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The efficacy of percutaneous AHI (arginine hydrochloride injection) for the treatment of recurrent thyroid cysts
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ScienceDirect www.sciencedirect.com Annales d’Endocrinologie 76 (2015) 281–285
Original article
The efficacy of percutaneous AHI (arginine hydrochloride injection) for the treatment of recurrent thyroid cysts Efficacité du chlorhydrate d’arginine (OK-432) en injection percutanée pour traiter les kystes de la thyroïde récidivants Yanru Zhao , Xiaoyan Guan , Yanjun Liu , Shu Liu , Aamir Hussain , Bingyin Shi ∗ Department of Endocrinology, The First Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an 710061, PR China
Abstract Objectives. – Thyroid cysts remain a common clinical problem. Although simple aspiration, ethanol ablation, and radiofrequency ablation are effective, they have some limitations. There is therefore a need to identify a new and effective sclerosant for resolving these problems. The aim of this study was to test the efficacy as an active compound for sclerotherapy of thyroid cysts. Patients and methods. – Eight subjects whose thyroid cysts were recurrent despite repeated simple aspiration treatments were included in this study. The cysts were aspirated and then subjected to AHI. Lack of a significant reduction in cyst size (i.e. < 50%) at follow-up resulted in further AHIs. Treatment success was defined as complete disappearance or a marked (i.e. > 50%) reduction in the size of the cystic portion of the thyroid nodule on follow-up ultrasonography at least 6 months after the final AHI. Results. – A marked size reduction of > 50% was ultimately found in all of the patients (100%), with a reduction varying from 73.68% to 99.07% (P < 0.029). Six of the patients received a single AHI treatment, one received two AHIs, and one received three AHIs. None of the patients suffered from a recurrence during the follow-up period. Three patients experienced tolerable pain and local tenderness. No serious side effects were reported. Conclusions. – Intracystic AHI may be a safe and effective treatment for benign thyroid cysts. © 2015 Elsevier Masson SAS. All rights reserved. Keywords: AHI (arginine hydrochloride injection); Thyroid cysts; Treatment; Recurrence
Résumé Objectifs. – Les kystes de la thyroïde sont un problème clinique courant. Bien qu’efficaces, la simple aspiration, l’ablation à l’éthanol ou la radio fréquence ont certaines limites. Il est donc nécessaire d’identifier une forme nouvelle et efficace d’agent sclérosant pour résoudre ces problèmes. Le but de cette étude était de tester l’efficacité de la sclérothérapie à l’OK-432 – également connu sous le nom d’injection de chlorhydrate d’arginine – pour traiter les kystes de la thyroïde. Patients et méthodes. – Huit patients, dont les kystes de la thyroïde étaient récurrents malgré des traitements répétés d’aspiration simple, ont été inclus dans cette étude. Les kystes ont été aspirés et ensuite injectés au chlorhydrate d’arginine. L’absence d’une réduction significative de la taille des kystes (i.e. < 50 %) lors du suivi a donné lieu à d’autres injections. La réussite du traitement a été définie comme la disparition complète ou marquée (> 50 %) de la taille de la portion kystique du nodule thyroïdien à l’échographie de suivi au moins six mois après la dernière injection de chlorhydrate d’arginine. Résultats. – Une réduction marquée (> 50 %) de la taille du kyste a finalement été retrouvée chez tous les patients (100 %), avec une réduction variant de 73,68 % à 99,07 % (p < 0,029). Six des patients ont rec¸u une seule injection, un a rec¸u deux injections, et un autre trois. Aucune récidive n’a été observée pendant la période de suivi. Trois patients ont ressenti des douleurs tolérables et une sensibilité locale. Aucun effet secondaire grave n’a été observé. Conclusions. – L’injection de chlorhydrate d’arginine intrakystique semble une approche thérapeutique efficace et sans danger des nodules kystiques bénins de la thyroïde. © 2015 Elsevier Masson SAS. Tous droits réservés. Mots clés : AHI ; Kystes thyroïdiens ; Traitement ; Récidive
∗
Corresponding author. E-mail address: [email protected] (B. Shi).
http://dx.doi.org/10.1016/j.ando.2015.03.039 0003-4266/© 2015 Elsevier Masson SAS. All rights reserved.
