RESEARCH

This page is dedicated to research that has been undertaken in to PROS.

Explanations of PROS:

Research papers in to PROS (PIK Related Overgrowth Spectrum)

Drug Trials for PROS (PIK Related Overgrowth Spectrum)

  • The various cells in our bodies usually follow a particular lifespan, this is the same for the growth gene PIK3CA. A normal cell will undergo a rapid death should anything become altered or damaged.
  • However, if through mutation this PIK3CA gene does not die or “switch off” they become known as “oncogenes.”
  • This means that the gene has the potential to cause cancer & tumour progression. however, this does not seem to be common place in PROS patients.
  • This link to cancer has led to an increase in research to find potential (non-invasive) treatment for cancer patients, but which could also benefit PROS patients.

2016: Cancer drug could treat blood vessel deformities

  • Conclusion of the study suggests that “Rapamycin is a drug that blocks a signalling process that happens downstream of PIK3CA, so it stops one of PIK3CA’s effects but does not block it at source,” explains lead author Dr Sandra Castillo (UCL Cancer Institute). “When we gave rapamycin to the mice, it showed clinical benefit, but in patients it can have serious side-effects and compromise the immune system”.

2017: ArQule Announces First Patient Dosed in Company Sponsored Phase 1/2 Trial of AKT Inhibitor, ARQ 092, for Rare Overgrowth Diseases

  • ArQule announced that the first patient has been dosed in a company sponsored phase 1/2 trial with its AKT inhibitor, ARQ 092, in patients with Overgrowth Diseases driven by genetic alterations of the PI3K/AKT1 pathway. ARQ 092 is an orally available, selective pan-AKT inhibitor.

2017: Study of ARQ 092 in Subjects With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome (MOSAIC)

  • Details of the study: “this is an open label, Phase 1/2 study of oral ARQ 092 (Miransertib) administered to subjects at least 2 years of age with PIK3CA-related Overgrowth Spectrum (PROS) and Proteus syndrome (PS) (MOSAIC)”.

2017/2018: Severe PI3Kinase Overgrowth Syndrome Treated with the AKT Inhibitor Miransertib

  • Results indicated as follows: “calculated volumes of fatty overgrowth declined by approximately 15% on treatment. The patient has now completed 25 months of therapy with clinically stable disease and clear radiological improvement. Miransertib was well tolerated with no significant toxicities other than hyperlipidaemia comparable to lipid profile derangement previously noted on sirolimus therapy”.

2017: Trial of Taselisib in Overgrowth (TOTEM)

  • “Taselisib is a selective inhibitor of class I PI3Ks and has direct inhibitory activity of the p110α isoform with a Kiapp value of 0.29 nmol/l”. Unfortunately the trial was: “Terminated (In accordance with the protocol, following the occurrence of two SUSARs, the TOTEM trial was stopped early for safety reasons.)”

2018: In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS)

  • Results from the trial suggest: “we demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.”
 
  • Results showed: “BYL719 was used to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
  • Results from this study offer the following thoughts: “This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS.”
  • As a side note, I (Mandy Sellars) began taking Rapamycin a number of years ago with amazing results. Along with a combination of exercise & healthy eating, my overgrowth stopped & began to shrink. I lost around 4/5 stone in weight from my affected areas. Unfortunately my body became tolerant of the dosage I was taking & it was recommended not to increase the dose. Therefore, sadly I had to stop taking the medication & my overgrowth started to increase again.
  • An overview of research in the UK from Professor R Semple.

2019: Managed Access Program (MAP) to Provide Alpelisib (BYL719) for Patients With PIK3CA-Related Overgrowth Spectrum (PROS)

    • The purpose of the study is “to allow access to alpelisib for patients diagnosed with PIK3CA-Related Overgrowth Spectrum (PROS) who fulfill certain eligibility criteria as specified in this document. The patient’s Treating Physician should follow the suggested treatment guidelines and comply with all local health authority regulations.”
    • To reiterate, this drug is available on “compassionate use” only. Please speak to your specialist/consultant who will hopefully be able to help you with this.
    • You can also contact Novartis for more information: mailto:novartis.email@novartis.com

2020: Retrospective Chart Review Study of Patients With PIK3CA-Related Overgrowth Spectrum Who Have Received Alpelisib (EPIK-P1)

  • This retrospective study aims to determine the effectiveness & safety of the drug Alpelisib. This was administered to patients through the “compassionate use” scheme for the treatment of PROS (PIK Related Overgrowth Spectrum)
  • Results of this study should be available July/August 2020. Should the results be favourable, this could hopefully lead to medical trials of Alpelisib for PROS patients.

