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Keywords:

  • Chemotherapy;
  • lymphoma;
  • post-transplant lymphoproliferative disorder;
  • rituximab

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Information regarding treatment of post-transplant lymphoproliferative disease (PTLD) beyond reduction in immunosuppression (RI) is limited. We retrospectively evaluated patients receiving rituximab and/or chemotherapy for PTLD for response, time to treatment failure (TTF) and overall survival (OS). Thirty-five patients met inclusion criteria. Twenty-two underwent rituximab treatment, with overall response rate (ORR) 68%. Median TTF was not reached at 19 months and estimated OS was 31 months. In univariable analysis, Epstein-Barr virus (EBV) positivity predicted response and TTF. LDH elevation predicted shorter OS. No patient died of rituximab toxicity and all patients who progressed underwent further treatment with chemotherapy. Twenty-three patients received chemotherapy. ORR was 74%, median TTF was 10.5 months and estimated OS was 42 months. Prognostic factors for response included stage, LDH and allograft involvement by tumor. These factors and lack of complete response (CR) predicted poor survival. Twenty-six percent of the patients receiving chemotherapy died of toxicity. Rituximab and chemotherapy are effective in patients with PTLD who fail or do not tolerate RI. While rituximab is well tolerated, toxicity of chemotherapy is marked. PTLD patients requiring therapy beyond RI should be considered for rituximab, especially with EBV-positive disease. Chemotherapy should be reserved for patients who fail rituximab, have EBV-negative tumors or need a rapid response.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of organ transplantation, occurring in 1% or more of patients, depending on the type of organ transplanted (1). The term PTLD encompasses a heterogeneous group of lymphoproliferative disorders, ranging from polyclonal proliferation to aggressive non-Hodgkin's lymphoma, and most show evidence of infection with the Epstein-Barr virus (EBV) (2,3). The pathophysiology of PTLD is thought to involve loss of control of virus-infected, transformed B cells by an immune system compromised by pharmacologic immunosuppression. Other factors likely contribute to the development of PTLD in some patients, as not all tumors arise in the setting of EBV.

Because of this integral association with immunosuppression, a key feature of PTLD treatment includes restoration of a functional immune system in the host. Initial therapy, therefore, is reduction in immunosuppression (RI) for most patients. Response rates vary, with some patients achieving complete remission with RI alone or in combination with localized therapy such as radiation or surgery and others experiencing progressive disease. Prognostic factors impacting the likelihood of response to RI have been identified, and negative factors include elevated LDH, organ dysfunction and presence of multiple visceral sites of disease (4). Antiviral antibiotics such as acyclovir and ganciclovir have been studied in treatment with mixed results (5–9). In general, it appears antiviral therapy is more effective in prevention than in treatment of established tumors.

Treatment for patients requiring therapy beyond RI remains suboptimal. Chemotherapy, either single agent or combination regimens, has been explored (10–12), but toxicities have been markedly higher when these regimens are used in immunocompetent populations. This excess toxicity, particularly severe infections, is likely related to the already immunosuppressed state of patients. Recently, use of anti-B cell monoclonal antibodies has been explored, with encouraging results (13–17). Because of the rarity of PTLD, however, reports frequently include small patient numbers, making general observations difficult.

We report results of treatment with rituximab and/or chemotherapy in patients with PTLD treated at the University of Pennsylvania Medical Center who did not respond optimally to RI.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Patients

Patients at the University of Pennsylvania with a diagnosis of PTLD who were treated with rituximab, chemotherapy or both between September 1996 and May 2005 were retrospectively identified. Reasons for transplantation included chronic obstructive pulmonary disease, pulmonary hypertension, idiopathic pulmonary fibrosis, idiopathic bronchiectasis, sarcoidosis, cardiomyopathy, congenital heart disease, hepatic cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hypertensive nephropathy, glomerulonephritis, glomerulosclerosis, diabetic nephropathy and systemic lupus erythematosis. Immunosuppression was administered per the transplant physician. Rejection episodes were treated with steroids and steroid refractory cases were further considered for therapy with anti-CD3 antibody (OKT3) or antithymocyte globulin (ATG).

