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

 
ORIGINAL ARTICLE
Ahead of print publication  

Effects of Goshajinkigan (TJ-107) for oxaliplatin-induced peripheral neurotoxicity using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire in a Phase II, multicenter, randomized, double-blind, placebo-controlled trial


1 Department of Surgery, Yokohama City University, Yokohama, Japan
2 Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3 Advanced Surgery Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
4 Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
5 Cancer Center, Aichi Medical University, Nagakute, Japan
6 Director of a Hospital, Tokai Central Hospital, Kakamigahara, Japan

Date of Submission17-Dec-2019
Date of Decision12-Apr-2020
Date of Acceptance06-May-2020
Date of Web Publication28-Oct-2020

Correspondence Address:
Toru Aoyama,
Department of Surgery, Yokohama City University, 3.9 Fukuura, Kanazawa.Ku, Yokohama 236.0004
Japan
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1123_19

 > Abstract 


Background: The aim of the present study was to evaluate the efficacy of TJ-107 for oxaliplatin-induced peripheral neurotoxicity in prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trials using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire (FACT-GOG-NTX-12).
Patients and Methods: The patients who were registered to the Goshajinkigan oxaliplatin neurotoxicity evaluation study (UMIN000002211) were analyzed. A NTX-12 from the validated FACT/GOG-NTX-12 was assessed before treatment and at the end of every 2 cycles.
Results: The comparisons of the median scores for TJ-107 and the placebo at 8 and 26 weeks were as follows: numbness or tingling in the hands (P = 0.5820), numbness or tingling in the feet (P = 0.3236), feeling of discomfort in the hands (P = 0.8219), feeling of discomfort in the feet (P = 0.5361), joint pain or muscle cramps (P = 0.1974), feeling weak all over (P = 0.2771), trouble hearing (P = 0.2832), ringing or buzzing in ears (P = 0.1031), trouble buttoning buttons (P = 0.1653), trouble feeling the shape of small objects when held in hand (P = 0.2919), trouble walking (P = 0.5406), and pain in the hands or feet when exposed to cold temperatures (P = 0.1872).
Conclusion: There might be no clinically significant difference between the use of TJ-107 and the severity and quality of life for patients treated with oxaliplatin.

Keywords: 12-item neurotoxicity questionnaire, colorectal cancer, oxaliplatin, peripheral neurotoxicity



How to cite this URL:
Aoyama T, Morita S, Kono T, Hata T, Mishima H, Sakamoto J. Effects of Goshajinkigan (TJ-107) for oxaliplatin-induced peripheral neurotoxicity using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire in a Phase II, multicenter, randomized, double-blind, placebo-controlled trial. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299455




 > Introduction Top


Colorectal cancer (CRC) is the third-most commonly diagnosed cancer in males and the second in females, with an estimated 1.4 million new cases and 693,900 deaths occurring in 2012.[1] Chemotherapy is an important treatment modality for operable and inoperable CRC.[2],[3] Among the numerous chemotherapy agents, oxaliplatin is considered a key drug for both advanced and adjuvant settings in CRC.[4],[5],[6],[7] However, while previous studies have shown that chemotherapy, including oxaliplatin, improves and prolongs the survival, it often causes severe toxicity and seriously compromises patients' quality of life (QOL).[8],[9]

Neurotoxicity is a common and severe toxicity associated with oxaliplatin in CRC treatment.[10],[11] In the pivotal Phase III trials of chemotherapy for CRC, the incidence of all grades of oxaliplatin-induced peripheral neurotoxicity (OPN) was almost 90%, and severe OPN was observed in approximately 10%–20% of patients.[12],[13] OPN results in severe discomfort and often requires a break from or a dose reduction in chemotherapy.[14] The treatment guidelines developed by the multinational association of supportive care in cancer have highlighted the need for higher levels of evidence for OPN.

Goshajinkigan (TJ-107) is a traditional Japanese medicine (Kampo medicine) containing 10 herbal crude drugs: Rehmanniae radix, Achyranthis radix, Corni Fructus, Moutan Cortex, Alismatis rhizome, Dioscoreae rhizome, Plantaginis Semen, Poria, processed Aconiti tuber, and Cinnamomi Cortex. Recently, we conducted a Phase 2, multicenter, randomized, double-blind, placebo-controlled trial to investigate the neuroprotective effect of TJ-107 for OPN in CRC patients undergoing oxaliplatin-based chemotherapy.[15] In this trial, TJ-107 appeared to have a promising effect in delaying the onset of grade ≥2 OPN without impairing the chemotherapy efficacy and with an acceptable safety margin. In addition, although the differences were statistically unremarkable, patients receiving TJ-107 tended to show milder symptoms of neurotoxicity than those who received the placebo.