2020: https://www.sciencedirect.com/science/article/pii/S0006291X2030886X

  • PIK3CA-related overgrowth spectrum is characterized by increased cell proliferation.
  • Strong activation of HSF1 is found in PIK3CA-related overgrowth spectrum fibroblasts.
  • AKT inhibitors reduces HSF1 activation and HSF1-dependent gene transcription.
  • HSF1 inhibition blocks the PIK3CA-related overgrowth spectrum proliferation.
  • As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target.

2020: Novartis receives Piqray approval in Europe – the first and only targeted medicine for HR+/HER2- advanced breast cancer with a PIK3CA mutation

  • Piqray (alpelisib) is the only treatment approved specifically to address PIK3CA mutation
  • This is very promising for those living with a PIK3CA mutation that is causes overgrowth, trials are in the pipeline.

2020: https://www.fiercepharma.com/pharma/esmo-novartis-posts-long-awaited-survival-data-for-breast-cancer-blockbuster-hopeful-piqray

  • Novartis has an ambitious development plan for the drug going forward. It’s preparing to file for approval in patients with a rare disorder called PIK3CA overgrowth syndrome.

2020: https://clinicaltrials.gov/ct2/show/NCT04409145

  • VT30-101 is a 2-part first-in-human trial of topically administered VT30 to subjects with cutaneous venous malformations, lymphatic malformations, or mixed venolymphatic malformations associated with PIK3CA or TEK mutations.
  • VT30 is a PI3K-inhibitor prodrug, formulated as a topical gel and dispensed from a metered dose pump; administration is once or twice daily, applied to target-treatment area(s) on the skin.

2020: https://clinicaltrials.gov/ct2/show/NCT04589650?cond=PIK3CA+Related+Overgrowth+Spectrum&draw=2&rank=2

  • This is a prospective Phase II multi-center study with an upfront 16-week, randomized, double-blind, placebo-controlled period, and extension periods, to assess the efficacy, safety and pharmacokinetics of alpelisib in pediatric and adult participants with PIK3CA-related overgrowth spectrum (PROS).
  • Study start date: February 2, 2021
  • For further information: mailto:novartis.email@novartis.com

2020: What is Apelisib

2020: Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth

  • We suspect that it is likely that the overall risk falls below 1%
  • There is a clear need for further publication of known cases and collaboration among institutions, so the denominator of patients with PROS can be further adjusted to understand true WT risk in this population.
  • In terms of current recommendations, tumor screening should be performed at the discretion of the provider based on the genetic change and clinical features of the PROS presentation, as well as the family perspective.

2021: https://link.springer.com/article/10.1007/s00109-020-02030-6#Fig1

  • Recently, this drug was used by us for one such case, that of a 29-year-old Canadian woman, and led to a spectacular response.
  • During the last years, moreover, ~ 60 patients were treated for PROS with this drug under the care of Dr. Guillaume Canaud at Necker–Enfants Malades Hospital, and all have experienced regression over their overgrowths.

2021: https://comptes-rendus.academie-sciences.fr/biologies/articles/10.5802/crbiol.50/

  • PIK3CA-related overgrowth spectrum: animal model and drug discovery
  • This review recapitulates the recent knowledge accumulation on overgrowth syndrome related to gain of function of the phosphoinositide3 kinase (PI3K)-alpha. These disorders, known as PIK3CA related overgrowth syndromes (PROS) are caused by somatic PIK3CA mutation occurring during embryogenesis. We summarize here the currently available animal models and new treatments undergoing development.

2021: https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01929-8

  • A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations.

  • PIK3CA-related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result in activation of the PI3K/AKT/mTOR signaling pathway. The goals of this review are to provide education on the underlying mechanism of disease for this group of rare conditions and to summarize recent advancements in the understanding of, as well as current and emerging treatment options for PIK3CA-related disorders.
  • Management of patients with PIK3CA-related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.

2021: A standard of care for individuals with PIK3CA-related disorders: an international expert consensus statement

  • Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019, macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.