Treatment

Initial treatment considered for patients was RI. This was in most cases accomplished by discontinuation of azathioprine or mycophenylate mofetil and decreasing the dose of other drugs. Patients experiencing active rejection of a heart or lung graft were excluded from this treatment. Patients with progression or unsatisfactory regression of PTLD or who relapsed after initial response, were considered for further therapy.

Patient treatment decisions were at the treating physician's discretion and were affected by factors including tumor CD20 status, medical status and date of treatment (prior to rituximab availability). This was a retrospective study with no attempt to control treatment decisions. Rituximab was administered at 375 mg/m2 weekly for four treatments. CHOP chemotherapy consisted of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 to maximum 2 mg and prednisone 100 mg/day for 5 days. Cycles were repeated every 21 days as tolerated up to six cycles. R/CHOP consisted of CHOP with the addition of rituximab 375 mg/m2 given once with each cycle. ESHAP (etoposide, methylprednisolone, cytarabine and cisplatin) and ProMACE CytaBOM (mechlorethamine, doxorubicin, cyclophosphamide, etoposide, vincristine, prednisone, procarbazine, methotrexate, cytarabine and bleomycin) were administered as published (18,19).

Pathology

Diagnosis was based on the examination of histologic material. Tumors were classified according to the World Health Organization (WHO) classification. EBV was detected by immunohistochemistry using a monoclonal antibody against LMP1 and/or in situ hybridization using a peptide nucleic acid (PNA) probe for EBER-1 (Dako, Carpinteria, CA) according to manufacturer's recommendations.

Disease evaluation and statistical analysis

Data were collected using retrospective chart review. Response assessment was performed using standard criteria (20). Time to development of PTLD was defined as the interval between transplantation and date of biopsy confirming PTLD. Time-to-treatment failure (TTF) was measured from the 1st day of therapy until time of disease progression, initiation of alternative therapy or disease/treatment-related death, with censoring at time of death unrelated to PTLD/treatment or last follow-up. Overall survival (OS) was measured from the 1st day of therapy until date of death, with censoring at time of last follow-up. All survival distributions and rates were calculated according to the Kaplan-Meier method. The relationship between several patient/disease characteristics and achievement of complete response (CR) was examined in univariable analysis using the chi-square test. Specifically, we evaluated history of prior rejection, time-to-PTLD, WHO morphology, EBV positivity, Ann Arbor stage, elevated LDH, ECOG performance status, presence of B symptoms, age over 60 years and allograft involvement by PTLD. Additionally, the relationship between these variables, achievement of CR and TTF or OS was examined in univariable analysis using the log-rank test. Univariable hazard ratios for TTF and OS were derived using a Cox proportional hazards regression model. All p-values are 2-tailed. Statistical analysis was performed with the STATA software (STATA Corporation v.8, Research Park, Texas, 2003).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Patients

Of 117 patients treated for PTLD at the University of Pennsylvania, 35 (30%) met criteria for inclusion, having undergone treatment with single-agent rituximab, chemotherapy or both. Patient characteristics are shown in Table 1. Patients had undergone transplantation of heart (11 patients), lung (8 patients), kidney (8 patients), liver (6 patients), bone marrow (1 patient) or combined liver and kidney (1 patient). The median time from transplantation to development of PTLD was 4 years (range 3 months to 23 years). All patients were actively undergoing pharmacologic immunosuppression, with the majority on combinations of mycophenolate mofetil or azathioprine, cyclosporine A or tacrolimus and prednisone. Eight patients (22%) had previously been treated with anti-T-cell therapies, such as OKT3 and ATG. Forty percent had experienced at least one episode of rejection resulting in modification of immunosuppression.

