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A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children
YJPSU-59317; No of Pages 4 Journal of Pediatric Surgery xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children☆,☆☆,★ Yudai Goto a,b, Michitoshi Yamashita a, Keiichi Kakuta a, Kakeru Mahchino a, Seiya Ogata a, Kotaro Mimori a, Hirofumi Shimizu a, Hideaki Tanaka a,⁎ a b
Department of Pediatric Surgery, Fukushima Medical University Hospital, Fukushima, Japan Department of Pediatric Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
a r t i c l e
i n f o
Article history: Received 11 August 2019 Accepted 24 August 2019 Available online xxxx Key words: Lymphatic malformation Children Eppikajutsuto Herbal medicine
a b s t r a c t Background: Eppikajutsuto (TJ-28) is an herbal medicine recently reported to be effective in treating lymphatic malformations (LMs). We report our experience concerning the clinical efficacy of TJ-28 for LMs. Methods: Medical records of 10 LM cases treated with TJ-28 between 2016 and 2018 were reviewed. TJ-28 was given at 0.3 g/kg/day and then increased to 0.5 if no improvement was noted after the first three months of treatment. Their clinical data were collected, and LM volume indices (depth×width×height) were measured with the first (LMVI-F) and latest (LMVI-L) imaging studies. The response rates were calculated as 1-LMVI-L / LMVI-F (%). Results: The median age at the diagnosis and treatment period was 1.5 years and 17.5 months, respectively. LMs were located in the neck (six), mesenterium or retroperitoneum (three), and inguinal region (one). The median response rate was 83%, including 100% in three cases and the apparent improvement of obstructive airway symptoms in one case. One case underwent surgery for insufficient improvement, and another that showed no effect is being considered for surgery. Most of the satisfactory outcomes were demonstrated in the first six months of treatment. Conclusion: TJ-28 seems to be effective in treating LMs in children, especially early in treatment. Level of evidence: IV © 2019 Elsevier Inc. All rights reserved.
Lymphatic malformations (LMs) are benign, slow-flow malformations composed of variously dilated lymphatic channels or cysts, lined by endothelial cells with a lymphatic phenotype [1]. LMs usually affect the head, neck, and axilla. Less common sites include mediastinum, groin, retroperitoneum, and other sites. They often cause cosmetic and functional complications. LMs may be treated with sclerotherapy and/or surgical resection. Although sclerotherapy with the percutaneous injection of sclerosants (e.g., OK-432 or bleomycin) [2] has been reported to be effective, especially for the treatment of macrocystic LMs, microcystic LMs are less responsive to sclerotherapy. Surgical resection potentially leads to a definitive cure of LMs, but is often technically challenging—especially for LMs located close to vital structures.
Medical therapies for LMs with the systemic administration of various agents, including sirolimus, sildenafil, and interferon-alpha, have been recently reported; however, the efficacy remains to be clarified [3]. Eppikajutsuto (TJ-28) (Tsumura & Co., Tokyo, Japan) is a Japanese herbal medicine that is reported to reduce redundant body fluids and to have anti-inflammatory effects [4]. Although some case reports indicate that TJ-28 may improve LMs [3–6], the therapeutic mechanism and appropriate treatment strategy have not been clarified. We herein report our single institution experience of the use of TJ-28 in treating LMs in children.
Abbreviations: TJ-28, Eppikajutsuto; LM, lymphatic malformation; LMVI-F, the first lymphatic malformation volume index; LMVI-L, the latest lymphatic malformation volume index; US, ultrasonography; CT, computed tomography; MRI, magnetic resonance imaging; NPPV, noninvasive positive pressure ventilation. ☆ Declarations of Interest: None. ☆☆ Acknowledgment: none ★ Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author at: Department of Pediatric Surgery, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, Fukushima, Japan 960-1295. Tel.: +81 24 547 1253; fax: +81 24 548 3249. E-mail address: [email protected] (H. Tanaka).