2021: Novartis announces findings from a real-world study of alpelisib

  • Novartis announces findings from a real-world study of alpelisib demonstrating clinical benefit in people with PIK3CA-Related Overgrowth Spectrum (PROS)

  • PROS is a spectrum of rare disorders caused by PIK3CA mutations and is characterized by atypical, visible overgrowths and anomalies in blood vessels, the lymphatic system and other tissues.
  • At 24 weeks, 38% of patients achieved ≥20% reduction in the volume of the PROS lesions assessed in the primary endpoint analysis; no patients experienced disease progression or death.
  • Alpelisib is the first potential treatment to specifically address the root cause of PROS conditions.

2021: https://www.science.org/doi/10.1126/scitranslmed.abg0809#.YV54vSeHixo.twitter

  • Gain-of-function mutations in the PIK3CA gene cause lymphatic malformations (LMs), genetic disorders characterized by vascular abnormalities causing pain, inflammation, and deformities. To identify potential treatments able to prevent LMs, Delestre et al. developed a genetic mouse model that recapitulates the main features of LMs and showed that the approved drug PIK3CA inhibitor alpelisib, used in oncology, prevented LMs, and increased survival. Alpelisib administration in six patients refractory to previous pharmacological or surgical approaches improved symptoms and reduced the volume of LMs. Although two patients developed adverse events potentially related to the treatment, the results suggest that inhibiting PIK3CA could be effective in treating LMs.

2021: Alpelisib to treat CLOVES syndrome, a member of the PIK3CA-related overgrowth syndrome spectrum

  • ***This is a preprint and has not been peer reviewed. Data may be preliminary.***
  • CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA-related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. Its favorable results in these settings suggest that its compassionate use in patients with PROS disorders could have clinical benefits. Another promising drug is Alpelisib, which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signaling pathway. A low dose of Alpelisib used on compassionate grounds was shown in an uncontrolled case series to have striking effects in a cohort of 19 PROS patients, several with life-threatening complications. Moreover, the low dose of Alpelisib provoked few side effects and did not impair linear growth of the often young patients. We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with Alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggest that there may even be collateral benefits of low-dose PI3K inhibition beyond mitigating disease-specific features of PROS.

2021:  Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype

  • A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110α. Preclinical studies have suggested that the PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence for such a correlation has been demonstrated in human tumors. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K/AKT/mTOR signaling scores and stemness scores. Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a “biphasic” relationship of mutant PIK3CA allele dosage with these scores. Relative to tumor samples without PIK3CA mutations, the presence of a single copy of a hotspot PIK3CA variant was associated with lower PI3K/AKT/mTOR signaling and stemness scores, whereas the presence of multiple copies of PIK3CA hotspot mutations correlated with higher PI3K/AKT/mTOR signaling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygous PIK3CAH1047R expression. Collectively, our analysis (1) provides evidence for a signaling strength-dependent PI3K-stemness relationship in human breast cancer; (2) supports evaluation of the potential benefit of patient stratification based on a combination of conventional PI3K pathway genetic information with transcriptomic indices of PI3K signaling activation.

2022:  Treatment of two infants with PIK3CA-relatedovergrowth spectrum by alpelisib.

  • PIK3CA-related overgrowth spectrum (PROS) includes rare genetic conditions due to gain-of-function mutations in the PIK3CA
    There is no approved medical therapy for patients with PROS, and alpelisib, an approved PIK3CA inhibitor in oncology,
    showed promising results in preclinical models and in patients. Here, we report for the first time the outcome of two infants
    with PROS having life-threatening conditions treated with alpelisib (25 mg) and monitored with pharmacokinetics. Patient
    1 was an 8-mo-old girl with voluminous vascular malformation. Patient 2 was a 9-mo-old boy presenting with asymmetrical
    body overgrowth and right hemimegalencephaly with West syndrome. After 12 mo of follow-up, alpelisib treatment was
    associated with improvement in signs and symptoms, morphological lesions and vascular anomalies in the two patients. No
    adverse events were reported during the study. In this case series, pharmacological inhibition of PIK3CA with low-dose alpelisib
    was feasible and associated with clinical improvements, including a smaller size of associated complex tissue malformations
    and good tolerability.

2022: PIK3CA mutation correlates with mTOR pathway expression but not clinical and pathological features in Fibfibroipose vascular anomaly (FAVA)

  • There was no significant association between the presence of PIK3CA mutations and the clinicopathological features of FAVA, suggesting that the PIK3CA gene is not necessarily involved in the onset of FAVA. FAVAs lacking PIK3CA mutations may be caused by other gene mutations that activate 4EBP1 and S6K1.

2022: 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

  • We 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.

