Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 3  |  Page : 712-717

Late outcomes in children and adolescents with non-Hodgkin lymphoma: A single-center experience


Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Ankara University, Ankara, Turkey

Date of Submission13-Jan-2021
Date of Decision25-Aug-2021
Date of Acceptance26-Aug-2021
Date of Web Publication10-Feb-2022

Correspondence Address:
Hatice Mine Çakmak
Department of Pediatric Hematology-Oncology, Eskisehir City Hospital, 71 Houses, 26080, Eskisehir
Turkey
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_80_21

Rights and Permissions
 > Abstract 


Background: Non-Hodgkin lymphoma (NHL) includes pathologies of different clinical courses, treatments, outcomes. Our study aims to investigate the late effects of NHL survivors (NHLS).
Materials and Methods: Among 59 NHL cases, 50 survivors completed their NHL treatment between 2003 and 2019. Out of 59 patients, the cumulative survival rates and event-free survival rates after 10 years since diagnosis were 82.9% ±5.2% and 84.1% ±5.2%, respectively. In addition, we compared the data related to chronic health and psychosocial conditions with their siblings (n = 61).
Results: The age and gender ratios were similar in the NHLS (n = 50) and the control group (n = 61). The rate of nephrotoxicity (P = 0.02) and the frequency of admission to the hospital (P < 0.01) were significantly higher in the survivors than in the control group. Cardiotoxicity is detected in 3 (6%) of NHLS with cumulative anthracycline dose <300 mg/m2. The social status (being married [P < 0.01], having children [P = 0.003]) is impaired in NHLS. The alcohol and smoking habits, education status, and health conditions (endocrinologic, cardiac, neurological, and pulmonary) were similar in both groups. One patient had acute myeloid leukemia as a secondary malignancy. Twenty NHLS took rituximab, two of them took brentuximab vedotin plus chemotherapy. NHLS have impairment in health status, social life.
Conclusion: Nephrotoxicity is a statistically more common late effect than the others in the survivors. We observe cardiotoxicity in low cumulative doses of anthracycline. A more significant number of patients is required to reveal late side effects on novel drugs.

Keywords: Children, late effects, non-Hodgkin lymphoma


How to cite this article:
Tacyildiz N, Çakmak HM, Ünal E, Dinçaslan H, Yılmaz Y, Kartal &, Tanyıldız G, Özdemir S&, Yavuz G. Late outcomes in children and adolescents with non-Hodgkin lymphoma: A single-center experience. J Can Res Ther 2022;18:712-7

How to cite this URL:
Tacyildiz N, Çakmak HM, Ünal E, Dinçaslan H, Yılmaz Y, Kartal &, Tanyıldız G, Özdemir S&, Yavuz G. Late outcomes in children and adolescents with non-Hodgkin lymphoma: A single-center experience. J Can Res Ther [serial online] 2022 [cited 2022 Aug 10];18:712-7. Available from: https://www.cancerjournal.net/text.asp?2022/18/3/712/337520




 > Introduction Top


Among the pediatric/adolescent cancers, non-Hodgkin lymphoma (NHL) is the fourth most common malignancy, representing approximately 7% of new cases.[1] Overall survival (OS) rates for childhood NHL by 5-year intervals exceed 90%.[2] While early deaths among pediatric cancer populations are primarily related to cancer recurrence or progression, those who achieved complete remission experience increased mortality and morbidity rates compared to the general population.[3] A report by Gibson et al. suggests that, in parallel to reductions in treatment intensity over time, more recently treated cohorts of survivors experience a lower incidence of severe chronic health conditions, supporting ongoing efforts to reduce treatment exposures with high cure rates.[4] The five most frequently occurring conditions were hypertension, dyslipidemia, cardiac arrhythmias, peripheral nervous system disorders, and structural heart defects.[5] In addition, many survivors who have taken central nervous system (CNS)-directed chemotherapies and or cranial radiation therapy have neurocognitive sequelae.[6] This study aims to characterize health conditions, neurocognitive function, and physical performance among a clinically evaluated cohort of 50 childhood NHL survivors (NHLS).