Twelve patients with LMs were treated using TJ-28 in our department between January 2016 and December 2018. In 2 of the 12 cases, the follow-up period was insufficient; thus, the patients were excluded in this study. The medical records of the remaining 10 patients were retrospectively reviewed. Our treatment protocol using TJ-28 was as follows: after the diagnosis of LM was confirmed by a physical examination and imaging studies, TJ-28 was orally administered at a dose of 0.3 g/kg/day in two divided doses. If the treatment efficacy was not considered satisfactory based on the physical examinations and imaging studies such as ultrasonography (US) after the initial
1. Patients and methods
https://doi.org/10.1016/j.jpedsurg.2019.08.025 0022-3468/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Y. Goto, M. Yamashita, K. Kakuta, et al., A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.025
2
Y. Goto et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
Table 1 The clinical features of the 10 cases included in this study. Case
Age
Gender
Location
Symptom
Bleeding
Type
Size (mm)
Response rate (%)
1 2 3 4 5 6 7 8 9 10
0m 7y 1m 1y 1m 2y 7y 12 y 4y 1m
f m f f m f f m f m
neck neck face neck neck neck mesenterium retroperitoneum retroperitoneum inguina
swelling swelling swelling swelling stridor swelling abdominal pain abdominal pain abdominal pain swelling
− − − − − − + + + −
macro macro micro micro mixed mixed macro macro mixed mixed
33*29*52 56*32*32 48*35*22 58*35*49 37*26*29 98*95*109 69*46*49 52*37*69 80*50*62 52*19*66
100 99 48 19 46 80a 100 100 86 −100
a
Combined with surgery.
three months of the treatment, the dose was increased to 0.5 g/kg/day. The TJ-28 treatment was discontinued, continued, or the next treatment (e.g., sclerotherapy or surgery) was considered and/or performed, depending on the outcome in the next three months. The outcome was determined based on US, computed tomography (CT), or magnetic resonance imaging (MRI), and the LM volume index (determined as follows: depth × width × height in mm) [3]. The response rates were calculated, using the first (LMVI-F) and latest (LMVI-L) LM volume indices, as follows: 1-LMVI-L/LMVI-F (%). The morphologic types of LMs were classified, based on imaging studies, as microcystic, macrocystic, or mixed, according to the International Society for the Study of Vascular Anomalies [1]. The age at the diagnosis, gender, symptoms, location, type, size, presence of bleeding inside the lesion, response rate and treatment period were collected and retrospectively analyzed. 2. Results The clinical features of the 10 patients are described in Table 1. The median age at the diagnosis was 1.5 years (0 month to 12 years). The locations and types were as follows: neck (n = 6 [macrocystic, n = 2; microcystic, n = 2; and mixed, n = 2]); abdomen (mesentery or retroperitoneum, n = 3 [macrocystic, n = 2; mixed, n-1]), and the inguinal region (n = 1 [mixed type]). The maximum diameter of the
lesions ranged from approximately 4 cm to 11 cm. All patients with abdominal lesions presented abdominal pain, and imaging studies revealed bleeding inside the abdominal lesions. One patient with a neck lesion suffered from upper respiratory symptoms such as inspiratory stridor requiring noninvasive positive pressure ventilation (NPPV) (Case 5). The other cases complained of cosmetic problems due to swollen lesions. The median period of treatment with TJ-28 was 17.5 months (3–49 months). The serial changes in the ratio of the LMVI at each evaluation to the LMVI-F are shown in Fig. 1, and demonstrate a rapid decrease in the LMVI in most patients during the first six months of treatment. The median response rate in this study group was 83% (range: −100%–100%), including three cases with a 100% response rate, indicating complete shrinkage. The median response rates according to the type of LMs were as follows: macrocystic type, 100%; microcystic type, 33.5%; and mixed type, 63%. The cosmetic improvement of the lesion in Case 1 is shown in Fig. 2 as an example of the excellent efficacy of TJ-28. The serial changes in the radiologic findings of the lesion in Case 5 are shown in Fig. 3. In this case, the patient's deviated upper respiratory tract returned to a central position and therefore the patient could eventually be weaned off NPPV. Case 6 showed insufficient improvement and underwent debulking surgery. The administration of TJ-28 was continued after the operation and the lesion tended to decrease in size thereafter. Case 10, which involved a patient with a huge inguinal lesion,
Fig. 1. Serial changes in the ratio of the LMVI at each evaluation to LMVI-F (%). LMVI, LM volume index (depth×width×height in mm); LMVI-F, first LMVI (the LMVI calculated at the first imaging study).
