grade 3 myelosuppresion was observed in 2 of the first 5 patients who were treated at 90 mg/m2; thus, the protocol was amended to reduce the starting dose to 15 mg/m2 intravenously three times per week, with a planned escalation of 15 mg/m2 per treatment cohort until the MTD was obtained. For each patient, the ATRA-IV dose remained constant. The planned IFN-α2b dose was 3 MU subcutaneously (SQ) daily, which was escalated to 5 MU then to 10 MU or as tolerated (3-5-10 MU SQ qD). Simultaneously, the protocol was amended after the first 5 patients, so that IFN was administered only 5 days per week (Monday through Friday).

The MTD of the IFN plus ATRA-IV combination was defined as the highest dose level at which fewer than two of a cohort of three to six patients experienced a dose limiting toxicity (DLT). DLT for the study was defined as the occurrence of any Grade 3 or 4 hematologic toxicity (except anemia), Grade 3 or 4 nonhematologic toxicity, or toxicity that resulted in a dose delay of > 3 weeks. If one of the first three patients experienced a DLT, then three additional patients were treated at the same dose level. The dose of IFN was reduced for Grade 2 toxicities (except for Grade 2 hematologic toxicity, fever for < 24 hours duration, and Grade 2 hypocalcemia). For Grade 3 or 4 toxicity, except neurologic toxicity or hematologic toxicity manifested by low hemoglobin, IFN was withheld until toxicity returned to Grade 0 or 1. Treatment was then resumed at the discretion of the participating investigator at the next lowest dose level, and, if Grade 3 or greater toxicity recurred, then the patient was taken off study.

Dose reductions for ATRA-IV occurred if Grade 3 or 4 toxicity (except dermatologic toxicity or low hemoglobin) occurred after the toxicity returned to Grade 0 or 1. The drug was restarted at the next lowest dose level or at a 25% reduction if the toxicity occurred at the lowest dose level. Patients with Grade 3 or 4 hematologic toxicity, as manifested by low hemoglobin from either drug, received transfusions as needed. Recombinant erythropoetin could be used at the discretion of the investigator. Patients were evaluable for toxicity if they had received at least one dose of ATRA-IV and IFN.

Standard response criteria were used. All patients who received a dose of study drug were evaluable for toxicity, and patients who received one course of therapy (8 weeks) were evaluable for response. All measurements of response were performed by a single radiologist (N.P.).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patient Characteristics

A total of 17 patients were entered onto this trial. Table 1 indicates the characteristics of the patients and tumor histology. The median age was 61 years (range, 37–72 years). Fourteen patients were treatment-naïve, and 1 patient each had been treated previously with radiation, chemotherapy, and interleukin-2. Ten patients had undergone nephrectomy, and all had metastatic disease at the time of enrollment. Lung metastases were present in 94% of patients, 29% of patients had bone metastases, and 1 patient had lung only metastases (2 patients had metastases of the lung and mediastinum only). Other sites of metastases are listed in Table 1.

Table 1. Patient Characteristics
CharacteristicNo. of patients (%)
  • a

    After nephrectomy.

Age (yrs) 
 Median61
 Range37–72
Gender 
 Male9 (53)
 Female8 (47)
Karnofsky performance status 
 703 (13)
 805 (31)
 909 (56)
Prior nephrectomy 
 Yes10 (63)
 No7 (38)
Disease free interval (months)a 
 Median25.5
 Range1–86
Prior therapy 
 Chemotherapy1 (6)
 Immunotherapy1 (6)
 Radiotherapy1 (6)
No. of disease sites 
 11 (6)
 212 (71)
 34 (24)
Metastatic sites 
 Lung16 (94)
 Bone5 (29)
 Local recurrencea4 (25)
 Liver3 (18)
 Skin and soft tissue3 (19)
 Retroperitoneum2 (13)
 Mediastinum2 (13)
 Brain1 (6)
Primary histology 
 Clear cell14 (82)
 Sarcomatoid2 (12)
 Collecting duct1 (6)

Toxicity

All 17 patients were evaluable for toxicity. The adverse effects of the combination of ATRA-IV and IFN are listed in Table 2. The first five patients on study were treated with ATRA-IV at a dose of 90 mg/m2 three times per week. One patient in that group developed a reversible Grade 3 allergic reaction during the first infusion of ATRA-IV and refused further therapy. None of the remaining four patients was able to tolerate more than 3 MU of IFN. Two patients developed Grade 3 leukopenia, and two patients developed Grade 2 fatigue. One patient developed reversible retinal toxicity at an IFN dose of 5 MU, requiring dose attenuation to 3 MU. Based on the Grade 3 leukopenia and the inability to escalate the dose of IFN beyond 3 MU daily, the trial was redesigned with a starting dose of ATRA-IV of 15 mg/m2 (with escalation by 15 mg/m2 in cohorts of 3 patients), and the IFN schedule was reduced from daily to 5 days each week (3-5-10 MU SQ M–F).

Table 2. Toxicities of Combination Therapy with Liposome-Encapsulated All-Trans Retinoic Acid and Interferon
ToxicityWHO grade (%)
1234
  • WHO: World Health Organization.