 > Materials and Methods Top


Patients

This retrospective study included 59 patients diagnosed with NHL in our university and completed a multiple-course chemotherapy regimen between January 2003 and January 2019. The ethics committee of our university approved this study. Of these patients, 50 were survivors, and nine were dead.

Treatment

In our small NHL cohort (n = 59), 36 had Burkitt lymphoma, 13 had T-cell lymphoma, 1 had anaplastic large cell lymphoma (ALCL), 5 had diffuse large B-cell lymphoma (DLBCL), and 4 had other pathological subcategories. Twenty-nine (58%) received the Pediatric Oncology Group 9317 regimen (doxorubicin, prednisone, vincristine, etoposide, etoposide, methotrexate, and high-dose cytarabine) and 4 (8%) took the French, American, British Mature B cell lymphoma (FAB LMB-96) regimen which includes doxorubicin, prednisone, vincristine, etoposide, etoposide, methotrexate, and high-dose cytarabine. Seventeen (34%) received the other regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [anthracycline, cyclophosphamide, etoposide, and vincristine] for DLBCL or Berlin, Frankfurt, Munster [BFM] 95 for lymphoblastic lymphoma or BFM-NHL 90 [anthracycline, cyclophosphamide, ifosfamide, etoposide, methotrexate, cytarabine, vincristine] for ALCL or R-CHOP [rituximab, cyclophosphamide, prednisolone, vincristine, doxorubicin]).[7-10] In addition, two patients with Burkitt lymphoma took brentuximab vedotin (BV).

Statistical analysis

The OS from the first visit until death or last contact was analyzed, with events defined as relapse or death. Using Kaplan–Meier survival analysis, we calculated the OS rates at the 1st year, 5th year, 10th, and event-free survival rates. The significance of the comparisons for the risk of adverse events was determined using a log-rank test. We compared the survivors’ (n = 50) heart, kidney, lung diseases, obesity, hypothyroidism, growth hormone deficiency, neurological disease, smoking and alcohol habits, psychosocial factors (marital status, children, and education), utilization of health-care services, and physical limitations with their siblings (n = 61). We used statistical analyses using the IBM SPSS Statistics Version 21.0. (Armonk, NY: IBM Corp. Released 2012). We evaluated the study variables using Mann–Whitney U test, Chi-square test, and Fisher's exact test. P ≤0.05 was considered statistically significant.

Data collection

We obtained the data from a retrospective review of the patient charts, analysis reports, consultation reports, and a questionnaire applied during phone calls to the families or relatives.

The patients are divided into three groups based on their frequency of the use of health-care services: patients with hospital admissions <3 times in the last 3 months; patients with hospital admissions ≥3 times in the previous 3 months; and patients with at least one hospitalization history in the previous year. We examined limitations in physical functioning in the means of decreased physical function and mobility. The ethics committee of our university approved this study.


 > Results Top


Demographic and clinical data

In our small NHL cohort (n = 59), the diagnoses were Burkitt lymphoma (n = 36), T-cell lymphoma (n = 13), ALCL (n = 1), and DLBCL (n = 5). Four had other pathological subcategories. Unfortunately, nine patients died, so the remaining 50 are survivors. In addition, five died due to relapsing disease, and four died because of refractory disease (n = 4) in diagnosis.

The mean age (19.09 ± 5.93 years in survivors [n = 50] and 20.97 ± 7.72 years in their siblings [n = 61]) and gender of the groups were similar. Of the total, 31 survivors (62%) were male, and 30 (49%) were males in the control group [Table 1]. In addition, three survivors (6%) had fertility preservation (semen cryopreservation).
Table 1: Demographic data of survivors and the control groups

Click here to view


Survival

The time since diagnosis was 0–15 years for 12 (24%), 5–10 years for 17 (34%), and more than 10 years for 21 (42%) survivors. The cumulative OS at 1st, 5th, and 10th years was 94.9% ± 2.9%, 85.3% ± 4.8%, and 82.9% ± 5.2%, respectively, and after the 10th year was 82.9% ± 5.2%. Out of the death cases, six were diagnosed with Burkitt, 2 with T-cell, and 1 with ALCL. Fifth-year survival in Burkitt Lymphoma was 84.2%, 83.9% in T-cell lymphoma, and 0% in ALCL (P < 0.001).