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Y. Zhao et al. / Annales d’Endocrinologie 76 (2015) 281–285
1. Introduction
2. Materials/patients
Thyroid cysts remain a common clinical problem, accounting for 15–25% of solitary thyroid nodules detected on ultrasound (US) [1]. They are thought to be caused by haemorrhage and subsequent degeneration of pre-existing nodules [2]. There are several methods for treating benign cystic thyroid nodules, such as simple fine-needle aspiration [3,4], thyroid hormone suppression therapy [5], sclerotherapy with various sclerosants [6–8], radiofrequency ablation (RFA) [9], and surgery. The firstline method is simple aspiration. However, although this is a satisfactory short-term non-operative treatment, the cysts commonly recur even after repeated aspirations, at reported rates of 10–80% depending on the number of previous aspirations and the cyst volume [3,10]. Both ethanol ablation and RFA are effective and safe treatment techniques. It has been suggested that ethanol ablation is better than RFA for benign, predominantly cystic thyroid nodules [9], since it requires fewer treatment sessions and is a less expensive and simpler procedure. Although ethanol ablation has only mild and transient side effects, any ethanol that escapes outside the capsule can induce paraglandular fibrosis and subsequent serious respiratory distress [11]. More importantly, it is difficult to obtain the 99% ethanol required for use as a sclerosant in our country. Therefore, there is a need for novel sclerosants. AHI, also known as arginine hydrochloride is a type of amino acid drug that is currently administered by injection mostly for the treatment of hepatic encephalopathy. It is safe, colorless, cheap, and easy to obtain. The aim of the present study was to prospectively determine the effectiveness of arginine hydrochloride injection (AHI) for the treatment of benign thyroid cysts.
Eligible subjects included patients who, despite having received multiple simple aspiration treatments, suffered from recurrent and biopsy-proven benign thyroid cysts from June 2012 to December 2012. Eight subjects were included (age range, 36–64 years; mean age, 49.25 years). Thyroid malignancy was an exclusion criterion. The study protocol was drawn up in compliance with the principles of the Helsinki Accord, and was reviewed and approved by the local Ethical Committee. Statement of informed consent was obtained from all participants after a full explanation of the procedure.
3. Methods 3.1. Treatment and study design US examinations were performed before and after treatment (Fig. 1) using a 7.5-MHz US scanner (Nemio17, Toshiba, Japan). After scrubbing the skin with alcohol, a 21-gauge needle was inserted into the cystic portion of the thyroid nodule with the patient in the supine position and without local anaesthesia. The fluid was first completely aspirated from the cystic portion of the thyroid nodule. The syringe tube was then replaced with another one containing arginine hydrochloride while keeping the puncture needle in place. A volume of arginine hydrochloride inferior to the aspirated volume was injected via the needle. The dose varied in the range 1–11 mL according to the volume of aspirate removed from the cyst. Finally, after rapidly removing the needle, the patient was asked to press gently on the puncture site during 15–20 minutes [6,9,12].
Fig. 1. US scan of a 44-year-old woman before and after treatment. A. US scan obtained before AHI sclerotherapy shows a huge thyroid nodule. B. US obtained 12 months after AHI sclerotherapy shows a decrease in the size of the postsclerotic thyroid nodule.
Y. Zhao et al. / Annales d’Endocrinologie 76 (2015) 281–285 Table 1 Clinical characteristics of patients with thyroid cysts.
283
Table 2 Treatment characteristics and outcomes.
Characteristic
No. of patients
Characteristic
Number of patients (gender, male/female) Median age, years (range) Median months from diagnosis (range) Previous number of aspirations, median (range) Previous time interval of aspirations, months, median (range) Median largest diameter before treatment, cm (range) Median follow-up, months (range)
8 (2/6) 48 (36–64) 9 (3–44) 3 (2–7) 3.5 (2–8)
Treatment Aspiration volume, mL, median (range) Injected AHI, mL, median (range) No. of treatments, median (range) Response, n (%) Near disappearance or cyst size marked reduction > 50% Minimal reduction < 50% Side effects Tolerable pain and local tenderness
3.45 (1.98–7.0) 12 (8–14)
The patients were followed up for at least 6 months after the sclerotherapy. If the size reduction at follow-up was < 50%, the AHI treatment was repeated. The patients ultimately require either one, two, or three AHIs for a positive result. Treatment success was defined as near disappearance of the cyst or a marked size reduction of > 50% on US at least 6 months after the final treatment [13]. The size was determined by comparing the product of the two largest diameters (D1 × D2) of the cyst measured on US before and after treatment.