  • a

    Grade 1 or 2 toxicity that occurred more than once and all Grade 3 and 4 toxicities are shown.

  • b

    Dose limiting toxicity.

  • c Grade 3 toxicity seen at the 90 mg/m2 dose level only.

Livera292412
Leukopeniab181212
Anemia18476
Fatigue3512
Headache356
Neurologic186
Nausea1212
Infection666
Fever18
Thrombocytopenia18
Skin126
Thyroid12
Hypocalcemia66
Altered mood12
Diarrhea66
Hyperuricemia6
Allergic6
Hyperglycemia6

Six patients were treated with an ATRA-IV dose of 15 mg/m2 with a maximum dose of IFN of 5 MU in five of six patients. Six patients were treated at the next dose level of 30 mg/m2. Two patients experienced Grade 3 liver toxicity. One patient with liver metastases developed a transaminitis while receiving 3 MU of IFN, and a second patient experienced similar reversible liver toxicity at an IFN dose of 5 MU. The MTD of ATRA-IV in combination with IFN is 15 mg/m2 and is the dose to be used in the Phase II study. Only 2 patients tolerated the highest IFN dose of 10 MU SQ daily; therefore, in the Phase II study, the IFN dosing will be modified to start at 3 MU SQ every Monday–Friday, and, if this is tolerated, the dose will be escalated to 5 MU and then to 7 MU (3-5-7 MU SQ M–F).

Other Grade 3 and 4 toxicities were as follows: There was one episode of sepsis with associated Grade 3 diarrhea, and there were single episodes of Grade 3 anemia, Grade 4 hyperuricemia, and Grade 3 hyperglycemia. Other mild toxicities that occurred in a significant proportion of patients were anemia (65%), fatigue (47%), headache (41%), neurologic toxicity (24%), nausea (24%), infection (18%), thrombocytopenia (18%), rash (18%), hypocalcemia (12%), mood alterations (12%), diarrhea (12%), hyperthyroidism (6%), and hypothyroidism (6%). In 12 patients who were treated at ATRA-IV doses of 15 mg/m2 or 30 mg/m2, IFN dose reductions occurred for diarrhea, fatigue, and/or hepatotoxicity in 5 patients.

Antitumor Activity

The antitumor activity of ATRA-IV and IFN is summarized in Table 3, which describes patients that achieved partial remission or prolonged stable disease (≥ 24 weeks), and the characteristics and responses of each patient are described in Table 4. Twelve of 17 patients who were enrolled on the study received at least 8 weeks of therapy and, thus, were evaluable for response. Two patients achieved a partial remission in response to combination therapy with ATRA-IV and IFN (Fig. 1). Both of these partial remissions occurred in patients who received the MTD level of ATRA-IV. One of these remissions is ongoing, with the last follow-up revealing a continued response at > 95 weeks. The other remission lasted for 18 weeks. One of these responses included a response in bone metastases. Three other patients achieved prolonged stable disease (≥ 24 weeks): One of those patients received ATRA-IV at the 90 mg/m2 dose level, and the other two patients received ATRA-IV at the 30 mg/m2 dose level. All five patients who achieved a response or had prolonged, stable disease had undergone nephrectomy, and four of those five patients were male. Both patients who achieved a partial response originally presented with localized disease, and both had clear cell histology, although one of these patients also had a focus of sarcomatoid histology. Of the three patients with prolonged stable disease, two patients had clear cell histology, and one patient had sarcomatoid histology. One patient has had ongoing stable disease for > 54 weeks. In patients who achieved a partial response or stable disease, the most common site of progression was in bone.

Table 3. Antitumor Activity of Liposome-Encapsulated All-Trans Retinoic Acid and Interferon in Responding Patients, including Patients with Prolonged Stable Disease (24 weeks)
ATRA-IV dosage (mg/m2)IFN MTD (MU)Time to progression (weeks)Site of progressionPrior nephrectomy
  1. ATRA-IV: liposome-encapsulated all-trans retinoic acid; IFN: interferon; MU: million units (daily); NA: not available; SD: stable disease.

Partial remission    
 155> 91NAYes (1996)
 15518BoneYes (1997)
Prolonged SD (24 weeks)    
 90324Bone/lungYes (1994)
 30524BoneYes (1997)
 3010> 49NAYes (1993)
Table 4. Characteristics, Treatment, and Response of Individual Patients Enrolled in the Trial
PatientGenderStage at diagnosisPrior nephrectomyHistologyResponseTime to progression (weeks)Site of progressionATRA-IV dose (mg/m2)IFN MTD (MU)a
  • ATRA-IV: liposome-encapsulated all-trans retinoic acid; IFN: interferon; MTD: maximum tolerated dose; F: female; CC: clear cell; SD: stable disease; MU: million units; PD: progressive disease; M: male; PR: partial response; NA: not available; CD: collecting duct; Sarc: sarcomatoid.

  • a

    MU daily for patients receiving ATRA-IV 90 mg/m2; Mu 5 days per week for patients at all other dose levels.

  • b

    Grade 3 allergic with first dose of ATRA-IV: not evaluable for response.

  • c

    Not evaluable for response; did not complete 8 weeks of therapy.