Please cite this article as: Y. Goto, M. Yamashita, K. Kakuta, et al., A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.025
Y. Goto et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
3
Fig. 2. (a) A large swollen lesion (circle) on the patient's neck was noted at the time of the diagnosis in Case 1. (b) Complete shrinkage of the lesion after 6 months of treatment with TJ-28.
exhibited no improvement and is currently being considered for surgery. No adverse events related to the administration of TJ-28 were observed during the treatment period. 3. Discussion TJ-28 is a Japanese herbal medicine that is covered under the National Health Insurance Plan of Japan. TJ-28 consists of six crude drug (herbs) components. Among these, Mao, also known as ephedra, may play a significant role in its pharmacological action. The mechanism of TJ-28 toward the shrinkage of LMs may be explained as follows: vascular endothelial growth factor (VEGF) is one of the key regulators of lymphoangiogenesis; LMs highly express VEGF with various types of gene mutation [7]; and Mao suppresses the activity of VEGF by inhibiting the synthesis of prostaglandin E2 and cyclooxygenase [8– 10], which may also induce anti-inflammatory effects toward LMs [4]. Our study showed relatively satisfactory outcomes within as early as 6 months of TJ-28 treatment, with a median response rate of 83%. There were three cases with a response rate of 100% (complete shrinkage), and another case in which the patient's obstructive airway symptoms
showed apparent improvement (Case 5). One case underwent surgical treatment for a neck lesion due to insufficient improvement (Case 6); however, the postoperative administration of TJ-28 seemed to reduce the volume of the LM. Combined treatment of LMs with TJ-28 and surgery has been reported after tube drainage for a mediastinal lesion [6] and before the resection of a retroperitoneal lesion [4]. These combinations of TJ-28 and surgical therapy may therefore be clinically relevant when monotherapy of TJ-28 is ineffective. The inguinal lesion in one of our cases (Case 10) continued to grow in spite of treatment with TJ28; thus, surgery is currently being considered. TJ-28 might not reach inguinal LMs effectively for an unknown reason, and surgery may need to be selected as the initial treatment, as reported in the literature [11]. Hashizume, et al. [3] reported their experience of TJ-28 monotherapy for eight patients with LMs located in the upper half of the body. Their median treatment period of 6 months was shorter than ours (17.5 months), and their dose of TJ-28 was fixed to 0.3 g/kg/day. Although their outcomes are difficult to compare to ours, the median response rate in their study was 46.9%. Their median response rate for macrocystic-type LMs was 22.9%, which was lower than our rate of
Fig. 3. (a) Computed tomography revealed that the trachea (arrow) was deviated to the left by the LM (circle) at the time of the diagnosis in Case 5. (b) The trachea returned to a central position center with partial shrinkage of the LM after 4 months of treatment with TJ-28, and the patient was weaned off noninvasive positive pressure ventilation.
Please cite this article as: Y. Goto, M. Yamashita, K. Kakuta, et al., A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.025
4
Y. Goto et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
100%. Considering that macrocystic-type LMs seem to respond well to sclerotherapy with OK-432 [2], combination therapy with TJ-28 and sclerotherapy may be a relevant strategy if TJ-28 monotherapy fails to lead to a successful outcome in cases involving macrocystic-type lesions. No adverse events related to TJ-28 were observed in our study. The drug information of TJ-28 has been open to the public in Japan and indicates that possible adverse events include pseudoaldosteronism, allergic reaction, nausea, diarrhea, dysuria, and symptoms of autonomic imbalance (e.g., palpitation, excess sweating, and agitation); however, each incidence of these symptoms was not described. Our study does not clarify the appropriate duration of TJ-28 treatment for patients who show satisfactory improvement without recurrence after the cessation of TJ-28. Patients receiving long-term treatment with TJ-28 should be closely monitored for these possible adverse events. The present study was associated with some limitations. Specifically, it was a retrospective study of a small case series with a relatively short follow-up period. Furthermore, as LMs may naturally decrease in size without treatment, it would have been ideal to include a control group in the analysis. 4. Conclusion The oral administration of TJ-28 seems to be effective for treating LMs in the head, neck, and abdominal regions in children, especially in the early stage of treatment. TJ-28 treatment combined with surgery may also be an alternative strategy. Further basic and clinical