Result 14.5 (2–71) 4 (1–11) 2 (1–3) 8/8 0 3/8
Table 3 Relationship between treatment response and original cyst size. Response
Cure after 1 treatment ≥ 2 treatments *
Initial cyst size, cm2 median (range)
No. of patients (%)
9.70 (3.4–23.5) 29.00 (16.0–42.0)*
6 (75) 2 (25)
P = 0.057 compared with 1 treatment.
3.2. Statistical analysis The results are expressed as median (range) or mean ± SD values. Paired-samples t-test and independent-samples t-test were used to evaluate the statistical significance of any differences. The threshold for statistical significance was set at P < 0.05.
sample may have been the reason for this lack of statistical significance. None of the patients suffered from a recurrence during the follow-up period. All eight patients (100%) exhibited either near disappearance of the cyst or else a significant reduction in its size. The size reduction varied from 73.68% to 99.07% (P < 0.029) (Table 4, Fig. 2).
4. Results 4.1. Pre-treatment findings Eight patients were enrolled in the AHI treatment protocol. The clinical data for these eight consecutive patients are given in Table 1. They had been diagnosed with thyroid cysts since 3 to 44 months (median: 9 months) and had undergone between two and seven aspiration treatments (median: 3), typically receiving treatment every 2–8 months before AHI (median: 3.5 months). 4.2. Treatment response Follow-up was performed between 8 to 14 months after sclerotherapy. More than one follow-up US scan was obtained from the eight patients at least 8 months after percutaneous AHI. The median aspiration volume was 14.5 mL (range, 2–71 mL), and a median of 4 mL (range, 1–11 mL) of arginine hydrochloride was injected into the thyroid cysts (Table 2). Among the patients, 6 received a single AHI, and two received more than one AHI. The original cyst size did not differ between those who received just one AHI and those who received multiple AHIs (P = 0.057) (Table 3). Among the two patients who received multiple AHIs, one received two and the other received three. On clinical grounds, and although non-statistically significant AHI, larger cysts seemed to need more AHIs. The small
4.3. Side effects Three of the eight patients experienced tolerable pain and local tenderness after AHI. There were no serious side effects. 5. Discussion Most thyroid cysts are benign. Fine-needle aspiration for cytology is generally used to check their status. Surgery is required if the findings indicate a carcinoma, and simple Table 4 Cyst size reduction of the 8 patients with outpatient clinic visit. Patient number
Cyst size reduction (%)
1 2 3 4 5 6 7 8
87.38 90.96 73.86 99.07 89.86 82.98 87.91 97.81
The size was defined as the change in the product of the two largest diameters (D1 × D2), calculated on US images, between before and after the final treatment.
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Fig. 2. Comparison of the mean size before and after treatment (means ± SD, * P < 0.05).
aspiration is generally recommended for benign cysts. However, the recurrence rate is high with the latter procedure, even after repeated aspirations. Sclerotherapy is one approach for reducing the recurrence rate. Since the introduction of ethanol instillation in 1989, its success rate, defined as near disappearance or marked size reduction (> 50%), has been reported to vary from 72% to 95% [12–14]. The corresponding rate was 100% when AHI was applied in the present study; all eight patients exhibited near disappearance of the cyst or a significant reduction in its size. However the criterion of success used by Bennedbaek et al. [13] was more strict than ours (cyst volum < 1 mL during follow-up). The same team also stated that the chance of success decreased with the number of previous aspirations and with increasing cyst volume. In our series, this was not confirmed as our patients had been treated three times (range 2–7) with simple aspiration before sclerotherapy, and despite this, we did not encounter a reduced efficacy. Also, we did not find a statistically significant link between the initial volume and chance of success. OK-432 is a lyophilized mixture of low-virulence group A Streptococcus pyogenes and Penicillin G potassium that is used to treat cancer [15], and was recently reported to be safe and highly effective for the treatment of various cystic lesions, including lymphangiomas [16,17]. Three previous studies found success rates (defined as a marked reduction of the original cyst size of > 50%) of OK-432 in the treatment of thyroid cysts of 92% [8], 88.9% [18], and 73% [19]. Moreover, in addition to temporary pain, low-grade fever was observed in 19 (42%) patients in 1 study [18]. The success rate (100%) of the present AHI study was much better than in those three studies, and no patient experienced fever. In another study comparing the efficacy and safety of ethanol ablation and RFA [9], the cyst size before treatment (largest diameter of the nodule exceeding 2 cm) was similar to the one of the present study (median largest diameter, 3.45 cm; range, 1.98–7.00 cm). Therapeutic success (volume reduction > 50%) was achieved in 34 out of 36 patients (94.4%) treated with PEA and 20 out of 21 patients (95.2%) treated with RFA, and the authors suggested that since ethanol ablation was cheaper, simpler to perform, and required fewer sessions, it was the preferred