The present study evaluated the efficacy of TJ-107 for OPN in a prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trial using the functional assessment of cancer therapy/gynecologic oncology Group 12-item neurotoxicity questionnaire (FACT/GOG-NTX-12).


 > Patients and Methods Top


Study design

The Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE) study was a prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trial (UMIN000002211). The study was initially designed to enroll approximately 90 patients and to include a 26-week double-blind treatment period. The eligible patients were randomly assigned in a 1:1 ratio to receive either TJ-107 or the placebo. Randomization was carried out centrally at the data center using dynamic randomization with the main prognostic factors. Both a dried powder (2.5 g) of TJ-107 and placebo were administered orally three times a day before each meal (7.5 g/day). The placebo formulation matched the texture, flavor, and other characteristics of the active drug. TJ-107 or placebo was given orally for 26 weeks starting on the day of oxaliplatin infusion.

Study population

The detailed inclusion and exclusion criteria have been described in previous reports. In brief, patients who were ≥20 years of age and undergoing chemotherapy with infusional 5-fluorouracil, leucovorin (I-LV), and oxaliplatin (either FOlFOX4 or a modified FOlFOX6 regimen) for CRC were considered eligible for this study. All participants were required to have a “good” performance status (i.e., scores of 0 or 1 on the Eastern Cooperative Oncology Group Performance Status scale). Patients with any of the following characteristics were not eligible for the study: use of Kampo medicine before registration; a history of severe hypersensitivity (allergy) to any medicine containing antiphlogistic, analgesics, opioids, or steroids; or serious constipation. Pregnant or lactating women were also excluded from the study. Any other medical conditions that made a patient unsuitable for inclusion in the study according to the opinion of the investigator were also regarded as exclusion criteria (e.g., mental disorders that might affect the ability or willingness to provide informed consent or abide by the study protocol; systemic treatment with a corticosteroid; systemic treatment with flucytosine, phenytoin, or warfarin potassium; pneumonitis, lung fibrosis, or emphysema in need for oxygen therapy; active inflammation due to bacteria or fungi; and unstable angina or cardiac infarction within the previous 6 months).

Efficacy and safety assessments

The primary endpoint of the GONE study was the incidence of OPN (grade ≥ 2) after 8 cycles of chemotherapy in the TJ-107 and placebo arms. The secondary endpoints were the incidence and grading of OPN after each cycle and the FACT/GOG-NTX-12 score in the TJ-14 and placebo arms.

Sensory neuropathy assessments

The NTX-12 from the validated FACT/GOG was assessed before treatment and at the end of every two cycles. The NTX-12 questionnaire comprised statements intended to measure the severity and impact of peripheral sensory neuropathy on patients' lives, including numbness or tingling in the hands or feet, discomfort in the hands or feet, joint pain, general weakness, trouble hearing, ringing or buzzing in the ears, trouble with buttons, trouble feeling the shape of objects while held, trouble walking, and pain in the hands or feet when exposed to cold temperatures.[16],[17],[18] Patients were instructed to choose the number corresponding to how true each statement was for them in the past week using a Likert-type scale, with 0 indicating not at all; 1, a little bit; 2, somewhat; 3, quite a bit; and 4, very much. The NTX-12 score at each evaluation referred to the sum of the ratings from the 12 items, which could range from 0 to 48, with lower scores indicating less neuropathy.

Statistical analyses

All clinical data were extracted and held centrally at the Epidemiological and Clinical Research Information Network data center. The difference between the groups in the incidence of grade ≥2 OPN and the 90% confidence intervals (CI) were calculated. Comparisons were made using the Chi-squared test. The baseline characteristics were compared using the Chi-squared test for categorical variables and the t-test for continuous variables. A hazard ratio larger than 1 indicated that TJ-107 accelerated the prevention of OPN. The frequencies of adverse events were compared using Fisher's exact test. All P values were two-sided. All statistical analyses were performed using the SAS software program (ver. 9.4 for Windows; SAS Institute, Cary, NC, USA).

Ethical considerations

The study data and informed consent were obtained in accordance with the Declaration of Helsinki and were approved by the Ethics Review Board of each participating institution. All patients were given a written explanation of each study protocol and provided their written informed consent before participating in the trial.