Recurrences

Disease-free survival was 98.2% ± 1.8% at 1st year, 86.5% ±4.8% at 5th year, and 84.1% ± 5.2% at 10 years since diagnosis. Among NHLS (N = 50), three with Burkitt lymphoma relapsed between the 1st and the 5th year from diagnosis. Two of them underwent stem cell transplantation.

Late effects of chemotherapy and targeted agents

We compared the survivors’ demographics and chronic health conditions with the control group. The most prevalent included nephrotoxicity (hypertension, acute renal failure), 8% (n = 4) in NHLS. We found no renal disease in the control group, and the difference was statistically significant (P = 0.02). Forty-seven (94%) NHLS received cytarabine with a median cumulative dose of 13.0 ± 6.4 g/m2. Three survivors with nephrotoxicity (75%) received cytarabine (two of them with a total dose of 0.3 g/m2, one of them did not receive cytarabine, and one acquired with a total dose of 16.2 g/m2). In addition, three (%75) patients with nephrotoxicity received a methotrexate-containing regimen. The total methotrexate dose was 1.2 gr/m2 in two. Among nephrotoxicity cases, one had Burkitt lymphoma.

Echocardiography findings or arrhythmia occurred in three survivors (6%), with no significant difference compared to their siblings (%0) (P = 0.15) [Table 1]. The mean total anthracycline dose was 171.0 ± 93.8 mg/m2, and in the survivors with cardiotoxicity, the total dose of anthracycline was 40 mg/m2 in one, 300 mg/m2 in one, and 100 mg/m2 in the other.

Comparing the NHLS with their siblings, we observed hypothyroidism (2% vs. 0%), retarded growth (4% vs. 0%), and obesity (12% vs. 5%) (P = 0.17) [Table 1]. In addition, hyperlipidemia was detected in 4 (8%) NHLS.

One survivor (2%) recorded impairments in the carbon monoxide (DLCO) diffusing capacity of the lungs and in a pulmonary function test, while no subjects in the control group had such impairments (P = 0.26) [Table 1]. One patient with bronchiolitis obliterans had both relapsing Burkitt lymphoma and CD70 deficiency. He took the LMB96 regimen and later R-CHOP as a rescue regimen with BV. In addition, this patient underwent allogeneic stem cell transplantation.

Patients diagnosed with Burkitt lymphoma (n = 17) and DLBCL (n = 3) received rituximab with a mean total dose of 100.5 ± 167.4 mg/m2 (n = 20). We applied premedication with methylprednisolone, paracetamol, and hydroxyzine. No allergic or anaphylactic reaction occurred, and patients had no acute side effects. Out of these with Burkitt lymphoma (n = 17) in the rituximab group, long-term hypothyroidism (n = 1), obesity (n = 2), cardiac findings (n = 2), hyperlipidemia (n = 3), nephrotoxicity (n = 19), and bronchiolitis obliterans (n = 1) were reported.

Two cases with Burkitt lymphoma received BV in relapsing disease. One of them had obesity. The other took rituximab and BV. In BV group, hypertension, hyperlipidemia, and bronchiolitis obliterans heart failure was detected after 5–10 years since diagnosis.

Among fifty NHLS, one patient had acute myeloid leukemia as a secondary neoplasm. Three survivors (6%) developed neurotoxicity (two neuropathies, one electroencephalography abnormality). Two with T-cell lymphoma received cranial radiotherapy (12 Gy). None of the siblings had a neurologic disease; this difference was not statistically significant (P = 0.15) [Table 1].

The rate of health-care services utilization was significantly higher among the survivors (P < 0.01) when compared to their siblings and 24 patients (48%) admitted to the hospital at <3-month intervals [Table 1].