treatment [9]. We achieved a 100% therapeutic success (size reduction > 50%) in eight patients. The findings of this study should be interpreted in light of several limitations, such as the small number of patients, the changes in thyroid hormone and thyroglobulin, and the lack of a control group. Although this prospective study comprised only a single treatment group and no controls for comparison, the observed success rate was better than those reported previously using ethanol, OK-432 injection or RFA. However, the optimum dose of arginine hydrochloride for AHI remains to be determined. In this study, the volume injected was 4.81 mL (range, 1–11 mL), similar to that used for ethanol in a previous study (mean, 4.8 mL; range, 1.5–10 mL) [14]. It is likely that arginine hydrochloride causes cell death; however, further investigation of the mechanism of action of arginine hydrochloride in the treatment of benign thyroid cysts is necessary. Finally, the parameter chosen to define a successful treatment is questionable. In some studies, it has been defined as the near disappearance or a marked size reduction (> 50%) of the cyst after the final treatment, where the size is calculated as a volume: V = × D1 × D2 × D3/6 (where D1, D2, and D3 are diameters of the three tumor axes), a reduction of > 50% after the last treatment [9,20], or as a cyst diameter of < 1 cm [19]. In the present study, the cyst size was defined as the change in the product of the two largest diameters (D1 × D2), calculated on US images, between before and after the final AHI. The findings of this study indicate that intracystic AHI is a safe, effective, inexpensive (2.6 RMB per AHI), and rapid treatment that can be performed on an outpatient basis. In short, it may be an effective alternative to ethanol injection. Further studies with larger patient samples are needed to confirm these findings and to determine the optimum dose of arginine hydrochloride. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements This work was supported technically by the Clinical Research Center, the First Affiliated Hospital, Xi’an Jiaotong University, China. References [1] Mazzaferri EL. Management of a solitary thyroid nodule. New Engl J Med 1993;328:553–9. [2] Yasuda K, Ozaki O, Sugino K, et al. Treatment of cystic lesions of the thyroid by ethanol instillation. World J Surg 1992;16:958–61. [3] Crile Jr G. Treatment of thyroid cysts by aspiration. Surgery 1966;59:210–2. [4] Miller JM, Zafar SU, Karo JJ. The cystic thyroid nodule. Recognition and management. Radiology 1974;110:257–61. [5] Cooper DS. Clinical review 66: thyroxine suppression therapy for benign nodular disease. J Clin Endocrinol Metab 1995;80:331–4. [6] Edmonds CJ, Tellez M. Treatment of thyroid cysts by aspiration and injection of sclerosant. Br Med J 1987;295:529.
Y. Zhao et al. / Annales d’Endocrinologie 76 (2015) 281–285 [7] Hegedus L, Hansen JM, Karstrup S, Torp-Pedersen S, Juul N. Tetracycline for sclerosis of thyroid cysts. A randomized study. Arch Int Med 1988;148:1116–8. [8] Chang HS, Yoon JH, Chung WY, Park CS. Sclerotherapy with OK-432 for recurrent cystic thyroid nodule. Yonsei Med J 1998;39:367–71. [9] Sung JY, Kim YS, Choi H, Lee JH, Baek JH. Optimum first-line treatment technique for benign cystic thyroid nodules: ethanol ablation or radiofrequency ablation? AJR Am J Roentgenol 2011;196:W210–4. [10] Jensen F, Rasmussen SN. The treatment of thyroid cysts by ultrasonically guided fine needle aspiration. Acta Chir Scand 1976;142:209–11. [11] Iacconi P, Spinelli C, Monzani F, Miccoli P. Percutaneous ethanol injection for thyroid cysts: a word of caution. Clin Endocrinol 1996;44:126. [12] Kim DW, Rho MH, Kim HJ, Kwon JS, Sung YS, Lee SW. Percutaneous ethanol injection for benign cystic thyroid nodules: is aspiration of ethanolmixed fluid advantageous? AJNR Am J Neuroradiol 2005;26:2122–7. [13] Bennedbaek FN, Hegedus L. Treatment of recurrent thyroid cysts with ethanol: a randomized double-blind controlled trial. J Clin Endocrinol Metab 2003;88:5773–7.