2022: Alpelisib to treat CLOVES syndrome, a member of the PIK3CA-related overgrowth syndrome spectrum

  • CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA-related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. The results have been promising and suggest that compassionate use of these treatments in patients with PROS disorders could have clinical benefits. Another promising drug is alpelisib (BYL719), which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signalling pathway. Compassionate use of low-dose alpelisib had striking effects in an uncontrolled case series of 19 PROS patients, several with life-threatening complications. Moreover, there were few adverse effects and the treatment did not impair linear growth, despite the young age of many of the patients. We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggests that low-dose PI3K inhibition may provide collateral benefits that extend beyond mitigation of disease-specific features of PROS.

2022: FDA approves Novartis Vijoice® (alpelisib) as first and only treatment for select patients with PIK3CA-Related Overgrowth Spectrum (PROS)

  • Vijoice is first approved treatment to specifically address the root cause of PROS conditions in select patients 2 years of age and older1
  • PROS is a spectrum of rare conditions and is characterized by atypical overgrowths and anomalies in blood vessels, the lymphatic system and other tissues2,3  

  • Approval based on real-world data from EPIK-P1 study, which showed patients treated with Vijoice experienced reduction in the size of PROS lesions and improvement of PROS-related signs and symptoms
  • Novartis to offer robust patient support program that includes assistance to access medication, financial resources for eligible patients and continued education

2022: Sexual Function and Fertility in Males With Vascular Malformations of the Genitourinary Tract and Pelvis

  • Males with VM involving or not involving the GU system may experience problems with sexual function and satisfaction. While prospective studies are needed to clarify the prevalence and extent of these symptoms, providers should be aware that such symptoms can occur in this patient population.

2022: Clinical Response to PI3K-α Inhibition in a Cohort of Children and Adults With PIK3CA-Related Overgrowth Spectrum Disorders

Objective:

The goal of this report is to describe, through a series of 5 cases, the clinical response and safety of alpelisib (BYL719) use in children and adults with PIK3CA-related overgrowth spectrum (PROS) disorders at our center.

Methods:

We reviewed clinical records of 5 patients from October 2019 through September 2021 followed by the pediatric hematology and multidisciplinary vascular anomalies teams at the Monroe Carell Jr. Children’s Hospital at Vanderbilt (MCJCHV). All patients carried a clinical or genetic diagnosis of PROS and were treated with alpelisib provided by a Novartis managed access program.

Results:

We highlight improvement in reported symptoms, objective overgrowth measurements, and quality of life to varying degrees in all patients. We note dose-dependent hyperglycemia and gastrointestinal side effects in 2 of the 5 patients. No patients experienced any serious side effects.

Conclusion:

This case series reports on the real-world use of PI3K-α inhibition in the management of PROS. Ongoing clinical trials will provide efficacy and safety data as these drugs become more widely used in patients with vascular anomalies and syndromes secondary to somatic PIK3CA mutations.

2022: At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy

  • Numerous agents targeting various phosphatidylinositol 3-kinase (PI3K) pathway components, including PI3K, AKT and mTOR, have been tested in oncology clinical trials, resulting in regulatory approvals for the treatment of selected patients with breast cancer, certain other solid tumours or particular haematological malignancies. However, given the prominence of PI3K signalling in cancer and the crucial role of this pathway in linking cancer growth with metabolism, these clinical results could arguably be improved upon. In this Review, we discuss past and present efforts to overcome the somewhat limited clinical efficacy of PI3Kα pathway inhibitors, including optimization of inhibitor specificity, patient selection and biomarkers across cancer types, with a focus on breast cancer, as well as identification and abrogation of signalling-related and metabolic mechanisms of resistance, and interventions to improve management of prohibitive adverse events. We highlight the advantages and limitations of laboratory-based model systems used to study the PI3K pathway, and propose technologies and experimental inquiries to guide the future clinical deployment of PI3K pathway inhibitors in the treatment of cancer.

2022: Alpelisib to Treat PIK3CA-Related Overgrowth Syndrome (PROS)

  • Video from Guillaume Canaud, MD, PhD, of the Paris Descartes University, describes the clinical studies that led to the approval of alpelisib to treat persons with PiK3CA-related overgrowth syndrome (PROS).