Table 1.  Patient characteristics
 OverallRituximabChemotherapy
Total352223
Gender
 Male25 (71)14 (64)19 (79)
 Female10 (29)8 (36)5 (21)
Transplant type
 Lung 8 (23) 5 (23) 4 (17)
 Heart11 (31) 5 (23)10 (43)
 Liver 6 (17) 5 (23) 3 (13)
 Kidney 8 (23) 6 (27) 5 (21)
 Bone marrow 1 (3) 1 (5) 0
 Liver/Kidney 1 (3) 0 1 (4)
Age58 (range 20–76)56 (range 21–76)58 (range 20–66)
 >6012 (34) 7 (32) 9 (39)
 <6023 (66)15 (68)14 (61)
Time to PTLD4 years (0.23–23)4.3 years (range 0.23–23)4.6 years (range 0.37–23)
Stage
 1 9 (26) 5 (23) 5 (22)
 2 6 (17) 3 (14) 5 (22)
 3 4 (11) 3 (14) 3 (13)
 416 (46)11 (50)10 (43)
Extranodal
 Yes26 (74)19 (86)15 (65)
 No 9 (26) 3 (14) 8 (35)
LDH
 Normal 8 (23) 4 (20)15 (65)
 >Normal24 (69)16 (80) 5 (22)
 NA 3 (9) 2 (6) 3 (13)
Immunosuppression
 aza/CSA/pred13 (37) 7 (32) 8 (35)
 MMF/tac/pred 5 (14) 5 (23) 2 (8)
 aza/CSA 3 (9) 2 (10) 2 (9)
 CSA 3 (9) 2 (10) 1 (4)
 MMF/CSA/pred 3 (9) 1 (5) 2 (9)
 CSA/pred 2 (6) 1 (5) 3 (12)
 tac/pred 1 (3) 1 (5) 1 (4)
 tac 1 (3) 2 (10) 0
 CSA/pred/rap 1 (3) 0 1 (4)
 aza/pred 1 (3) 0 2 (8)
 aza/tac 1 (3) 0 1 (4)
 aza/rap 1 (3) 1 (5) 0
Prior anti-T-cell therapy
 Yes 8 (23) 3 (14) 6 (26)
 No27 (77)19 (86)17 (74)
Prior rejection
 Yes14 (40) 8 (36)10 (43)
 No21 (60)14 (64)13 (57)
Histology
 Monomorphic24 (73)17 (85)14 (64)
 Polymorphic 6 (18) 3 (15) 5 (23)
 Plasmacytoid 2 (6)  2 (9)
 GD T cell 1 (3)  1 (5)
 NA 2 (6) 2 (9) 1 (5)
Clonality
 Monoclonal14 (40) 6 (27)10 (43)
 Polyclonal 4 (11) 4 (18) 2 (9)
 Unknown17 (49)12 (55)11 (48)
EBV
 Positive25 (74)16 (73)16 (70)
 Negative 9 (26) 6 (27) 7 (30)
Organ dysfunction
 No30 (86) 4 (18) 3 (13)
 Yes 5 (14)18 (82)20 (87)
CD 20 Status
 Yes31 (89)22 (100)19 (83)
 No 4 (11) 0 4 (17)

Nineteen patients (57%) presented with advanced stage (stage III or IV), with 74% involving extranodal sites. Histology was monomorphic in 24 (71%), polymorphic in 7 (21%), plasmacytoid in 2 (6%), gamma/delta T cell in one patient and not available in one. Clonality assessment was available in 18 patients, with 14 being monoclonal. EBV was detected in 25 (74%), with nine tumors testing negative for EBV. Prognostic factors for response to RI were also assessed. A majority of patients (71%) had elevated LDH levels. Eight patients (23%) had disease at multiple visceral sites and six (17%) had organ dysfunction.

The majority (91%) of the patients were initially treated with RI. In three patients (9%), RI was not feasible due to active rejection of the allograft. Two patients initially showed a CR to RI, but they subsequently relapsed upon reinstitution of immunosuppression. One patient had a partial response (PR), but required further therapy. Seventeen patients had progressive disease following RI and 13 patients were treated with another modality before response to RI could be assessed. The response of one patient to RI was unknown.

Patients were divided into two groups depending on treatment: (1) rituximab single agent and (2) chemotherapy, with or without rituximab or radiation. Eleven patients were treated with both rituximab as a single agent and with chemotherapy, at separate times, and these patients have been analyzed in both groups according to the appropriate therapy.