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[14] Jayesh SR, Mehta P, Cherian MP, Ilayaraja V, Gupta P, Venkatesh K. Efficacy and safety of USG-guided ethanol sclerotherapy in cystic thyroid nodules. Ind J Radiol Imaging 2009;19:199–202. [15] Okamoto H, Minami M, Shoin S, Koshimura S, Shimizu R. Experimental anticancer studies XXXI. On the streptococcal preparation having potent anticancer activity. Japn J Exp Med 1966;36:175–86. [16] Ogita S, Tsuto T, Nakamura K, Deguchi E, Iwai N. OK-432 therapy in 64 patients with lymphangioma. J Pediatr Surg 1994;29:784–5. [17] Roh JL. Primary treatment of ranula with intracystic injection of OK-432. Laryngoscope 2006;116:169–72. [18] Roh JL, Park 2nd C. Treatment of benign thyroid cysts by intracystic injection of OK-432. Surgery 2008;144:775–9. [19] Cho SH, Lee SH, Jung KY, et al. Sonography-guided OK-432 sclerotherapy for benign thyroid cysts. Acta Oto-laryngol 2008;128:597–600. [20] Raggiunti B, Fiore G, Mongia A, Balducci G, Ballone E, Capone F. A 7-year follow-up of patients with thyroid cysts and pseudocysts treated with percutaneous ethanol injection: volume change and cost analysis. J Ultrasound 2009;12:107–11.
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie 76 (2015) 281–285
Original article
The efficacy of percutaneous AHI (arginine hydrochloride injection) for the treatment of recurrent thyroid cysts Efficacité du chlorhydrate d’arginine (OK-432) en injection percutanée pour traiter les kystes de la thyroïde récidivants Yanru Zhao , Xiaoyan Guan , Yanjun Liu , Shu Liu , Aamir Hussain , Bingyin Shi ∗ Department of Endocrinology, The First Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an 710061, PR China
Abstract Objectives. – Thyroid cysts remain a common clinical problem. Although simple aspiration, ethanol ablation, and radiofrequency ablation are effective, they have some limitations. There is therefore a need to identify a new and effective sclerosant for resolving these problems. The aim of this study was to test the efficacy as an active compound for sclerotherapy of thyroid cysts. Patients and methods. – Eight subjects whose thyroid cysts were recurrent despite repeated simple aspiration treatments were included in this study. The cysts were aspirated and then subjected to AHI. Lack of a significant reduction in cyst size (i.e. < 50%) at follow-up resulted in further AHIs. Treatment success was defined as complete disappearance or a marked (i.e. > 50%) reduction in the size of the cystic portion of the thyroid nodule on follow-up ultrasonography at least 6 months after the final AHI. Results. – A marked size reduction of > 50% was ultimately found in all of the patients (100%), with a reduction varying from 73.68% to 99.07% (P < 0.029). Six of the patients received a single AHI treatment, one received two AHIs, and one received three AHIs. None of the patients suffered from a recurrence during the follow-up period. Three patients experienced tolerable pain and local tenderness. No serious side effects were reported. Conclusions. – Intracystic AHI may be a safe and effective treatment for benign thyroid cysts. © 2015 Elsevier Masson SAS. All rights reserved. Keywords: AHI (arginine hydrochloride injection); Thyroid cysts; Treatment; Recurrence
Résumé Objectifs. – Les kystes de la thyroïde sont un problème clinique courant. Bien qu’efficaces, la simple aspiration, l’ablation à l’éthanol ou la radio fréquence ont certaines limites. Il est donc nécessaire d’identifier une forme nouvelle et efficace d’agent sclérosant pour résoudre ces problèmes. Le but de cette étude était de tester l’efficacité de la sclérothérapie à l’OK-432 – également connu sous le nom d’injection de chlorhydrate d’arginine – pour traiter les kystes de la thyroïde. Patients et méthodes. – Huit patients, dont les kystes de la thyroïde étaient récurrents malgré des traitements répétés d’aspiration simple, ont été inclus dans cette étude. Les kystes ont été aspirés et ensuite injectés au chlorhydrate d’arginine. L’absence d’une réduction significative de la taille des kystes (i.e. < 50 %) lors du suivi a donné lieu à d’autres injections. La réussite du traitement a été définie comme la disparition complète ou marquée (> 50 %) de la taille de la portion kystique du nodule thyroïdien à l’échographie de suivi au moins six mois après la dernière injection de chlorhydrate d’arginine. Résultats. – Une réduction marquée (> 50 %) de la taille du kyste a finalement été retrouvée chez tous les patients (100 %), avec une réduction variant de 73,68 % à 99,07 % (p < 0,029). Six des patients ont rec¸u une seule injection, un a rec¸u deux injections, et un autre trois. Aucune récidive n’a été observée pendant la période de suivi. Trois patients ont ressenti des douleurs tolérables et une sensibilité locale. Aucun effet secondaire grave n’a été observé. Conclusions. – L’injection de chlorhydrate d’arginine intrakystique semble une approche thérapeutique efficace et sans danger des nodules kystiques bénins de la thyroïde. © 2015 Elsevier Masson SAS. Tous droits réservés. Mots clés : AHI ; Kystes thyroïdiens ; Traitement ; Récidive
∗
Corresponding author. E-mail address: [email protected] (B. Shi).