W1FLocalizedYesCCSD24Bone/lung903
W2FLocalizedYesCCPD8Lung90< 3
W3MMetastaticYesCCb6Brain903
W4MLocalizedYesCCPD8Bone903
C1MMetastaticNoCCbcc90c
W5MLocalizedYesCCPR> 91NA155
W6FMetastaticNoCDb4Soft tissue15< 3
W7MLocalizedYesCC, SarcPR18Bone155
W8FMetastaticNoCCSD10Bone155
W9FMetastaticNoCC, Sarcb7Liver/lung155
W10MMetastaticYesSarcPD8Liver/lung155
W11MLocalizedYesSarcSD24Bone305
W12FMetastaticNoCCb4Liver303
W13MLocalizedYesCCSD18Lung/lymph3010
C2FMetastaticNoCCPD8Lung/kidney305
C3FMetastaticNoCCPD8Lung/liver305
C4MMetastaticYesCCSD> 49NA3010
thumbnail image

Figure 1. Computed tomography (CT) scans pretherapy and posttherapy. (A,B) Chest CT from Patient W7. LM: lung metastases. (C,D) Biopsy-confirmed renal carcinoma destroying the right clavicle with adjacent soft tissue mass. Note decreased size of the mass and new bone formation after therapy (D).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

A Phase II trial combining oral 13-cis RA with IFN-α in patients with advanced RC resulted in a 30% major response proportion (13 of 43 patients; 3 complete responses and 10 partial responses).5 In that trial, responding sites included bone metastases and renal primary tumors, sites of disease that usually do not respond to single-agent IFN. Moreover, the duration of response was considerably longer than the response observed with IFN alone.23 Based on these encouraging results, a randomized Phase III trial comparing IFN alone with IFN plus 13-cis RA was performed on 284 patients. A low response rate was observed with a 12% response proportion (5 complete responses and 11 partial responses) in the combination arm compared with 6% (1 complete response and 8 partial responses) in the IFN-only arm (P = 0.14).24 However, the median response duration in the group of patients who received both drugs was 33 months compared with 22 months in the IFN-only group (P = 0.03), with 19% versus 10% of patients progression free at 24 months in the 13-cis plus IFN group versus the IFN-only group, respectively (P = 0.05). The median survival was not significantly different between the two groups at the time of publication.24 Similarly, another randomized trial of IFN, interleukin-2, and 5-flourouracil with or without oral 13-cis RA showed a higher complete response rate in the 13-cis RA arm (9% vs. 3%).25 Moreover, the median survival of patients who received 13-cis RA had not been achieved at > 4 years, whereas the median survival of patients who received the same regimen without 13-cis RA was 28 months. Other trials also have demonstrated antitumor activity using a combination of RA and IFN.26, 27 Taken together, these data suggest that RA may augment the antitumor effects of IFN-based therapy but that this benefit has not been achieved convincingly using oral formulations of 13-cis RA and ATRA.

In the current study, we assessed the combination of ATRA-IV in combination with IFN. Preclinical studies suggested that ATRA-IV may be a more potent retinoid, and our initial experience in combining this drug with IFN supported that observation. Although the MTD for ATRA-IV alone is 140 mg/m2, the initial starting dose of ATRA-IV in this trial had to be reduced from 90 mg/m2 to 15 mg/m2 due to excessive toxicity at the lowest dose of IFN, suggesting an unanticipated interaction with regard to myelosuppression between these two agents. In addition, only 2 of 16 patients who received IFN tolerated a dose of 10 MU, with 8 patients tolerating a dose of 5 MU, and 6 patients tolerating a dose of 3 MU or less. Consequently, the Phase II dose of ATRA-IV will be 15 mg/m2, but the dose escalation of IFN will be scaled back to 3-5-7 MU SQ M–F. However, individual patients will be evaluated weekly to identify the safe and tolerable dose IFN for each patient.

Two partial responses were seen in this study, and both were at the proposed Phase II dose level of 15 mg/m2 three times per week, resulting in a 50% response rate in patients who were treated at the MTD of ATRA-IV. The overall response rate for the trial was 16.7%. One of the responses is ongoing at > 95 weeks duration. In addition, another three patients likely derived benefit from this treatment regimen, because they experienced prolonged stable disease. One of those patients has ongoing stable disease at > 54 weeks of follow-up.

The benefit of adding a retinoid to IFN therapy in patients with advanced RC remains controversial. Previous work by our group has demonstrated that RC cells are deficient in retinoid stores,10 and, when retinoid signaling was augmented (as indicated by expression of RARβ) in patients who were treated with retinoids and IFN, there was a correlation with response to therapy.6 Nevertheless, trials using other RA formulations have not proven convincingly that there is a role for RA in the treatment of patients with this disease. Our Phase I trial indicates that ATRA-IV at our proposed Phase II dose is well tolerated and has antitumor activity, although it was necessary to reduce significantly the dose of ATRA-IV from the MTD of the drug alone to combine it with IFN. An ongoing Phase II trial will determine whether this combination may have a role in the treatment of patients with advanced RC.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank Catherine Kearney for secretarial assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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