Clapo Syndrome: Effective Response to Treatment With Oral Rapamycin

González-Hermosa, M.R.; Guerra, Eneritz; Limousin, I Tuduri; Vicente, I Deprada; Lopez-Almaraz, R.

doi:10.1111/dth.12991

Cited by 9 publications

(6 citation statements)

References 11 publications

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“…In one study each, 3.5–6 ng/mL [ 30 ], 4–8 ng/mL [ 21 ], 4–10 ng/mL [ 38 ], 4–13 ng/mL [ 36 ], 5–12 ng/mL [ 33 ], 10–12 ng/mL [ 27 ], 10–13 ng/mL [ 19 ] and 12–20 ng/mL [ 35 ] were the target concentrations. Eight studies did not report the target blood level of sirolimus [ 12 , 13 , 15 , 18 , 22 , 29 , 32 , 37 ]. Not in all studies the planned target trough level for sirolimus was achieved [ 14 , 20 ].…”

Section: Resultsmentioning

confidence: 99%

“…Akyüz et al [ 13 ] and Yesil et al [ 17 ] reported a decrease in size of 60% and 70% after 3 months, respectively. Gomez-Sanchez et al [ 34 ] reported a clinical response time from 3.5 to 9 months, Amodeo et al [ 20 ] reported about a response after two months of treatment, while Gonzalez-Hermosa et al [ 29 ] reported 13 months.…”

Section: Resultsmentioning

confidence: 99%

“…Twenty-three studies commented on possible adverse events associated with and probably being a result of sirolimus therapy [ 15 – 17 , 19 – 31 , 33 – 39 ]. In five studies no patients experienced side effects [ 15 , 22 , 29 , 30 , 37 ]. In the other 18 studies, different adverse effects were reported [ 16 , 17 , 19 – 21 , 23 – 28 , 31 , 33 – 36 , 38 , 39 ], the most common were hyperlipidemia, neutropenia and infections such as cellulitis.…”

Section: Resultsmentioning

confidence: 99%

“…Freixo et al [ 46 ] demonstrated for vascular anomalies that 75% of the first clinical response was reported in less than 21 days. In this review, the time to (reported) clinical response varied between 10 days [ 18 ] and 13 months [ 29 ]. However, the time to reach the optimum treatment effect remains unclear.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of sirolimus in children with lymphatic malformations of the head and neck

Wiegand

Dietz

Wichmann

2022

Eur Arch Otorhinolaryngol

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Purpose Children with extensive lymphatic malformations of the head and neck often suffer from functional impairment and aesthetic deformity which significantly affect the quality of life and may be life-threatening. Treatment with sirolimus has the potential to improve symptoms and downsize lymphatic malformations. This systematic review summarizes the current information about sirolimus treatment of lymphatic malformations of the head and neck in children, its efficacy and side effects. Methods A systematic search of the literature regarding studies on sirolimus treatment of children with lymphatic malformations of the head and neck was performed in PubMed, Embase, and Google Scholar up to July 2021 with the search terms “lymphatic malformation”, “lymphangioma”, “cystic hygroma”, “low-flow malformation”, “sirolimus”, “rapamycin”, “mTOR inhibitor” and “children”. Results In all, 28 studies including 105 children from newborn to 17 years treated with sirolimus for lymphatic malformations of the head and neck were analyzed. The most frequent initial dose was 0.8 mg/m2 per dose, twice daily at 12-h interval. The target blood level differed between studies, 10–15 ng/mL and 5–15 ng/mL were most often used. More than 91% of the children responded to sirolimus treatment which lasts from 6 months to 4 years. Typical side effects were hyperlipidemia, neutropenia and infections. Methods Sirolimus could be an effective treatment for children with large complicated lymphatic malformations of the head and neck. As not all patients will benefit from treatment, the decision to treat sirolimus should be made by a multidisciplinary team.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Efficacy of sirolimus in children with lymphatic malformations of the head and neck

Wiegand

Dietz

Wichmann

2022

Eur Arch Otorhinolaryngol

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“…Over the past decade, molecular classification of PROS has paved the way to several novel targeted treatment options derived from oncology57 including direct PIK3CA inhibitors,58 59 such as the alpha-specific Alpelisib (BYL719) recently used in a compassionate access scheme in PROS 26 60 61. Also drugs reducing oversignalling through the PI3K pathway have been successfully employed in PROS or related/overlapping conditions, such as miransertib (ARQ092), an oral, allosteric pan-AKT inhibitor62–66 or rapamycin, the first identified mTOR inhibitor 24 67–73…”

Section: Discussionmentioning

confidence: 99%

Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants

et al. 2022

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BackgroundPostzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture.MethodsWe performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ, GNA11, RASA1 and TEK. Additionally, 914 patients previously reported were systematically reviewed.Results93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ, GNA11, RASA1 or TEK.ConclusionWe confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping ‘vascular’ phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA.

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Sirolimus treatment for paediatric head and neck lymphatic malformations: a systematic review

Saibene

Rosso

Felisati

et al. 2023

Eur Arch Otorhinolaryngol

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Purpose This PRISMA-compliant systematic review aimed to assess risks and benefits of sirolimus treatment for paediatric lymphatic malformations by focusing not only on treatment efficacy but also on possible treatment-related adverse events, and treatment combinations with other techniques. Methods Search criteria were applied to MEDLINE, Embase, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov databases and included all studies published up to March 2022 reporting paediatric lymphatic malformations treated with sirolimus. We selected all original studies that included treatment outcomes. After the removal of duplicates, selection of abstracts and full-text articles, and quality assessment, we reviewed eligible articles for patient demographics, lymphatic malformation type, size or stage, site, clinical response rates, sirolimus administration route and dose, related adverse events, follow-up time, and concurrent treatments. Results Among 153 unique citations, 19 studies were considered eligible, with reported treatment data for 97 paediatric patients. Most studies (n = 9) were case reports. Clinical response was described for 89 patients, in whom 94 mild-to-moderate adverse events were reported. The most frequently administered treatment regimen was oral sirolimus 0.8 mg/m2 twice a day, with the aim of achieving a blood concentration of 10–15 ng/mL. Conclusion Despite promising results for sirolimus treatment in lymphatic malformation, the efficacy and safety profile of remains unclear due to the lack of high-quality studies. Systematic reporting of known side effects, especially in younger children, should assist clinicians in minimising treatment-associated risks. At the same time, we advocate for prospective multicentre studies with minimum reporting standards to facilitate improved candidate selection.

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Clapo Syndrome: Effective Response to Treatment With Oral Rapamycin

Cited by 9 publications

References 11 publications

Efficacy of sirolimus in children with lymphatic malformations of the head and neck

Efficacy of sirolimus in children with lymphatic malformations of the head and neck

Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants

Sirolimus treatment for paediatric head and neck lymphatic malformations: a systematic review

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