http://dx.doi.org/10.1016/j.ando.2015.03.039 0003-4266/© 2015 Elsevier Masson SAS. All rights reserved.
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Y. Zhao et al. / Annales d’Endocrinologie 76 (2015) 281–285
1. Introduction
2. Materials/patients
Thyroid cysts remain a common clinical problem, accounting for 15–25% of solitary thyroid nodules detected on ultrasound (US) [1]. They are thought to be caused by haemorrhage and subsequent degeneration of pre-existing nodules [2]. There are several methods for treating benign cystic thyroid nodules, such as simple fine-needle aspiration [3,4], thyroid hormone suppression therapy [5], sclerotherapy with various sclerosants [6–8], radiofrequency ablation (RFA) [9], and surgery. The firstline method is simple aspiration. However, although this is a satisfactory short-term non-operative treatment, the cysts commonly recur even after repeated aspirations, at reported rates of 10–80% depending on the number of previous aspirations and the cyst volume [3,10]. Both ethanol ablation and RFA are effective and safe treatment techniques. It has been suggested that ethanol ablation is better than RFA for benign, predominantly cystic thyroid nodules [9], since it requires fewer treatment sessions and is a less expensive and simpler procedure. Although ethanol ablation has only mild and transient side effects, any ethanol that escapes outside the capsule can induce paraglandular fibrosis and subsequent serious respiratory distress [11]. More importantly, it is difficult to obtain the 99% ethanol required for use as a sclerosant in our country. Therefore, there is a need for novel sclerosants. AHI, also known as arginine hydrochloride is a type of amino acid drug that is currently administered by injection mostly for the treatment of hepatic encephalopathy. It is safe, colorless, cheap, and easy to obtain. The aim of the present study was to prospectively determine the effectiveness of arginine hydrochloride injection (AHI) for the treatment of benign thyroid cysts.
Eligible subjects included patients who, despite having received multiple simple aspiration treatments, suffered from recurrent and biopsy-proven benign thyroid cysts from June 2012 to December 2012. Eight subjects were included (age range, 36–64 years; mean age, 49.25 years). Thyroid malignancy was an exclusion criterion. The study protocol was drawn up in compliance with the principles of the Helsinki Accord, and was reviewed and approved by the local Ethical Committee. Statement of informed consent was obtained from all participants after a full explanation of the procedure.
3. Methods 3.1. Treatment and study design US examinations were performed before and after treatment (Fig. 1) using a 7.5-MHz US scanner (Nemio17, Toshiba, Japan). After scrubbing the skin with alcohol, a 21-gauge needle was inserted into the cystic portion of the thyroid nodule with the patient in the supine position and without local anaesthesia. The fluid was first completely aspirated from the cystic portion of the thyroid nodule. The syringe tube was then replaced with another one containing arginine hydrochloride while keeping the puncture needle in place. A volume of arginine hydrochloride inferior to the aspirated volume was injected via the needle. The dose varied in the range 1–11 mL according to the volume of aspirate removed from the cyst. Finally, after rapidly removing the needle, the patient was asked to press gently on the puncture site during 15–20 minutes [6,9,12].
Fig. 1. US scan of a 44-year-old woman before and after treatment. A. US scan obtained before AHI sclerotherapy shows a huge thyroid nodule. B. US obtained 12 months after AHI sclerotherapy shows a decrease in the size of the postsclerotic thyroid nodule.