Rituximab

Twenty-two patients were treated with rituximab as a single agent. Nineteen of these patients received rituximab as first-line therapy (after RI) and three received rituximab upon progression or relapse after chemotherapy. Baseline characteristics were similar to those of the entire cohort.

Thirteen of 22 patients (59%) treated with rituximab achieved a CR and two patients (9%) achieved a PR for an overall response rate (ORR) of 68%. Six experienced disease progression and one patient was not evaluable due to death from allograft rejection. Median time to treatment failure (TTF) for all patients treated with rituximab (Figure 1A) was not reached at a median follow-up of 19 months (range 0.8–51 months). Eight patients either progressed on rituximab (6 patients) or relapsed after an initial response (2 patients). All received further treatment with chemotherapy. By Kaplan-Meier estimate, median OS (Figure 1B) was 31 months (range 1.5–51 months). Nine of 22 patients have died. Cause of death was progression of PTLD in 2 patients, sepsis in 2 and multiorgan failure in 1 (all 3 after salvage chemotherapy), graft failure in 3 and CVA in 1. Of patients who received rituximab after prior chemotherapy, all achieved a CR. Two remain alive in CR and 1 has died of allograft failure.

image

Figure 1. Kaplan-Meier estimates of time to treatment failure (A) and overall survival (B) for patients receiving rituximab.

Download figure to PowerPoint

In a univariable analysis, the only factor that influenced likelihood of response after treatment with rituximab was EBV status (Table 2). Patients whose tumor was EBV positive were significantly more likely to achieve CR than patients with tumors that were EBV negative (p = 0.014). Factors influencing TTF included both EBV status and achievement of CR. In contrast, these factors were not significant predictors of OS, with normal LDH being the only significant predictor of survival in these patients (p = 0.047).

Table 2.  Prognostic factors
 RituximabChemotherapy
  1. 1Odds ratio (OR) of achieving a complete remission if the risk factor is present.

  2. 2Hazard ratio (HR) of death or treatment-failure if the risk factor is present.

CR1EBV positiveOR 4.8, p < 0.01Stage III/IVOR 0.4, p = 0.02
LDH > normalOR 0.4, p = 0.01
Graft involvementOR n/a, p < 0.01
OS2LDH > normalHR 6.7, p = 0.04Stage III/IVHR 2.1, p = 0.04
LDH > normalHR 6.6, p = 0.04
Graft involvementHR 3.5, p = 0.05
CRHR 0.05, p < 0.001
TTF2EBV positiveHR 0.16, p = 0.01LDH > normalHR 6.8, p = 0.04
CRHR n/a, p < 0.001CRHR 0.08, p < 0.001
 Early PTLDHR 3.5, p = 0.02

Treatment with rituximab was well tolerated. Two patients were hospitalized during treatment, 1 for infection and 1 for allograft rejection. No patient died from complications of rituximab treatment. Five patients experienced graft rejection while on therapy, all in the setting of reduced immunosuppression.

Chemotherapy

Twenty-three patients received treatment including chemotherapy. The regimens used are listed in Table 3, with 10 patients receiving CHOP 9 patients R/CHOP and 4 patients other regimens. Seven patients underwent radiotherapy before or after chemotherapy. Sixteen patients received chemotherapy as first-line (after RI) and seven received chemotherapy after prior treatment with rituximab. One patient was initiating chemotherapy at the time of this analysis and therefore is not included in analysis of the chemotherapy cohort. Baseline characteristics of these patients were not significantly different from those of the cohort as a whole.

Table 3.  Chemotherapy regimens
  1. CEP = cyclophosphamide, etoposide, prednisone; R/C = rituximab, cyclophosphamide; Other regimens as in Methods.