 > Results Top


Patient's characteristics

[Figure 1] shows the consort diagram of the present study. The baseline demographics and disease characteristics for the per protocol set population are shown in [Table 1]. A total of 54.0% were men and 46.0% were women. All patients had histologically confirmed adenocarcinoma of the colon (65.2%) or rectum (34.8%). The majority of patients received treatment in the metastatic setting (79.8%), while treatment was in the adjuvant setting in 20.2%, and the treatment groups were balanced for chemotherapy regimens. No patients received radiation therapy or molecular-targeted drugs before enrollment. No patients were enrolled in the study if there was any clinical evidence of another active peripheral neurotoxicity disease at baseline.
Figure 1: Consort diagram of the present study

Click here to view
Table 1: Patient characteristics of the TJ-107 and placebo groups

Click here to view


Twelve-item neurotoxicity questionnaire

There were no significant differences in the overall score between the TJ-107 and placebo groups [Figure 2]. [Table 2] shows each score. The comparisons of the median scores for TJ-107 and the placebo at 8 and 26 weeks are as follows: numbness or tingling in the hands (NTX1), 2.4 and 2.4 in TJ-107 and 2.5 and 2.2 in placebo (P = 0.5820); numbness or tingling in the feet (NTX2), 3.0 and 2.6 in TJ-107 and 3.1 and 2.1 in placebo (P = 0.3236); feeling of discomfort in the hands (NTX3), 3.1 and 2.7 in TJ-107 and 3.1 and 2.4 in placebo (P = 0.8219); feeling of discomfort in the feet (NTX4), 3.5 and 2.8 in TJ-107 and 3.4 and 2.4 in placebo (P = 0.5361); joint pain or muscle cramps (NTX5), 3.7 and 3.7 in TJ-107 and 3.5 and 3.6 in placebo (P = 0.1974); feeling weak all over (HI12), 3.4 and 3.4 in TJ-107 and 3.1 and 3.2 in placebo (P = 0.2771); trouble hearing (NTX6), 3.8 and 3.8 in TJ-107 and 3.6 and 3.6 in placebo (P = 0.2832); ringing or buzzing in ears, 3.9 and 3.8 in TJ-107 and 3.6 and 3.7 in placebo (P = 0.1031); trouble buttoning buttons (NTX8), 3.6 and 3.4 in TJ-107 and 3.7 and 3.3 in placebo (P = 0.1653); trouble feeling the shape of small objects when held in hand (NTX9), 3.9 and 3.5 in TJ-107 and 3.8 and 3.4 in placebo (P = 0.2919); trouble walking (An6), 3.9 and 3.8 in TJ-107 and 3.7 and 3.4 in placebo (P = 0.5406); and pain in hands or feet when exposed to cold temperatures (NTX10), 2.3 and 2.7 in TJ-107 and 2.4 and 2.4 in placebo (P = 0.1872).
Figure 2: There were no significant differences in the overall score between TJ-107 and placebo

Click here to view
Table 2: Comparison the each scores of neurotoxicity 12 scores between the TJ-107 and placebo groups

Click here to view


In addition, the sensory domain (NTX1-4, and NTX10) was 14.1 and 13.2 in TJ-107 and 14.6 and 11.6 in placebo, respectively (P = 0.4342). The functional domain (NTX8 and NTX9) was 7.4 and 6.9 in TJ-107 and 7.5 and 6.7 in placebo, respectively (P = 0.3674). The auto domain (NTX6 and NTX7) was 7.7 and 7.6 in TJ-107 and 7.2 and 7.3 in placebo, respectively (P = 0.3885). The motor domain (NTX5, HI12, and An6) was 10.9 and 10.9 in TJ-107 and 10.3 and 10.3 in placebo, respectively (P = 0.2159).

Safety profile

[Table 3] shows adverse events between the TJ-107 and placebo groups. There were no significantly differences between two groups.
Table 3: Adverse events between the TJ-107 and placebo groups

Click here to view



 > Discussion Top


The aim of the present study was to evaluate the efficacy of TJ-107 for OPN in a prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trial using the NTX-12. The major findings were that the median NTX-12 scores were similar between the TJ-107 and placebo groups at both 8 and 26 weeks. Therefore, although TJ-107 might appear to have a promising effect of delaying the onset of grade ≥2 OPN, there might be no clinically significant difference between the use of TJ-107 and the severity and QOL for patients treated with oxaliplatin.