Y. Zhao et al. / Annales d’Endocrinologie 76 (2015) 281–285 Table 1 Clinical characteristics of patients with thyroid cysts.
283
Table 2 Treatment characteristics and outcomes.
Characteristic
No. of patients
Characteristic
Number of patients (gender, male/female) Median age, years (range) Median months from diagnosis (range) Previous number of aspirations, median (range) Previous time interval of aspirations, months, median (range) Median largest diameter before treatment, cm (range) Median follow-up, months (range)
8 (2/6) 48 (36–64) 9 (3–44) 3 (2–7) 3.5 (2–8)
Treatment Aspiration volume, mL, median (range) Injected AHI, mL, median (range) No. of treatments, median (range) Response, n (%) Near disappearance or cyst size marked reduction > 50% Minimal reduction < 50% Side effects Tolerable pain and local tenderness
3.45 (1.98–7.0) 12 (8–14)
The patients were followed up for at least 6 months after the sclerotherapy. If the size reduction at follow-up was < 50%, the AHI treatment was repeated. The patients ultimately require either one, two, or three AHIs for a positive result. Treatment success was defined as near disappearance of the cyst or a marked size reduction of > 50% on US at least 6 months after the final treatment [13]. The size was determined by comparing the product of the two largest diameters (D1 × D2) of the cyst measured on US before and after treatment.
Result 14.5 (2–71) 4 (1–11) 2 (1–3) 8/8 0 3/8
Table 3 Relationship between treatment response and original cyst size. Response
Cure after 1 treatment ≥ 2 treatments *
Initial cyst size, cm2 median (range)
No. of patients (%)
9.70 (3.4–23.5) 29.00 (16.0–42.0)*
6 (75) 2 (25)
P = 0.057 compared with 1 treatment.
3.2. Statistical analysis The results are expressed as median (range) or mean ± SD values. Paired-samples t-test and independent-samples t-test were used to evaluate the statistical significance of any differences. The threshold for statistical significance was set at P < 0.05.
sample may have been the reason for this lack of statistical significance. None of the patients suffered from a recurrence during the follow-up period. All eight patients (100%) exhibited either near disappearance of the cyst or else a significant reduction in its size. The size reduction varied from 73.68% to 99.07% (P < 0.029) (Table 4, Fig. 2).
4. Results 4.1. Pre-treatment findings Eight patients were enrolled in the AHI treatment protocol. The clinical data for these eight consecutive patients are given in Table 1. They had been diagnosed with thyroid cysts since 3 to 44 months (median: 9 months) and had undergone between two and seven aspiration treatments (median: 3), typically receiving treatment every 2–8 months before AHI (median: 3.5 months). 4.2. Treatment response Follow-up was performed between 8 to 14 months after sclerotherapy. More than one follow-up US scan was obtained from the eight patients at least 8 months after percutaneous AHI. The median aspiration volume was 14.5 mL (range, 2–71 mL), and a median of 4 mL (range, 1–11 mL) of arginine hydrochloride was injected into the thyroid cysts (Table 2). Among the patients, 6 received a single AHI, and two received more than one AHI. The original cyst size did not differ between those who received just one AHI and those who received multiple AHIs (P = 0.057) (Table 3). Among the two patients who received multiple AHIs, one received two and the other received three. On clinical grounds, and although non-statistically significant AHI, larger cysts seemed to need more AHIs. The small
4.3. Side effects Three of the eight patients experienced tolerable pain and local tenderness after AHI. There were no serious side effects. 5. Discussion Most thyroid cysts are benign. Fine-needle aspiration for cytology is generally used to check their status. Surgery is required if the findings indicate a carcinoma, and simple Table 4 Cyst size reduction of the 8 patients with outpatient clinic visit. Patient number
Cyst size reduction (%)
1 2 3 4 5 6 7 8
87.38 90.96 73.86 99.07 89.86 82.98 87.91 97.81
The size was defined as the change in the product of the two largest diameters (D1 × D2), calculated on US images, between before and after the final treatment.