multicenter studies using a unified treatment protocol are necessary to investigate the precise efficacy of TJ-28 in the treatment of LMs. References [1] Wassef M, Blei F, Adams D, et al. Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies. Pediatrics 2015;136:e203–14. [2] Acevedo JL, Shah RK, Brietzke SE. Nonsurgical therapies for lymphangiomas: a systematic review. Otolaryngol Head Neck Surg 2008;138:418–24. [3] Hashizume N, Yagi M, Egami H, et al. Clinical efficacy of herbal medicine for pediatric lymphatic malformations: a pilot study. Pediatr Dermatol 2016;33:191–5. [4] Shinkai T, Masumoto K, Chiba F, et al. A large retroperitoneal lymphatic malformation successfully treated with traditional Japanese Kampo medicine in combination with surgery. Surg Case Rep 2017;3:80. [5] Ogawa-Ochiai K, Sekiya N, Kasahara Y, et al. A case of mediastinal lymphanigoma successfully treated with Kampo medicine. J Altern Complement Med 2011;17: 563–5. [6] Tanaka H, Masumoto K, Aoyama T, et al. Prenatally diagnosed large mediastinal lymphangioma: a case report. Clin Case Rep 2018;14:1880–4. [7] Sidle DM, Maddalozzo J, Meier JD, et al. Altered pigment epithelium-derived factor and vascular endothelial growth factor levels in lymphangioma pathogenesis and clinical recurrence. Arch Otolaryngol Head Neck Surg 2005;131:990–5. [8] Kasahara Y, Hikino H, Tsurufuji S, et al. Antiinflammatory actions of ephedrines in acute inflammations. Planta Med 1985;51:325–31. [9] Matsuo K, Koizumi K, Fujita M, et al. Efficient use of a crude drug/herb library reveals ephedra herb as a specific antagonist for TH2-specific chemokine receptors CCR3, CCR4 and CCR8. Front Cell Dev Biol 2016;4:54. [10] Aoki K, Yamakuni T, Yoshida M, et al. Ephedorae herba decreases lipoploysaccharide-induced cyclooxgenase-2 protein expression and NF-κB-dependent transcription in C6 rat glioma cells. J Pharmacol Sci 2005;98:327–30. [11] Patoulias I, Prodromou K, Feidantsis T, et al. Cystic lymphangioma of the inguinal and scrotal regions in childhood — report of three cases. Hippokratia 2014;18: 88–91.
Please cite this article as: Y. Goto, M. Yamashita, K. Kakuta, et al., A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.025
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children☆,☆☆,★ Yudai Goto a,b, Michitoshi Yamashita a, Keiichi Kakuta a, Kakeru Mahchino a, Seiya Ogata a, Kotaro Mimori a, Hirofumi Shimizu a, Hideaki Tanaka a,⁎ a b
Department of Pediatric Surgery, Fukushima Medical University Hospital, Fukushima, Japan Department of Pediatric Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
a r t i c l e
i n f o
Article history: Received 11 August 2019 Accepted 24 August 2019 Available online xxxx Key words: Lymphatic malformation Children Eppikajutsuto Herbal medicine
a b s t r a c t Background: Eppikajutsuto (TJ-28) is an herbal medicine recently reported to be effective in treating lymphatic malformations (LMs). We report our experience concerning the clinical efficacy of TJ-28 for LMs. Methods: Medical records of 10 LM cases treated with TJ-28 between 2016 and 2018 were reviewed. TJ-28 was given at 0.3 g/kg/day and then increased to 0.5 if no improvement was noted after the first three months of treatment. Their clinical data were collected, and LM volume indices (depth×width×height) were measured with the first (LMVI-F) and latest (LMVI-L) imaging studies. The response rates were calculated as 1-LMVI-L / LMVI-F (%). Results: The median age at the diagnosis and treatment period was 1.5 years and 17.5 months, respectively. LMs were located in the neck (six), mesenterium or retroperitoneum (three), and inguinal region (one). The median response rate was 83%, including 100% in three cases and the apparent improvement of obstructive airway symptoms in one case. One case underwent surgery for insufficient improvement, and another that showed no effect is being considered for surgery. Most of the satisfactory outcomes were demonstrated in the first six months of treatment. Conclusion: TJ-28 seems to be effective in treating LMs in children, especially early in treatment. Level of evidence: IV © 2019 Elsevier Inc. All rights reserved.