Although there was no physical limitation in the control group, limited physical function developed in a total of five patients (10%), one (2%) of whom had difficulty in walking/extremity movements (P = 0.07) [Table 1]. Unfortunately, the data of limitation in physical functioning were not available for four patients.

The social status in NHLS and control group is different, the rate of getting married (38% in the control group and 6% in survivors, P < 0.01) and the rate of having children (25% in the control group and 4% in survivors, P = 0.003) were higher in the control group than in the survivors [Table 1]. However, alcohol use and education status were similar between the survivors and the control group [Table 1]; the smokers’ rate was 2% in survivors, whereas none of the siblings had a smoking habit (P = 0.26).


 > Discussion Top


The heterogeneity in NHL histology and complementary treatment approaches has caused challenges in studying the late effects.[9] A risk-based clinical assessment provides detailed health characterization of survivors of pediatric NHL. Implementing risk-adapted therapy in newly diagnosed NHL patients has to increase the OS rates to >80%–90% during the past 25–30 years.[10] We found that the cumulative OS exceeds 80% (82.9% ±5.2, and disease-free survival was 84.1% ±5.2%) after the 10th year since diagnosis. These treatment results are excellent with acute and long-term toxicities.

In the St Jude Life Cohort (200 prospectively NHLS), the most prevalent conditions were overweight/obesity (65%), elevated fasting glucose (37%), high total cholesterol (35%), hypertension (25%), and prehypertension (37%). Among 164 individuals exposed to cardiotoxic therapies (i.e. anthracyclines and or cardiac radiation), 12% developed cardiomyopathy.[11] Our study results indicate a high prevalence of chronic health conditions. These are renal failure (8%), cardiotoxicity (6%), obesity (12%), hypothyroidism (2%), retarded growth (4%), neurologic disease (6%), and lung disease (2%). All of our survivors with cardiotoxicity received anthracycline with a total dose of <300 mg/m2 (one with 300 mg/m2, one with 200 mg/m2, one with 100 mg/m2).

Persentiles for total chemotherapy doses are defined.[7] However; low doses of anthracycline (100 mg/m2, 200 mg/m2) can cause cardiotoxicity. Among these late effects, only renal failure frequency was significantly higher in the survivor group than the siblings (8% vs. 0% respectively) (P = 0.02). Among the four nephrotoxicity cases, three of them had hypertension, and one had Grade 4 renal failure. Al-Shbool et al. reported increased numbers of lymphoma survivors who developed chronic kidney disease over the study period reaching 31% at 10 years. Thus, renal injury in lymphoma survivors is probably multifactorial.[12]

Steffens et al. described endocrine and metabolic conditions in childhood acute lymphoblastic leukemia and NHLS. Hypothyroidism (56%) was found in the chemotherapy + bone morrow transplantation + total body irradiation group. Severe growth hormone deficiency (22%–50%) was detected in chemotherapy + bone morrow transplantation + total body irradiation group plus chemotherapy + cranial irradiation group.[13] In our study, NHLS had obesity (12%), hypothyroidism (2%), and retarded growth (4%), but we did not find that the differences of these frequencies between NHLS and siblings were statistically similar.

Tward et al. reported that out of 77823 NHLS followed up to 30 years since diagnosis, second cancers developed in 5638. In addition, the risk for head-and-neck cancers, melanoma, lung cancer, colon cancer, bladder cancer, renal cancer, Hodgkin disease, leukemia, and Kaposi sarcoma is increased.[14] This study reports one secondary cancer (acute myeloid leukemia) among 50 NHLS in a follow-up period of 16 years since diagnosis.

In another study, survivors with leukemia, CNS tumors, NHL, and neuroblastoma were significantly less likely to finish high school than siblings; however, when survivors received special education services, risk estimates approximated those of the sibling education population.[15] However, we found that NHLS and their siblings had similar education profiles. Thus, education similarity can be due to the particular education program of our government for cancer patients.