2022: Mapping the PIK3CA-related overgrowth spectrum (PROS) patient and caregiver journey using a patient-centered approach

  • PROS disorders are driven by somatic, gain-of-function mutations in PIK3CA that result in hyperactivation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway. PROS encompasses a broad spectrum of overlapping phenotypes (including overgrowth and vascular malformations) that vary significantly in their severity; every case is unique, leading to different, complex experiences. Here, we aim to describe the PROS experience from the patients’ and caregivers’ points of view, from onset to diagnosis to treatment and support.

2022: PIK3CA-related overgrowth with an uncommon phenotype: case report

  • Megalencephaly-capillary malformation syndrome is a rare multiple-malformation syndrome secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway. This is included in a heterogeneous group of disorders, now defined “PIK3CA-related overgrowth spectrum”.

2022: Treating Alpelisib-Induced Hyperglycemia with Very Low Carbohydrate Diets and Sodium-Glucose Co-Transporter 2 Inhibitors: A Case Series

  • Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor approved for treatment of postmenopausal women, and men, with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–), PIK3CA-mutated, advanced breast cancer (ABC). Hyperglycemia is a common, on-target adverse effect that impairs treatment efficacy and increases the rate of treatment delays, dose reductions, and discontinuation. Currently, there are no clear guidelines on how to manage hyperglycemia due to alpelisib when metformin is not effective. In this case series, we review 3 subjects with ABC that developed hyperglycemia during alpelisib-fulvestrant therapy and were successfully managed with dietary and pharmacologic interventions. These cases provide anecdotal evidence to support the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and very low carbohydrate diets to minimize hyperglycemia during alpelisib therapy.

2022: 4 questions for professor Guillaume Canaud

2022: Undergrowth Of First Toe In PiK3CA-Related Overgrowth Spectrum (PROS)

  • PIK3CA-related overgrowth syndrome (PROS) include a heterogeneous group of disorders characterized by segmental overgrowth secondary to somatic mosaic activating variants in PIK3CA. Segmental undergrowth is more uncommon and has been less studied but pathogenic variants in PIK3CA have also been found. With this in mind, we have noticed a group of patients with PROS that present an undergrowth component associated with their focal overgrowth.

2022: Vijoice & PIK3CA Related Overgrowth Spectrum (PROS)

2022: When, where and which PIK3CA mutations are pathogenic in congenital disorders

  • PIK3CA encodes the class I PI3Kα isoform and is frequently mutated in cancer. Activating mutations in PIK3CA also cause a range of congenital disorders featuring asymmetric tissue overgrowth, known as the PIK3CA-related overgrowth spectrum (PROS), with frequent vascular involvement. In PROS, PIK3CA mutations arise postzygotically, during embryonic development, leading to a mosaic body pattern distribution resulting in a variety of phenotypic features. A clear skewed pattern of overgrowth favoring some mesoderm-derived and ectoderm-derived tissues is observed but not understood. Here, we summarize our current knowledge of the determinants of PIK3CA-related pathogenesis in PROS, including intrinsic factors such as cell lineage susceptibility and PIK3CA variant bias, and extrinsic factors, which refers to environmental modifiers. We also include a section on PIK3CA-related vascular malformations given that the vasculature is frequently affected in PROS. Increasing our biological understanding of PIK3CA mutations in PROS will contribute toward unraveling the onset and progression of these conditions and ultimately impact on their treatment. Given that PIK3CA mutations are similar in PROS and cancer, deeper insights into one will also inform about the other.

2022: Prime Standard _ _ Vijoice (alpelisib) Prior Authorization with Quantity Limit _ 8/18/2022 _ © Copyright Prime Therapeutics LLC. July 2022 All Rights Reserved Page 1 of 6 Vijoice (alpelisib) Prior Authorization with Quantity Limit

  • Treatment of adult and pediatric patients 2 years of age and older with
    severe manifestations of PIK3CA–Related Overgrowth Spectrum (PROS)
    who require systemic therap

2022: Alpelisib for the treatment of PIK3CA-related head and neck lymphatic malformations and overgrowth

  • Purpose: PIK3CA-related overgrowth spectrum (PROS) conditions of the head and neck are treatment challenges. Traditionally, these conditions require multiple invasive interventions, with incomplete malformation removal, disfigurement, and possible dysfunction. Use of the PI3K inhibitor alpelisib, previously shown to be effective in PROS, has not been reported in PIK3CA-associated head and neck lymphatic malformations (HNLMs) or facial infiltrating lipomatosis (FIL). We describe prospective treatment of 5 children with PIK3CA-associated HNLMs or head and neck FIL with alpelisib monotherapy.