Lymphatic malformations (LMs) are benign, slow-flow malformations composed of variously dilated lymphatic channels or cysts, lined by endothelial cells with a lymphatic phenotype [1]. LMs usually affect the head, neck, and axilla. Less common sites include mediastinum, groin, retroperitoneum, and other sites. They often cause cosmetic and functional complications. LMs may be treated with sclerotherapy and/or surgical resection. Although sclerotherapy with the percutaneous injection of sclerosants (e.g., OK-432 or bleomycin) [2] has been reported to be effective, especially for the treatment of macrocystic LMs, microcystic LMs are less responsive to sclerotherapy. Surgical resection potentially leads to a definitive cure of LMs, but is often technically challenging—especially for LMs located close to vital structures.
Medical therapies for LMs with the systemic administration of various agents, including sirolimus, sildenafil, and interferon-alpha, have been recently reported; however, the efficacy remains to be clarified [3]. Eppikajutsuto (TJ-28) (Tsumura & Co., Tokyo, Japan) is a Japanese herbal medicine that is reported to reduce redundant body fluids and to have anti-inflammatory effects [4]. Although some case reports indicate that TJ-28 may improve LMs [3–6], the therapeutic mechanism and appropriate treatment strategy have not been clarified. We herein report our single institution experience of the use of TJ-28 in treating LMs in children.
Abbreviations: TJ-28, Eppikajutsuto; LM, lymphatic malformation; LMVI-F, the first lymphatic malformation volume index; LMVI-L, the latest lymphatic malformation volume index; US, ultrasonography; CT, computed tomography; MRI, magnetic resonance imaging; NPPV, noninvasive positive pressure ventilation. ☆ Declarations of Interest: None. ☆☆ Acknowledgment: none ★ Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author at: Department of Pediatric Surgery, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, Fukushima, Japan 960-1295. Tel.: +81 24 547 1253; fax: +81 24 548 3249. E-mail address: [email protected] (H. Tanaka).
Twelve patients with LMs were treated using TJ-28 in our department between January 2016 and December 2018. In 2 of the 12 cases, the follow-up period was insufficient; thus, the patients were excluded in this study. The medical records of the remaining 10 patients were retrospectively reviewed. Our treatment protocol using TJ-28 was as follows: after the diagnosis of LM was confirmed by a physical examination and imaging studies, TJ-28 was orally administered at a dose of 0.3 g/kg/day in two divided doses. If the treatment efficacy was not considered satisfactory based on the physical examinations and imaging studies such as ultrasonography (US) after the initial
1. Patients and methods
https://doi.org/10.1016/j.jpedsurg.2019.08.025 0022-3468/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Y. Goto, M. Yamashita, K. Kakuta, et al., A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.025
2
Y. Goto et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
Table 1 The clinical features of the 10 cases included in this study. Case
Age
Gender
Location
Symptom
Bleeding
Type
Size (mm)
Response rate (%)
1 2 3 4 5 6 7 8 9 10
0m 7y 1m 1y 1m 2y 7y 12 y 4y 1m
f m f f m f f m f m
neck neck face neck neck neck mesenterium retroperitoneum retroperitoneum inguina
swelling swelling swelling swelling stridor swelling abdominal pain abdominal pain abdominal pain swelling
− − − − − − + + + −
macro macro micro micro mixed mixed macro macro mixed mixed
33*29*52 56*32*32 48*35*22 58*35*49 37*26*29 98*95*109 69*46*49 52*37*69 80*50*62 52*19*66
100 99 48 19 46 80a 100 100 86 −100
a
Combined with surgery.