In previous reports, the incidence of grade ≥2 OPN up to the eighth cycle was 39% and 51% in the TJ-107 and placebo groups, respectively (relative risk, 0.76; 95% CI, 0.47–1.21). The incidence of Grade 3 OPN was 7% (TJ107) vs. 13% (placebo) (0.51, 0.14–1.92).[15] There were marginal differences in the incidence of OPN between TJ-107 and placebo. TJ-107 is a complex drug containing 10 medicinal herbs with a wide spectrum of pharmacologic actions.[19] Experimental studies have shown that TJ-107 relieves neurologic symptoms of diabetic peripheral neuropathy, such as cold hyperalgesia and mechanical allodynia, primarily by the action of its analgesic component, detoxified aconiti tuber.[20],[21] The purported mechanisms by which this component works in concert with the other components of TJ-107 to exert a neuroprotective effect include (1) evoking the release of dynorphin and activating endogenous κ-opioid receptors to improve numbness or paresthesia,[22] (2) decreasing the release of transmitter proteins and sensory receptors associated with C-fiber nociceptor activation,[23] and (3) promoting nitric oxide production to improve blood supply to the nerves.[24] However, there were no marked differences in the severity of or changes in the QOL due to OPN for patients treated with oxaliplatin according to the NTX-12 evaluation. These discrepancies in the present study may be due to differences in the evaluator. In the present trial, the incidence and grade of OPN was evaluated by the physician. However, the NTX-12 scores were evaluated by the patient. The application of patient-based versus physician-based evaluations might misfit in the present trial. The scores for numbness, cold sensation, and paresthesia/dysesthesia which was diagnosed as OPN were similar between the TJ-107 and placebo groups.

Marginal significant differences were noted for “ringing or buzzing in the ears.” Laryngopharynx sensory abnormalities are included among OPN symptoms, and patients typically recognize these symptoms as “ringing or buzzing in the ears.” Therefore, TJ-107 might be effective for relieving laryngopharynx sensory abnormalities. However, there have been no similar reports published, and the mechanism by which this might be achieved is unclear.

The present study had several strengths, such as its huge, well-defined cohort of individual patient data. However, several limitations also warrant mention. First, the sample size was relatively small. Second, there was a lack of the data on the doses of TJ-107 and oxaliplatin applied.


 > Conclusion Top


There might be no clinically significant difference between the use of TJ-107 and the severity and QOL for patients treated with oxaliplatin by using the NTX-12.

Acknowledgments

GONE study is supported, in part, by the nonprofit organization Epidemiological and Clinical Research Information Network. This report is funded by Asahi Kasei Pharma Corporation.

Financial support and sponsorship

GONE study is supported, in part, by the nonprofit organization Epidemiological and Clinical Research Information Network. This report is funded by Asahi Kasei Pharma Corporation.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.  Back to cited text no. 1
    
2.
Labianca R, Nordlinger B, Beretta GD, Brouquet A, Cervantes A; ESMO Guidelines Working Group. Primary colon cancer: ESMO Clinical Practice Guidelines for diagnosis, adjuvant treatment and follow-up. Ann Oncol 2010;21 Suppl 5:v70-7.  Back to cited text no. 2
    
3.
NCCN. NCCN Clinical Practice Guidelines in Oncology. Available from: https://www.nccn.org/professionals/physician_gls/default.aspx. [Last accessed on 2019 Sep 10].  Back to cited text no. 3
    
4.
André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51..  Back to cited text no. 4
    
5.
Kim MB, Hong TS, Wo JY. Treatment of stage II-III rectal cancer patients. Curr Oncol Rep 2014;16:362.  Back to cited text no. 5
    
6.
Oki E, Ando K, Kasagi Y, Zaitsu Y, Sugiyama M, Nakashima Y, et al. Recent advances in multidisciplinary approach for rectal cancer. Int J Clin Oncol 2015;20:641-9.  Back to cited text no. 6
    
7.
National Comprehensive Care Network. Clinical Practice Guidelines in Oncology (NCCNGuidelines®). Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines. Asp. [Last accessed on 2019 Sep 10].  Back to cited text no. 7
    
8.
André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-51.  Back to cited text no. 8
    
9.
de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-47.  Back to cited text no. 9
    
10.
Griffith KA, Zhu S, Johantgen M, Kessler MD, Renn C, Beutler AS, et al. Oxaliplatin-induced peripheral neuropathy and identification of unique severity groups in colorectal cancer. J Pain Symptom Manage 2017;54:701-60.  Back to cited text no. 10
    