2022: Alpelisib Displays Clinical Benefit in Pediatric PIK3CA-Related Overgrowth Spectrum Disease

  • Alpelisib decreased the need for surgery and led to improvements in performance status and disease-related signs and symptoms in pediatric patients with PIK3CA-related overgrowth spectrum disease who received treatment with the PI3K inhibitor under compassionate use.

2022: Clinical and genetic analyses of patients with lateralized overgrowth

Background

The genetic features and treatment strategies of lateralized overgrowth have been elusive. We performed this study to analyze the genetic characteristics and treatment results of propranolol- or alpelisib-treated patients with lateralized overgrowth.

Methods

Fifteen patients with lateralized overgrowth were involved. Clinical characteristics and whole-body magnetic resonance imaging (WB-MRI) findings were evaluated. Targeted exome sequencing with a gene panel of affected tissue and peripheral white blood cells was performed. Propranolol was administered and treatment results were evaluated. The PIK3CA inhibitor alpelisib was prescribed via a managed access program.

Results

The identified mutations were PIK3CA (n = 7), KRAS (n = 2), PTEN (n = 1), MAP2K3 (n = 1), GNAQ (n = 1), TBC1D4 (n = 1), and TEK (n = 1). Propranolol was prescribed in 12 patients, and 7 experienced mild improvement of symptoms. Alpelisib was prescribed in two patients with a PIK3CA mutation, and the reduction of proliferated masses after 1 year of treatment was proved by WB-MRI.

Conclusions

Targeted exome sequencing identified various genetic features of lateralized overgrowth. Propranolol could be applied as an adjuvant therapy for reducing vascular symptoms, but a PIK3CA inhibitor would be the primary therapeutic strategy for PIK3CA-related overgrowth syndrome.

2022: Clinical and genetic analysis of patients with segmental overgrowth features and somatic mammalian target of rapamycin (mTOR) pathway disruption: Possible novel clinical issues

  • Segmental overgrowth syndromes include a group of clinical entities, all characterized by the abundant proliferation of tissues or organs in association with vascular abnormalities. These syndromes show a wide spectrum of severity ranging from limited involvement of only small areas of the body to complex cases with impressive distortions of multiple tissues and organs. It is now clear that somatic mutations in genes of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (in brief “mTOR pathway”) are responsible for such entities. Not all the cells of the body carry the same causative mutation, which is mosaic, appearing from two (or more) distinct cell lineages after fertilization. In this article, we reconsider the clinical spectrum and surveillance programs of patients with segmental overgrowth syndromes, based on the features of six patients with diverse clinical forms of overgrowth and pathogenic variants in genes of the mTOR pathway.

2022: PIK3CA gain-of-function mutation in adipose tissue induces metabolic reprogramming with Warburg-like effect and severe endocrine disruption

  • PIK3CA-related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of PIK3CA. Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not been elucidated. Here, we created a mouse model of PIK3CA-related adipose tissue overgrowth that recapitulates patient phenotype. We demonstrate that PIK3CA mutation leads to GLUT4 membrane accumulation with a negative feedback loop on insulin secretion, a burst of liver IGFBP1 synthesis with IGF-1 sequestration, and low circulating levels. Mouse phenotype was mainly driven through AKT2. We also observed that PIK3CA mutation induces metabolic reprogramming with Warburg-like effect and protein and lipid synthesis, hallmarks of cancer cells, in vitro, in vivo, and in patients. We lastly show that alpelisib is efficient at preventing and improving PIK3CA-adipose tissue overgrowth and reversing metabolomic anomalies in both animal models and patients.

2023: Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: Impact on symptomatology, quality of life, and radiographic response

  • Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel–Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large-scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM.

2023: Ultrasound-Guided Percutaneous Intercostal Cryoneurolysis for Acute-on-Chronic Pain in CLOVES Syndrome

  • Cryoneurolysis is an analgesic method that has been shown to provide extended pain relief in postoperative patients. However, to date, this method has not been described in nonsurgical inpatients with chronic pain experiencing an acute exacerbation. This analgesic modality has the potential to provide pain relief for patients whose expected duration of severe acute pain would outlast that of other regional anesthetic techniques while avoiding opioid escalation and facilitating discharge.

    We present a patient with acute exacerbation of chronic pain from breast ulcerations caused by congenital lipomatous overgrowth, vascular malformations, epidermal nevis, spinal/skeletal anomalies/scoliosis (CLOVES) syndrome that was successfully treated as an inpatient with a portable cryoneurolysis device.