three months of the treatment, the dose was increased to 0.5 g/kg/day. The TJ-28 treatment was discontinued, continued, or the next treatment (e.g., sclerotherapy or surgery) was considered and/or performed, depending on the outcome in the next three months. The outcome was determined based on US, computed tomography (CT), or magnetic resonance imaging (MRI), and the LM volume index (determined as follows: depth × width × height in mm) [3]. The response rates were calculated, using the first (LMVI-F) and latest (LMVI-L) LM volume indices, as follows: 1-LMVI-L/LMVI-F (%). The morphologic types of LMs were classified, based on imaging studies, as microcystic, macrocystic, or mixed, according to the International Society for the Study of Vascular Anomalies [1]. The age at the diagnosis, gender, symptoms, location, type, size, presence of bleeding inside the lesion, response rate and treatment period were collected and retrospectively analyzed. 2. Results The clinical features of the 10 patients are described in Table 1. The median age at the diagnosis was 1.5 years (0 month to 12 years). The locations and types were as follows: neck (n = 6 [macrocystic, n = 2; microcystic, n = 2; and mixed, n = 2]); abdomen (mesentery or retroperitoneum, n = 3 [macrocystic, n = 2; mixed, n-1]), and the inguinal region (n = 1 [mixed type]). The maximum diameter of the
lesions ranged from approximately 4 cm to 11 cm. All patients with abdominal lesions presented abdominal pain, and imaging studies revealed bleeding inside the abdominal lesions. One patient with a neck lesion suffered from upper respiratory symptoms such as inspiratory stridor requiring noninvasive positive pressure ventilation (NPPV) (Case 5). The other cases complained of cosmetic problems due to swollen lesions. The median period of treatment with TJ-28 was 17.5 months (3–49 months). The serial changes in the ratio of the LMVI at each evaluation to the LMVI-F are shown in Fig. 1, and demonstrate a rapid decrease in the LMVI in most patients during the first six months of treatment. The median response rate in this study group was 83% (range: −100%–100%), including three cases with a 100% response rate, indicating complete shrinkage. The median response rates according to the type of LMs were as follows: macrocystic type, 100%; microcystic type, 33.5%; and mixed type, 63%. The cosmetic improvement of the lesion in Case 1 is shown in Fig. 2 as an example of the excellent efficacy of TJ-28. The serial changes in the radiologic findings of the lesion in Case 5 are shown in Fig. 3. In this case, the patient's deviated upper respiratory tract returned to a central position and therefore the patient could eventually be weaned off NPPV. Case 6 showed insufficient improvement and underwent debulking surgery. The administration of TJ-28 was continued after the operation and the lesion tended to decrease in size thereafter. Case 10, which involved a patient with a huge inguinal lesion,
Fig. 1. Serial changes in the ratio of the LMVI at each evaluation to LMVI-F (%). LMVI, LM volume index (depth×width×height in mm); LMVI-F, first LMVI (the LMVI calculated at the first imaging study).
Please cite this article as: Y. Goto, M. Yamashita, K. Kakuta, et al., A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.025
Y. Goto et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
3
Fig. 2. (a) A large swollen lesion (circle) on the patient's neck was noted at the time of the diagnosis in Case 1. (b) Complete shrinkage of the lesion after 6 months of treatment with TJ-28.
exhibited no improvement and is currently being considered for surgery. No adverse events related to the administration of TJ-28 were observed during the treatment period. 3. Discussion TJ-28 is a Japanese herbal medicine that is covered under the National Health Insurance Plan of Japan. TJ-28 consists of six crude drug (herbs) components. Among these, Mao, also known as ephedra, may play a significant role in its pharmacological action. The mechanism of TJ-28 toward the shrinkage of LMs may be explained as follows: vascular endothelial growth factor (VEGF) is one of the key regulators of lymphoangiogenesis; LMs highly express VEGF with various types of gene mutation [7]; and Mao suppresses the activity of VEGF by inhibiting the synthesis of prostaglandin E2 and cyclooxygenase [8– 10], which may also induce anti-inflammatory effects toward LMs [4]. Our study showed relatively satisfactory outcomes within as early as 6 months of TJ-28 treatment, with a median response rate of 83%. There were three cases with a response rate of 100% (complete shrinkage), and another case in which the patient's obstructive airway symptoms
showed apparent improvement (Case 5). One case underwent surgical treatment for a neck lesion due to insufficient improvement (Case 6); however, the postoperative administration of TJ-28 seemed to reduce the volume of the LM. Combined treatment of LMs with TJ-28 and surgery has been reported after tube drainage for a mediastinal lesion [6] and before the resection of a retroperitoneal lesion [4]. These combinations of TJ-28 and surgical therapy may therefore be clinically relevant when monotherapy of TJ-28 is ineffective. The inguinal lesion in one of our cases (Case 10) continued to grow in spite of treatment with TJ28; thus, surgery is currently being considered. TJ-28 might not reach inguinal LMs effectively for an unknown reason, and surgery may need to be selected as the initial treatment, as reported in the literature [11]. Hashizume, et al. [3] reported their experience of TJ-28 monotherapy for eight patients with LMs located in the upper half of the body. Their median treatment period of 6 months was shorter than ours (17.5 months), and their dose of TJ-28 was fixed to 0.3 g/kg/day. Although their outcomes are difficult to compare to ours, the median response rate in their study was 46.9%. Their median response rate for macrocystic-type LMs was 22.9%, which was lower than our rate of
Fig. 3. (a) Computed tomography revealed that the trachea (arrow) was deviated to the left by the LM (circle) at the time of the diagnosis in Case 5. (b) The trachea returned to a central position center with partial shrinkage of the LM after 4 months of treatment with TJ-28, and the patient was weaned off noninvasive positive pressure ventilation.