CHOP10 (43%)
R/CHOP 9 (39%)
ESHAP 1 (4%)
CEP 1 (4%)
ProMACE CytaBOM 1 (4%)
R/C 1 (4%)

Of 23 patients treated with chemotherapy, 13 (57%) achieved CR and 4 (17%) PR, for an ORR of 74%. Five patients had progression of disease. One patient was not evaluable for response due to early death from treatment and was excluded from further response analysis. Median TTF for this group (Figure 2A) was 10.5 months (range 0.4–54 months). At a median follow-up of 27 months, Kaplan-Meier estimate of median OS (Figure 2B) was 42 months (range 0.4–70 months), with 12 of 23 patients having died. Of the seven patients having previously received rituximab, four achieved CR and remained alive in CR at last follow-up. One achieved PR but died of chemotherapy toxicity and two died of progressive disease. In order to address the possibility that inclusion of patients previously treated with rituximab would negatively bias results, we re-analyzed the data including only patients not previously treated and found similar results, with median TTF 10.5 months (0.4–48 months) and median OS 42 months (0.4–70 months).

image

Figure 2. Kaplan-Meier estimates of time to treatment failure (A) and overall survival (B) for patients receiving chemotherapy.

Download figure to PowerPoint

A univariable analysis of factors affecting response in patients receiving chemotherapy identified advanced stage (stage III or IV), elevated LDH and allograft involvement by tumor as negative prognostic factors (Table 2). These same factors, with the addition of lack of CR, predicted poorer OS. Characteristics affecting TTF, on the other hand, included early development of PTLD (<2 years), in addition to elevated LDH and lack of achievement of CR. In this small group of patients, the addition of rituximab to CHOP did not significantly affect response, TTF or OS.

Toxicities associated with chemotherapy treatment were significant. Twelve (52%) patients were hospitalized, mostly for infections, and six (26%) died from treatment-related causes. One patient experienced cardiotoxicity following CHOP chemotherapy, which ultimately led to that patient's death, while all other treatment-related deaths were due to infection. One patient experienced graft rejection during treatment in the setting of reduced immunosuppression. There was no increase in the rate of serious toxicity (hospitalization and/or death due to treatment) associated with addition of rituximab to CHOP. Overall serious toxicity was 50% in patients receiving CHOP (4 deaths and 1 patient hospitalized) and 55% in patients receiving R/CHOP (1 death and 4 patients hospitalized).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

In this retrospective study, we report the results of treatment with rituximab or chemotherapy for patients with PTLD. The baseline characteristics of the patients suggest an overall poorer prognosis than the general population of PTLD patients, as is expected since the group was defined based on need for therapy beyond RI. This poorer prognosis is evidenced by the long interval from transplantation to development of PTLD, a high proportion of monomorphic tumors and a majority of patients with elevated LDH. EBV negative disease was also relatively common in this cohort.

Statistical analysis demonstrated that several prognostic factors are useful in predicting response to rituximab or chemotherapy. EBV status was the most important characteristic influencing likelihood of response to rituximab. However, the only significant factor influencing OS in this group of patients was the LDH level. This finding likely reflects the fact that patients who progressed following rituximab treatment were uniformly able to undergo treatment with chemotherapy, making the prognostic factors relating to chemotherapy most relevant for survival. Prognostic factors important in predicting outcome following chemotherapy were more similar to those factors important for prognosis in nonimmunosuppressed lymphoma patients, including stage and LDH. The finding that patients who develop PTLD early post-transplantation have a poorer prognosis in our cohort is somewhat surprising, given previous reports suggesting that late disease has a worse prognosis (21–23). This finding may reflect patient selection, however, indicating that patients in this group who do not respond to first-line immune manipulation have an inherently different, more resistant disease. Factors such as histology and clonality did not appear to significantly impact on prognosis in our study. It is possible that the small numbers of polymorphic and polyclonal tumors might have made differences difficult to detect.

Others have reported factors having prognostic value in patients with PTLD. Leblond et al. reported performance status and number of disease sites as important prognostic characteristics (22). While number of disease sites likely correlates with stage, also a significant contributor to prognosis in our study, we did not find PS to have significant impact. The reason for this difference may lie in the fact that Leblond et al. evaluated all patients with PTLD, not just those receiving treatment beyond RI.