    This is the first reported use of cryoneurolysis in an inpatient setting to treat acute-on-chronic pain in a nonsurgical patient. The authors recommend regional anesthesiologists and acute pain specialists to utilize this technique to provide analgesia in patients with complex pain to facilitate hospital throughput.

2023: The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations

  • Objective(s): 

    To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations.

    Methods: 

    VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings.

    Results: 

    The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies.

    Conclusion: 

    The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/)

2023: Condition causing big feet is ruining girl’s life
          A young girl’s feet are so big that she is forced to use a wheelchair. But now a new drug has given her hope.
 
 
  • Abstract : Background
  • Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by unilateral facial swelling, for which surgery is the prevailing therapeutic option. Several studies have shown that the development of FIL is closely associated with PIK3CA mutations. This study aimed to further identify rare clinical features and underlying molecular variants in patients with FIL.
  • Results:
  • Eighteen patients were included in this study, and all patients presented with infiltrating adipose tissues confirmed by magnetic resonance imaging. Macrodactyly, polydactyly, hemimegalencephaly and hemihyperplasia were also observed in patients with FIL. In total, eight different PIK3CA mutations were detected in tissues obtained from sixteen patients, including the missense mutations p.His1047Arg (n = 4), p.Cys420Arg (n = 2), p.Glu453Lys (n = 2), p.Glu542Lys (n = 2), p.Glu418Lys (n = 1), p.Glu545Lys (n = 1), and p.His1047Tyr (n = 1) and the deletion mutation p.Glu110del (n = 3). Furthermore, the GNAQ mutation p.Arg183Gln was detected in the epidermal nevus tissue of one patient. Imaging revealed that several patients carrying hotspot mutations had more severe adipose infiltration and skeletal deformities.
  • Conclusions:
  • The abundant clinical presentations and genetic profiles of FIL make it difficult to treat. PIK3CA mutations drive the pathogenesis of FIL, and PIK3CA hotspot mutations may lead to more extensive infiltration of lipomatosis. Understanding the molecular variant profile of FIL will facilitate the application of novel PI3K-targeted inhibitors.

2023: Alpelisib for Treatment of Patients With PIK3CA-Related Overgrowth Spectrum (PROS)

  • Abstract

    PURPOSE

    PROS encompasses several rare conditions resulting from activating variants in PIK3CA. Alpelisib, a PI3Kα-selective inhibitor, targets the underlying etiology of PROS, offering a novel therapeutic approach to current management strategies. This study evaluated the safety and efficacy of alpelisib in pediatric and adult patients with PROS.

    METHODS

    EPIK-P1 (NCT04285723) was a non-interventional, retrospective chart review of 57 patients with PROS (≥2 years) treated with alpelisib through compassionate use. Patients had severe/life-threatening PROS-related conditions and confirmed PIK3CA pathogenic variant. The primary endpoint assessed patient response to treatment at Week 24 (6 months).

    RESULTS

    Twenty-four weeks (6 months) after treatment initiation, 12/32 (37.5%) patients with complete case records included in the analysis of the primary endpoint experienced a ≥20% reduction in target lesion(s) volume. Additional clinical benefit independent from lesion volume reduction was observed across the full study population. Adverse events (AEs) and treatment-related AEs were experienced by 82.5% (47/57) and 38.6% (22/57) of patients, respectively; the most common treatment-related AEs were hyperglycemia (12.3%) and aphthous ulcer (10.5%). No deaths occurred.

    CONCLUSIONS

    EPIK-P1 provides real-world evidence of alpelisib effectiveness and safety in patients with PROS and confirms PI3Kα as a valid therapeutic target for PROS symptom management.

2023: Klippel–Trenaunay Syndrome, Segmental/Focal Overgrowth Malformations: A Review

  • Abstract
    Klippel–Trenaunay syndrome is an uncommon, infrequent, congenital disorder characterized by a triad of capillary malformation, varicosities, and tissue and bone hypertrophy. The presence of two of these three signs is enough to obtain the diagnosis. Capillary malformations are usually present at birth, whereas venous varicosities and limb hypertrophy become more evident later. The syndrome has usually a benign course, but serious complications involving various organs, such as gastrointestinal and genitourinary organs, as well as the central nervous system, may be observed. Recently, Klippel–Trenaunay syndrome has been included in the group of PIK3CA-related overgrowth spectrum (PROS) disorders. In terms of this disorder, new results in etiopathogenesis and in modalities of treatment have been advanced. We report here a review of the recent genetic findings, the main clinical characteristics and related severe complications, differential diagnoses with a similar disorder, and the management of patients with this complex and uncommon syndrome.
     

