Browsing by Subject "sirolimus"

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  • Holm, Annegret; te Loo, Maroeska; Schultze Kool, Leo; Salminen, Päivi; Celis, Veronica; Baselga, Eulalia; Duignan, Sophie; Dvorakova, Veronika; Irvine, Alan D.; Boon, Laurence M.; Vikkula, Miikka; Ghaffarpour, Nader; Niemeyer, Charlotte M.; Rössler, Jochen; Kapp, Friedrich G. (2021)
    Extensive lymphatic malformations (LMs) of the head and neck region may require tracheostomy to secure the airway. Treatment of these life-threatening LMs is usually multimodal and includes sclerotherapy and surgery, among others. Recently, systemic therapy with sirolimus has been introduced as an effective treatment for venous and lymphatic malformations; its efficacy and safety profile in patients with extensive LM requiring tracheostomy are, however, as yet not fully known. We performed a retrospective, multicenter review and identified 13 patients with an extensive LM of the head and neck region, who previously underwent placement of tracheostomy and subsequently received sirolimus treatment with the aim to improve the local respiratory situation and remove the tracheostomy. Under sirolimus therapy, tracheostomy could be reversed in 8/13 (62%) patients, a further 2/13 (15%) patients improved markedly, and removal of the tracheostomy was planned at the time of writing, while 3/13 (23%) patients showed insufficient or absent response to sirolimus, rendering tracheostomy reversal not feasible. The median duration of sirolimus treatment until removal of tracheostomy was 18 months (range, 8 months to 5.6 years). Adverse events of sirolimus therapy were common [10/13 (77%) patients], yet the majority of these were mild [9/10 (90%) patients] and only one severe adverse event was recorded, with ulceration and necrosis at a catheter insertion site. In conclusion, sirolimus can be considered an effective and safe salvage treatment in patients with extensive LM even after placement of a tracheostomy, as closure of the latter was possible in the majority of patients (62%) of our retrospective cohort. A better understanding of when to start sirolimus therapy, of the duration of treatment, and of factors allowing the prediction of treatment response will require further investigation.
  • Tesch, Victoria Katharina; Abolhassani, Hassan; Shadur, Bella; Zobel, Joachim; Mareika, Yuliya; Sharapova, Svetlana; Karakoc-Aydiner, Elif; Rivière, Jacques G.; Garcia-Prat, Marina; Moes, Nicolette; Haerynck, Filomeen; Gonzales-Granado, Luis I.; Santos Pérez, Juan Luis; Mukhina, Anna; Shcherbina, Anna; Aghamohammadi, Asghar; Hammarström, Lennart; Dogu, Figen; Haskologlu, Sule; İkincioğulları, Aydan İ.; Köstel Bal, Sevgi; Baris, Safa; Kilic, Sara Sebnem; Karaca, Neslihan Edeer; Kutukculer, Necil; Girschick, Hermann; Kolios, Antonios; Keles, Sevgi; Uygun, Vedat; Stepensky, Polina; Worth, Austen; van Montfrans, Joris M.; Peters, Anke M.J.; Meyts, Isabelle; Adeli, Mehdi; Marzollo, Antonio; Padem, Nurcicek; Khojah, Amer M.; Chavoshzadeh, Zahra; Avbelj Stefanija, Magdalena; Bakhtiar, Shahrzad; Florkin, Benoit; Meeths, Marie; Gamez, Laura; Grimbacher, Bodo; Seppänen, Mikko R.J.; Lankester, Arjan; Gennery, Andrew R.; Seidel, Markus G. (2020)
    Background Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. Objective This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. Method We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. Results Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. Conclusion The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.
  • Mäkinen, Taija; Boon, Laurence M.; Vikkula, Miikka; Alitalo, Kari (2021)
    Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell-autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.