Several groups have reported results of chemotherapy in small case series of patients with PTLD (10–12). In general, these studies have shown chemotherapy to be effective, with response rates ranging from 33% to 97%. However, toxicity of combination chemotherapy was significant, with most studies reporting mortality during treatment of 25–50%. These findings are consistent with our results. The improved tolerability of rituximab over chemotherapy is consistent with experience in nonimmunosuppressed patients. This finding may be accentuated in this patient population because of their particularly high infection risk, a hazard which chemotherapy, in contrast to rituximab, exacerbates. Furthermore, the ability to give full doses of the monoclonal antibody without risk of further organ damage, even in patients with pre-existing organ dysfunction, provides a clear advantage in this patient population.

Anti-B cell antibodies have been explored for treatment of patients with PTLD since the 1990s. Initial studies evaluated anti-CD21 and anti-CD24, with promising results (13,16). Although these antibodies are not currently available commercially, the introduction of rituximab, a humanized mouse anti-human CD20 antibody, has contributed markedly to care of patients with B-cell lymphomas. In PTLD, rituximab has shown effectiveness in several small case series (14,15). The largest group reported to date includes 32 patients, of whom 69% of patients responded (17). We evaluated 22 patients and found similar results, with an ORR of 74%.

Since this is a retrospective study with heterogeneous groups of patients, no comparisons regarding treatment effectiveness can be drawn between the two groups. Both treatment approaches showed effectiveness in patients who had failed initial RI or who were unable to undergo RI due to active allograft rejection or urgent need of rapid response. However, the toxicities encountered with each treatment differed markedly. Twenty-six percent of patients treated with chemotherapy died from causes related to therapy, whereas none of the rituximab treated patients died of treatment toxicity. The high rate of infection in transplant patients treated with chemotherapy likely stems from the fact that their defenses against infection are already compromised. This immune compromise stems not only from T-cell dysfunction induced by immunosuppressive drugs, but possibly also impaired bone marrow reserve caused by some of these same drugs, leading to more severe neutropenia with standard chemotherapy regimens. A recent study evaluating the addition of rituximab to CHOP in HIV-infected patients with lymphoma showed a higher rate of toxicity with the addition of rituximab (24), raising the possibility that rituximab might increase toxicity in any immunosuppressed population receiving chemotherapy. Although the numbers reported here are small, we did not observe any increase in severe toxicity associated with the addition of rituximab to CHOP in patients with PTLD.

An important observation from this study is that all patients who progressed on or relapsed following treatment with rituximab received further treatment. This finding demonstrates that initial rituximab therapy does not compromise the ability to administer salvage treatment. The finding of good efficacy and low toxicity of treatment with rituximab, as well as the ability to pursue chemotherapy later if necessary, leads us to favor the use of rituximab as first-line therapy in patients with B cell PTLD who have failed or are unable to undergo RI, particularly those with EBV positive disease. Chemotherapy can then be reserved for patients who do not respond optimally to rituximab or those with EBV negative PTLD in need of a rapid response, limiting patients' exposure to its marked toxicity.

In this cohort, as well as in other reported studies evaluating monoclonal antibody therapy in PTLD, many patients appear to achieve long-term disease-free survival, and possibly even cure. This is in contrast to nonimmunosuppressed patients, in whom rituximab is frequently effective in eliciting a response, but is not curative. The explanation for this is unclear, but likely involves the markedly differing immune status of the patients. Rituximab might simply elicit a response which lasts long enough for the patient's immune system to reactivate and destroy the tumor. Alternatively, rituximab could directly induce some specific activation of the patient's immune system, allowing it to recognize the lymphoma and clear it from the body. Such an idea is consistent with the likelihood that one mechanism of action by which rituximab works is activation of antibody-directed cellular cytotoxicity (ADCC) (25).

Since infection appears to be the most prevalent and dangerous toxicity of chemotherapy, prophylactic use of myeloid growth factors and/or antibiotics might decrease morbidity and mortality associated with treatment. Furthermore, intensity of pharmacologic immunosuppression should be minimized for patients receiving chemotherapy, particularly since chemotherapy itself is immunosuppressive and organ rejection while on treatment is relatively rare.

In summary, rituximab and chemotherapy are effective regimens in treatment of RI-resistant PTLD. However, treatment toxicity appears to be significantly greater with chemotherapy in this fragile population. Future prospective trials are needed to clarify which patients will most benefit from which therapy and how to minimize toxicity during treatment.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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