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Fig. 2. Comparison of the mean size before and after treatment (means ± SD, * P < 0.05).
aspiration is generally recommended for benign cysts. However, the recurrence rate is high with the latter procedure, even after repeated aspirations. Sclerotherapy is one approach for reducing the recurrence rate. Since the introduction of ethanol instillation in 1989, its success rate, defined as near disappearance or marked size reduction (> 50%), has been reported to vary from 72% to 95% [12–14]. The corresponding rate was 100% when AHI was applied in the present study; all eight patients exhibited near disappearance of the cyst or a significant reduction in its size. However the criterion of success used by Bennedbaek et al. [13] was more strict than ours (cyst volum < 1 mL during follow-up). The same team also stated that the chance of success decreased with the number of previous aspirations and with increasing cyst volume. In our series, this was not confirmed as our patients had been treated three times (range 2–7) with simple aspiration before sclerotherapy, and despite this, we did not encounter a reduced efficacy. Also, we did not find a statistically significant link between the initial volume and chance of success. OK-432 is a lyophilized mixture of low-virulence group A Streptococcus pyogenes and Penicillin G potassium that is used to treat cancer [15], and was recently reported to be safe and highly effective for the treatment of various cystic lesions, including lymphangiomas [16,17]. Three previous studies found success rates (defined as a marked reduction of the original cyst size of > 50%) of OK-432 in the treatment of thyroid cysts of 92% [8], 88.9% [18], and 73% [19]. Moreover, in addition to temporary pain, low-grade fever was observed in 19 (42%) patients in 1 study [18]. The success rate (100%) of the present AHI study was much better than in those three studies, and no patient experienced fever. In another study comparing the efficacy and safety of ethanol ablation and RFA [9], the cyst size before treatment (largest diameter of the nodule exceeding 2 cm) was similar to the one of the present study (median largest diameter, 3.45 cm; range, 1.98–7.00 cm). Therapeutic success (volume reduction > 50%) was achieved in 34 out of 36 patients (94.4%) treated with PEA and 20 out of 21 patients (95.2%) treated with RFA, and the authors suggested that since ethanol ablation was cheaper, simpler to perform, and required fewer sessions, it was the preferred
treatment [9]. We achieved a 100% therapeutic success (size reduction > 50%) in eight patients. The findings of this study should be interpreted in light of several limitations, such as the small number of patients, the changes in thyroid hormone and thyroglobulin, and the lack of a control group. Although this prospective study comprised only a single treatment group and no controls for comparison, the observed success rate was better than those reported previously using ethanol, OK-432 injection or RFA. However, the optimum dose of arginine hydrochloride for AHI remains to be determined. In this study, the volume injected was 4.81 mL (range, 1–11 mL), similar to that used for ethanol in a previous study (mean, 4.8 mL; range, 1.5–10 mL) [14]. It is likely that arginine hydrochloride causes cell death; however, further investigation of the mechanism of action of arginine hydrochloride in the treatment of benign thyroid cysts is necessary. Finally, the parameter chosen to define a successful treatment is questionable. In some studies, it has been defined as the near disappearance or a marked size reduction (> 50%) of the cyst after the final treatment, where the size is calculated as a volume: V = × D1 × D2 × D3/6 (where D1, D2, and D3 are diameters of the three tumor axes), a reduction of > 50% after the last treatment [9,20], or as a cyst diameter of < 1 cm [19]. In the present study, the cyst size was defined as the change in the product of the two largest diameters (D1 × D2), calculated on US images, between before and after the final AHI. The findings of this study indicate that intracystic AHI is a safe, effective, inexpensive (2.6 RMB per AHI), and rapid treatment that can be performed on an outpatient basis. In short, it may be an effective alternative to ethanol injection. Further studies with larger patient samples are needed to confirm these findings and to determine the optimum dose of arginine hydrochloride. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements This work was supported technically by the Clinical Research Center, the First Affiliated Hospital, Xi’an Jiaotong University, China. References [1] Mazzaferri EL. Management of a solitary thyroid nodule. New Engl J Med 1993;328:553–9. [2] Yasuda K, Ozaki O, Sugino K, et al. Treatment of cystic lesions of the thyroid by ethanol instillation. World J Surg 1992;16:958–61. [3] Crile Jr G. Treatment of thyroid cysts by aspiration. Surgery 1966;59:210–2. [4] Miller JM, Zafar SU, Karo JJ. The cystic thyroid nodule. Recognition and management. Radiology 1974;110:257–61. [5] Cooper DS. Clinical review 66: thyroxine suppression therapy for benign nodular disease. J Clin Endocrinol Metab 1995;80:331–4. [6] Edmonds CJ, Tellez M. Treatment of thyroid cysts by aspiration and injection of sclerosant. Br Med J 1987;295:529.
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