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Hemangiomas and vascular malformations
Published in Prem Puri, Newborn Surgery, 2017
Belinda Hsi Dickie, Arin K. Greene, Steven J. Fishman
CLOVE syndrome is an overgrowth condition associated with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi in a very distinct phenotype. This cohort of patients has characteristic features of truncal lipomatous overgrowth in combination with vascular anomalies, including capillary, lymphatic, venous, and arteriovenous. In addition, deformities of the extremities include wide feet and hands, macrodactyly, and a wide sandal gap. Scoliosis and renal issues are also seen, with a potential increase risk in the development of Wilms’ tumors.98 Genetic analysis of these patients demonstrates a somatic mutation in the PI3 kinase pathway.99
CLOVES Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
CLOVES syndrome is a severe overgrowth disorder that typically demonstrates following clinical features [18,19]: Overgrowth: Asymmetric lipomatous overgrowth (typically truncal, complex, congenital, progressive); spinal-paraspinal extension; limb/digital overgrowth; bony overgrowth, leg-length discrepancy (Figure 88.2) [20]Cutaneous/vascular malformations: Low-flow (capillary, venous, lymphatic; typically overlying truncal overgrowth); high-flow (arteriovenous; esp. spinal-paraspinal); venous thrombosis/embolism; epidermal nevi (single/multiple)Musculoskeletal/acral abnormalities: Scoliosis; chondromalacia patellae; dislocated knees; macrodactyly (enlargement of all tissues localized to the terminal portions of a limb, typically within a nerve territory), wide hands/feet; sandal gap toes; symmetric overgrowth feet; plantar-palmar overgrowthVisceral abnormalities: Renal agenesis/hypoplasia; splenic lesionsNeurologic abnormalities: Neural tube defect; tethered cord; megalencephaly/hemimegalencephaly; Chiari malformation; polymicrogyriaTumors: Chorangioma, extradural spinal tumor, hemangioma, and multiple angiomatosis
Alpelisib for the treatment of PIK3CA-mutated, hormone receptor-positive, HER2-negative metastatic breast cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Fanny Leenhardt, Marie Alexandre, William Jacot
On 24 May 2019, alpelisib was approved by the United States FDA in combination with fulvestrant for the treatment of postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic BC as detected by an FDA-approved test following progression on or after an endocrine-based regimen. The European Medicines Agency (EMA) approved alpelisib on 27 July 2020, in combination with fulvestrant for the treatment of postmenopausal women, and men, with HR-positive, HER2-negative, locally advanced or metastatic BC with a PIK3CA mutation after disease progression following endocrine therapy as monotherapy. In Europe, alpelisib is also available for CLOVES syndrome under a temporary use authorization.
Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Dima A. Sabbah, Rima Hajjo, Sanaa K. Bardaweel, Haizhen A. Zhong
Dactolisib (or BEZ235) (47) is a dual PI3K/mTOR inhibitor and is under clinical investigation for use in hematological malignancies (NCT01756118) [124]. A recent patent shows that improved efficacy was observed in the combination therapy of dactolisib (47) with anti-CD19 antibody drug conjugate (ADC) [125]. A recent patent reports the combination therapy of serabelisib (10) with metformin, or GDC-0077 with an ER antagonist fulvestrant, or GDC-0077 with non-steroidal aromatase inhibitor letrozole has been registered in clinical trials with enrolling patients with locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast cancer [126]. A combination of GDC-0077 with fulvestrant, or with CDK4 inhibitor palbociclib was reported in a recent patent [127]. Omipalisib (GSK2126458), dactolisib (or BEZ235) (47), and alpelisib (BYL719, 9) are reported to treat squamous cell carcinoma (SCC) in various cell lines with different PIK3CA mutants, including the commonly observed H1047R and E542K mutants [128]. In a phase III clinical trial, taselisib (11), a potent, selective PI3K inhibitor, combined with standard hormone therapy fulvestrant (Faslodex) arrested the growth of advanced breast cancer by 2 months longer than hormone therapy alone (NCT02340221) [76]. Taselisib (11) was shown in a patent to inhibit HCC1954 breast cancer cells that contains PIK3CA H1047R mutant at 0.18 µM concentration [129]. In GY008 study, copanlisib (3) mono-treatment demonstrated limited activity in patients with persistent or recurrent endometrial cancer harboring hotspot PIK3CA mutations [130]. In addition, in an open-label phase 1/2 trial, combination of copanlisib and gemcitabine appears to be a safe and effective treatment strategy in relapsed/refractory peripheral T-cell lymphomas (PTCLs) [131]. A patent shows that the combination of copanlisib (3) with triazolone derivatives led to a significantly reduced tumor volume in diffuse large B-cell lymphoma (TMD8) xenograft model [132]. Isoindolone II (48) was shown to inhibit PI3Kδ and PI3Kγ with IC50 values of 0.7 and 0.9 nM, respectively [133]. ARQ 092 blocks AKP phosphorylation and activation of neutrophils and platelets isolated from sickle cell disease mice ex vivo [134]. A robust efficacy was observed in alpelisib (9)-treated patients with PIK3CA-related overgrowth spectrum (PROS-CLOVES syndrome) [135]. A combination of alpelisib and B-RAF inhibitor dabrafenib was used to treat various types of lymphoma and leukemia [136]. Addition of PDK1 inhibitors such as GSK2334470 and BX-795 to alpelisib treatment was reported to sensitize alpelisib-resistant cells [137]. The combination of buparlisib (NVP-BKM 120) (1) with the WNT pathway inhibitor (WNT974) significantly reduced tumor size [138]. A combination treatment of pictilisib (GDC-0941) with ERK inhibitor shows synergistic effect [139].