Twenty years after treatment of childhood lymphoma, female survivors’ pregnancy initiation attempts are primarily successful, while males seem at higher risk of infertility. Hypogonadism is a problem in 10% of the male Non-Hodgkin Lymphoma Survivors (NHLS).[16] We achieved sperm preservation in three survivors. In our questionnaire, we learned only three survivors got married (6%), two of them had children (4%), 23 siblings (38%) got married (P < 0.01), and 15 of them (25%) had children (P = 0.03). These data showed the impairment of social conditions of NHLS.

We report that health-care service utilization is significantly common in NHLS (80.5%) versus siblings (0%). In addition, most of the survivors (n = 26) received health-care service frequently, <3 months.

Specific to NHLs, those in the childhood cancer survivor study (n = 867) were more likely than siblings to report functional impairment and activity limitations.[17] We report in this study, 5 (10%) NHLS had physical limitations. However, it was not significantly inferior compared with the siblings (0%) (P = 0.07).

The chimeric anti-CD20 monoclonal antibody rituximab improved response rates, duration of response, OS, and has become the new standard of care for many children with primary or relapsed B-cell disease. The postmarketing several adverse reactions of this drug are cardiac failures, nephrotoxicity, and bronchiolitis obliterans.[18] In our study, twenty NHLS (Burkitt lymphoma, primary mediastinal large cell lymphoma) received rituximab. In these patients with Burkitt lymphoma (n = 17), long-term hypothyroidism (n = 1), obesity (n = 2), cardiotoxicity (n = 2), hyperlipidemia (n = 3), nephrotoxicity (n = 1), and pulmonary toxicity (n = 1) were observed. Sixty-six percent (n = 2) of the patients with cardiotoxicity were in the rituximab group.

The BV is used to treat ALCL, and Hodgkin lymphoma links anti-CD30 to an anti-tubulin agent. The most significant adverse event is peripheral neuropathy.[19] However, in our small cohort, out of two survivors, none had peripheral neuropathy. The one with bronchiolitis obliterans, hypertension, hyperlipidemia, and heart failure received rituximab and BV.

In response to recognizing associations between cancer treatment-related exposures and late occurring adverse health effects experienced by childhood cancer survivors, many leading organizations have developed surveillance guidelines intended to inform risk-based care for this heterogeneous group. We are currently preparing a survivorship guideline that complies with Turkey's circumstances. The purpose of preparing such a guideline is to allow early detection of asymptomatic patients and promote follow-up of patients according to multidisciplinary approaches. These efforts will increase the quality of life and follow-up in NHLS.


 > Conclusion Top


Nephrotoxicty and hospital administiration frequencies are significantly higher in NHLS compared with the healthy siblings. Cardiotoxicity can be even found with a cumulative antrasiklin dose below 300 mg/m2. NHLS are also socially impaired. One secondary cancer developed as an acute myeloid leukemia. Long-term consequences of cancer and it's treatment must be carefully checked.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Ehrhardt M, Hochberg J, Bjornard KL, Brinkman TM. Long-term survivors of childhood, adolescent, and young adult non-Hodgkin lymphoma. Br J Haematol 2019;185:1099-110.  Back to cited text no. 1
    
2.
Noone AM, Cronin KA, Altekruse SF, Howlader N, Lewis DR, Petkov VI et al. Cancer incidence and survival trends by subtype using data from the Surveillance Epidemiology and End Results Program, 1992–2013. Cancer Epidemiol Biomarkers Prev 2017;26:632-41.  Back to cited text no. 2
    
3.
Kero AE, Jarvela LS, Mikko A, Malila N, Madanat-Harjuoja LM, Matomaki J, et al. Late mortality among 5-year survivors of early-onset cancer: A population-based register study. Int J Cancer 2015;136:1655-64.  Back to cited text no. 3
    
4.
Gibson TM, Mostoufi-Moab S, Stratton KL, Leisenring WM, Barnea D, Chow EJ, et al. Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: A report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2018;19:1590-601.  Back to cited text no. 4
    
