Acetylsalicylic acid suppression of the PI3K pathway as a novel medical therapy for head and neck lymphatic malformations,International Journal of Pediatric Otorhinolaryngology

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Acetylsalicylic acid suppression of the PI3K pathway as a novel medical therapy for head and neck lymphatic malformations
International Journal of Pediatric Otorhinolaryngology ( IF 1.5 ) Pub Date : 2021-08-05 , DOI: 10.1016/j.ijporl.2021.110869
Juliana Bonilla-Velez ₁ , Kathryn B Whitlock ₂ , Sheila Ganti ₂ , Kaitlyn Zenner ₁ , Chi Vicky Cheng ₃ , Dana M Jensen ₄ , Minh-Hang M Pham ₃ , Ryan M Mitchell ₅ , William Dobyns ₃ , Randall A Bly ₁ , James T Bennett ₆ , John P Dahl ₁ , Jonathan A Perkins ₇

Affiliation

Division of Pediatric Otolaryngology, Seattle Children's Hospital, Seattle, WA, USA; Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA, USA.
Division of Pediatric Otolaryngology, Seattle Children's Hospital, Seattle, WA, USA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA, USA.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
Division of Pediatric Otolaryngology, Seattle Children's Hospital, Seattle, WA, USA; Department of Otolaryngology-Head and Neck Surgery, Indiana University, Indianapolis, IN, USA.
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA; Division of Genetic Medicine, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
Division of Pediatric Otolaryngology, Seattle Children's Hospital, Seattle, WA, USA; Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA, USA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA, USA.

Objectives

Head and neck lymphatic malformations (HNLM) are caused by gain-of-function somatic mutations in PIK3CA. Acetylsalicylic acid (ASA/aspirin) is thought to limit growth in PIK3CA-mutated neoplasms through PI3K pathway suppression. We sought to determine if ASA could be beneficial for HNLM.

Methods

Retrospective case series of patients (0–18 years) offered ASA (3–5 mg/kg/day) for HNLM treatment (2010–2018). Clinical and treatment characteristics, patient-reported symptom improvement, medication tolerance, compliance, and complications were recorded. Treatment response was determined by change in patient/caregiver-reported symptoms, or HNLM size [complete (resolved), partial (decreased), or stable].

Results

Fifty-three patients were offered ASA, 23 (43%) accepted (median age 10 years, IQR 6–14). Compared to patients who declined, patients receiving ASA were more likely to have extensive malformations: ex-utero intrapartum treatment procedure, bilateral malformations, oral cavity location, ≥2 invasive treatments, or tracheotomy (p < 0.05). All patients with tissue available had PIK3CA mutations (13/23). Treatment indications included oral pain/blebs (12, 52%), recurrent pain/swelling (6, 26%), or sudden/persistent swelling (5, 22%). Treatment plan was commonly one 81 mg tablet daily (19, 83%) for 3–12 months (8, 42%). Therapeutic adherence was reported by 18 patients (78%). Symptoms improved in 18 patients [78%; decreased pain (9, 39%) and swelling (8, 35%)]. Treatment resulted in partial (14, 61%) or complete response (4, 17%). Three patients developed oral bleb bleeding, which resolved with medication discontinuation.

Conclusion

ASA seems to be a well-tolerated, low-risk medication for HNLM treatment. This pilot study suggests that it often improves symptoms and reduces HNLM size. Further prospective, randomized studies are warranted to comprehensively assess indications, safety, and efficacy.

Level of evidence

Level 4.

中文翻译：

乙酰水杨酸抑制 PI3K 通路作为治疗头颈部淋巴管畸形的新药物

目标

头颈部淋巴管畸形 (HNLM) 是由PIK3CA中的功能获得性体细胞突变引起的。乙酰水杨酸（ASA/阿司匹林）被认为通过 PI3K 通路抑制来限制PIK3CA突变肿瘤的生长。我们试图确定 ASA 是否对 HNLM 有益。

方法

回顾性病例系列患者（0-18 岁）提供 ASA（3-5 mg/kg/天）用于 HNLM 治疗（2010-2018 年）。记录临床和治疗特征、患者报告的症状改善、药物耐受性、依从性和并发症。治疗反应由患者/护理人员报告的症状或 HNLM 大小的变化确定[完全（解决）、部分（减少）或稳定]。

结果

53 名患者接受了 ASA，其中 23 名（43%）被接受（中位年龄 10 岁，IQR 6-14）。与下降的患者相比，接受 ASA 的患者更容易出现广泛畸形：宫外产时治疗程序、双侧畸形、口腔定位、≥2 次侵入性治疗或气管切开术（p < 0.05）。所有有可用组织的患者都有PIK3CA突变（13/23）。治疗适应症包括口腔疼痛/起泡 (12, 52%)、反复疼痛/肿胀 (6, 26%) 或突然/持续性肿胀 (5, 22%)。治疗计划通常是每天一片 81 mg 片剂 (19, 83%)，持续 3-12 个月 (8, 42%)。18 名患者（78%）报告了治疗依从性。18 名患者的症状得到改善 [78%; 减轻疼痛 (9, 39%) 和肿胀 (8, 35%)]。治疗导致部分（14, 61%）或完全缓解（4, 17%）。三名患者出现口腔疱疹出血，停药后缓解。