11.
Han CH, Kilfoyle DH, Hill AG, Jameson MB, McKeage MJ. Preventing oxaliplatin-induced neurotoxicity: Rationale and design of phase Ib randomized, double-blind, placebo-controlled, cross-over trials for early clinical evaluation of investigational therapeutics. Expert Opin Drug Metab Toxicol 2016;12:1479-90.  Back to cited text no. 11
    
12.
Lucchetta M, Lonardi S, Bergamo F, Alberti P, Velasco R, Argyriou AA, et al. Incidence of atypical acute nerve hyperexcitability symptoms in oxaliplatin-treated patients with colorectal cancer. Cancer Chemother Pharmacol 2012;70:899-902.  Back to cited text no. 12
    
13.
Cersosimo RJ. Oxaliplatin-associated neuropathy: A review. Ann Pharmacother 2005;39:128-35.  Back to cited text no. 13
    
14.
Land SR, Kopec JA, Cecchini RS, Ganz PA, Wieand HS, Colangelo LH, et al. Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07. J Clin Oncol 2007;25:2205-11.  Back to cited text no. 14
    
15.
Kono T, Hata T, Morita S, Munemoto Y, Matsui T, Kojima H, et al. Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): A phase 2, multicenter, randomized, double-blind, placebo-controlled trial of goshajinkigan to prevent oxaliplatin-induced neuropathy. Cancer Chemother Pharmacol 2013;72:1283-90.  Back to cited text no. 15
    
16.
Kuroi K, Shimozuma K. Neurotoxicity of taxanes: Symptoms and quality of life assessment. Breast Cancer 2004;11:92-9.  Back to cited text no. 16
    
17.
Cella D, Peterman A, Hudgens S, Webster K, Socinski MA. Measuring the side effects of taxane therapy in oncology: The functional assesment of cancer therapy-taxane (FACT-taxane). Cancer 2003;98:822-31. Available from: http://www.supportiveoncology.net/jso/journal/abstracts/0408396.html. [Last accessed on 2019 Sep 10].  Back to cited text no. 17
    
18.
Kidwell KM, Yothers G, Ganz PA, Land SR, Ko CY, Cecchini RS, et al. Long-term neurotoxicity effects of oxaliplatin added to fluorouracil and leucovorin as adjuvant therapy for colon cancer: results from National Surgical Adjuvant Breast and Bowel Project trials C-07 and LTS-01. Cancer. 2012;118:5614-22.  Back to cited text no. 18
    
19.
Kono T, Mamiya N, Chisato N, Ebisawa Y, Yamazaki H, Watari J, et al. Efficacy of goshajinkigan for peripheral neurotoxicity of oxaliplatin in patients with advanced or recurrent colorectal cancer. Evid Based Complement Alternat Med 2011;2011:418481.  Back to cited text no. 19
    
20.
Tawata M, Kurihara A, Nitta K, Iwase E, Gan N, Onaya T. The effects of goshajinkigan, a herbal medicine, on subjective symptoms and vibratory threshold in patients with diabetic neuropathy. Diabetes Res Clin Pract 1994;26:121-8.  Back to cited text no. 20
    
21.
Uno T, Ohsawa I, Tokudome M, Sato Y. Effects of Goshajinkigan on insulin resistance in patients with type 2 diabetes. Diabetes Res Clin Pract 2005;69:129-35.  Back to cited text no. 21
    
22.
Gotoh A, Goto K, Sengoku A, Shirakawa T, Akao Y, Fujisawa M, et al. Inhibition mechanism of Gosha-jinki-gan on the micturition reflex in rats. J Pharmacol Sci 2004;96:115-23.  Back to cited text no. 22
    
23.
Joseph EK, Chen X, Bogen O, Levine JD. Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. J Pain 2008;9:463-72.  Back to cited text no. 23
    
24.
Hu X, Sato J, Oshida Y, Xu M, Bajotto G, Sato Y. Effect of Gosha-Jinki-Gan (Chinese herbal medicine: Niu-Che-Sen-Qi-Wan) on insulin resistance in streptozotocin-induced diabetic rats. Diabetes Res Clin Pract 2003;59:103-11.  Back to cited text no. 24
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

 
Top
 
 
  Search
 
     Search Pubmed for
 
    -  Aoyama T
    -  Morita S
    -  Kono T
    -  Hata T
    -  Mishima H
    -  Sakamoto J
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  >Abstract>Introduction>Patients and Methods>Results>Discussion>Conclusion>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed107    
    PDF Downloaded2    

Recommend this journal