Please cite this article as: Y. Goto, M. Yamashita, K. Kakuta, et al., A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.025
4
Y. Goto et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
100%. Considering that macrocystic-type LMs seem to respond well to sclerotherapy with OK-432 [2], combination therapy with TJ-28 and sclerotherapy may be a relevant strategy if TJ-28 monotherapy fails to lead to a successful outcome in cases involving macrocystic-type lesions. No adverse events related to TJ-28 were observed in our study. The drug information of TJ-28 has been open to the public in Japan and indicates that possible adverse events include pseudoaldosteronism, allergic reaction, nausea, diarrhea, dysuria, and symptoms of autonomic imbalance (e.g., palpitation, excess sweating, and agitation); however, each incidence of these symptoms was not described. Our study does not clarify the appropriate duration of TJ-28 treatment for patients who show satisfactory improvement without recurrence after the cessation of TJ-28. Patients receiving long-term treatment with TJ-28 should be closely monitored for these possible adverse events. The present study was associated with some limitations. Specifically, it was a retrospective study of a small case series with a relatively short follow-up period. Furthermore, as LMs may naturally decrease in size without treatment, it would have been ideal to include a control group in the analysis. 4. Conclusion The oral administration of TJ-28 seems to be effective for treating LMs in the head, neck, and abdominal regions in children, especially in the early stage of treatment. TJ-28 treatment combined with surgery may also be an alternative strategy. Further basic and clinical
multicenter studies using a unified treatment protocol are necessary to investigate the precise efficacy of TJ-28 in the treatment of LMs. References [1] Wassef M, Blei F, Adams D, et al. Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies. Pediatrics 2015;136:e203–14. [2] Acevedo JL, Shah RK, Brietzke SE. Nonsurgical therapies for lymphangiomas: a systematic review. Otolaryngol Head Neck Surg 2008;138:418–24. [3] Hashizume N, Yagi M, Egami H, et al. Clinical efficacy of herbal medicine for pediatric lymphatic malformations: a pilot study. Pediatr Dermatol 2016;33:191–5. [4] Shinkai T, Masumoto K, Chiba F, et al. A large retroperitoneal lymphatic malformation successfully treated with traditional Japanese Kampo medicine in combination with surgery. Surg Case Rep 2017;3:80. [5] Ogawa-Ochiai K, Sekiya N, Kasahara Y, et al. A case of mediastinal lymphanigoma successfully treated with Kampo medicine. J Altern Complement Med 2011;17: 563–5. [6] Tanaka H, Masumoto K, Aoyama T, et al. Prenatally diagnosed large mediastinal lymphangioma: a case report. Clin Case Rep 2018;14:1880–4. [7] Sidle DM, Maddalozzo J, Meier JD, et al. Altered pigment epithelium-derived factor and vascular endothelial growth factor levels in lymphangioma pathogenesis and clinical recurrence. Arch Otolaryngol Head Neck Surg 2005;131:990–5. [8] Kasahara Y, Hikino H, Tsurufuji S, et al. Antiinflammatory actions of ephedrines in acute inflammations. Planta Med 1985;51:325–31. [9] Matsuo K, Koizumi K, Fujita M, et al. Efficient use of a crude drug/herb library reveals ephedra herb as a specific antagonist for TH2-specific chemokine receptors CCR3, CCR4 and CCR8. Front Cell Dev Biol 2016;4:54. [10] Aoki K, Yamakuni T, Yoshida M, et al. Ephedorae herba decreases lipoploysaccharide-induced cyclooxgenase-2 protein expression and NF-κB-dependent transcription in C6 rat glioma cells. J Pharmacol Sci 2005;98:327–30. [11] Patoulias I, Prodromou K, Feidantsis T, et al. Cystic lymphangioma of the inguinal and scrotal regions in childhood — report of three cases. Hippokratia 2014;18: 88–91.
Please cite this article as: Y. Goto, M. Yamashita, K. Kakuta, et al., A single institution experience of Eppikajutsuto for the treatment of lymphatic malformations in children, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.025