5.
Bhakta N, Liu Q, Ness KK, Baassiri M, Eissa H, Yeo F, et al. The cumulative burden of surviving childhood cancer: An initial report from the St Jude Lifetime Cohort Study (SJLIFE). Lancet 2017;390:2569-82.  Back to cited text no. 5
    
6.
Minard-Colin V, Brugieres L, Reiter A, Cairo MS, Gross TG, Woessmann W, et al. Non-Hodgkin lymphoma in children and adolescents: Progress through effective collaboration, current knowledge, and challenges ahead. J Clin Oncol 2015;33:2963-74.  Back to cited text no. 6
    
7.
Robison LL, Mertens AC, Boice JD, Breslow NE, Donaldson SS, Green DM, et al. Study design and cohort characteristics of the Childhood Cancer Survivor Study: A multi-institutional collaborative project. Med Pediatr Oncol 2002;38:229-39.  Back to cited text no. 7
    
8.
Patte C, Auperin A, Michon J, Behrendt H, Leverger G, Frappaz D, et al. The Société Française d'Oncologie Pédiatrique LMB89 protocol: Highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood 2001;97:3370-9.  Back to cited text no. 8
    
9.
Cairo MS, Pinkerton R. Childhood, adolescent and young adult non-Hodgkin lymphoma: State of the science. Br J Haematol 2016;173:507-30.  Back to cited text no. 9
    
10.
Tsurusawa M, Mori T, Kikuchi A, Mitsui T, Sunami S, Kobayashi R, et al. Improved treatment results of children with B-cell non-Hodgkin lymphoma: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group B-NHL03 study. Pediatr Blood Cancer 2014;61:1215-21.  Back to cited text no. 10
    
11.
Ehrhardt MJ, Sandlund JT, Zhang N, Liu W, Ness KK, Bhakta N, et al. Late outcomes of adult survivors of childhood non-Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study. Pediatr Blood Cancer 2017;64:e26338.  Back to cited text no. 11
    
12.
Al-Shbool G, Desale S, Veis J, Malkovska V, Desai S. Prevalence of chronic kidney disease (CKD) in lymphoma survivors. Blood 2019;134:2912.  Back to cited text no. 12
    
13.
Steffens M, Beauloye V, Brichard B, Robert A, Alexopoulou O, Vermylen Ch, et al. Endocrine and metabolic disorders in young adult survivors of childhood acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL). Clin Endocrinol (Oxf) 2008;69:819-27.  Back to cited text no. 13
    
14.
Tward JD, Wendland MM, Shrieve DC, Szabo A, Gaffney DK. The risk of secondary malignancies over 30 years after the treatment of non-Hodgkin lymphoma. Cancer 2006;107:108-15.  Back to cited text no. 14
    
15.
Mitby PA, Robison LL, Whitton JA, Zevon MA, Gibbs IC, Tersak JM, et al. Utilization of special education services and educational attainment among long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 2003;97:1115-26.  Back to cited text no. 15
    
16.
Hamre H, Kiserud CE, Ruud E, Thorsby PM, Fosså SD. Gonadal function and parenthood 20 years after treatment for childhood lymphoma: A cross-sectional study. Pediatr Blood Cancer 2012;59:271-7.  Back to cited text no. 16
    
17.
Hudson MM, Mertens AC, Yasui Y, Hobbie W, Chen H, Gurney JG, et al. Health status of adult long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. J Am Med Assoc 2003;290:1583-92.  Back to cited text no. 17
    
18.
de Zwart V, Gouw SC, Meyer-Wentrup FA. Antibody therapies for lymphoma in children. Cochrane Database Syst Rev 2016;1:CD011181.  Back to cited text no. 18
    
19.
Vaklavas C, Forero-Torres A. Safety and efficacy of brentuximab vedotin in patients with Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Ther Adv Hematol 2012;3:209-25.  Back to cited text no. 19
    



 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and Me...>Results>Discussion>Conclusion>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed570    
    Printed20    
    Emailed0    
    PDF Downloaded38    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]