2023: Targeted next-generation sequencing for detection of PIK3CA mutations in archival tissues from patients with Klippel–Trenaunay syndrome in an Asian population

  • Abstract

        Background

Klippel–Trenaunay syndrome (KTS) is a rare slow-flow combined vascular malformation with limb hypertrophy. KTS is thought to lie on the PIK3CA-related overgrowth spectrum, but reports are limited. PIK3CA encodes p110α, a catalytic subunit of phosphatidylinositol 3-kinase (PI3K) that plays an essential role in the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway. We aimed to demonstrate the clinical utility of targeted next-generation sequencing (NGS) in identifying PIK3CA mosaicism in archival formalin-fixed paraffin-embedded (FFPE) tissues from patients with KTS.

Results

Participants were 9 female and 5 male patients with KTS diagnosed as capillaro-venous malformation (CVM) or capillaro-lymphatico-venous malformation (CLVM). Median age at resection was 14 years (range, 5–57 years). Median archival period before DNA extraction from FFPE tissues was 5.4 years (range, 3–7 years). NGS-based sequencing of PIK3CA achieved an amplicon mean coverage of 119,000x. PIK3CA missense mutations were found in 12 of 14 patients (85.7%; 6/8 CVM and 6/6 CLVM), with 8 patients showing the hotspot variants E542K, E545K, H1047R, and H1047L. The non-hotspot PIK3CA variants C420R, Q546K, and Q546R were identified in 4 patients. Overall, the mean variant allele frequency for identified PIK3CA variants was 6.9% (range, 1.6–17.4%). All patients with geographic capillary malformation, histopathological lymphatic malformation or macrodactyly of the foot had PIK3CA variants. No genotype–phenotype association between hotspot and non-hotspot PIK3CA variants was found. Histologically, the vessels and adipose tissues of the lesions showed phosphorylation of the proteins in the PI3K/AKT/mTOR signaling pathway, including p-AKT, p-mTOR, and p-4EBP1.

Conclusions

The PI3K/AKT/mTOR pathway in mesenchymal tissues was activated in patients with KTS. Amplicon-based targeted NGS could identify low-level mosaicism from low-input DNA extracted from FFPE tissues, potentially providing a diagnostic option for personalized medicine with inhibitors of the PI3K/AKT/mTOR signaling pathway.

2023: Whole mount of adult ear skin as a model to study vascular malformations

  • Abstract

    Background

    Genetic analysis in human patients has linked mutations in PIK3CA, the catalytic subunit of PI-3′Kinase, to sporadic incidences of vascular malformations.

    Methods

    We have developed a mouse model with inducible and endothelial-specific expression of PIK3CAH1047R, resulting in the development of vascular malformations. Systemic induction of this mutation in adult mice results in rapid lethality, limiting our ability to track and study these lesions; therefore, we developed a topical and local induction protocol using the active metabolite of tamoxifen, 4OH-T, on the ear skin of adults.

    Results

    This approach allows us to successfully model the human disease in a mature and established vascular bed and track the development of vascular malformations. To validate the utility of this model, we applied a topical rapamycin ointment, as rapamycin is therapeutically beneficial to patients in clinical trials. We found that the induced ear lesions showed significant attenuation after treatment, which was easily quantified.

    Conclusions

    These data collectively provide evidence of a new model to study vascular malformations in adult tissues, which should be particularly useful in environments lacking specialized small-animal imaging facilities.

2023: Gastrointestinal involvement in Klippel-Trénaunay syndrome: pathophysiology, evaluation, and management

  • Abstract

    Klippel-Trénaunay syndrome is typically a complex combined capillary-lymphatic-venous malformation in lower limb. Gastrointestinal involvement is not infrequent in Klippel-Trénaunay syndrome. Rectal bleeding is the most common complication. In recent years, this condition has been increasingly reported. However, most authors simply described extreme manifestations or various combinations of clinical observations. The underlying pathophysiology of gastrointestinal involvement in Klippel-Trénaunay syndrome has been underrecognized. Pathophysiologically, some seemingly adequate managements are pitfalls in treatment. Anorectosigmoid vascular malformations in KTS have distinct and more complicated pathophysiologies than anorectal vascular malformation. Once understanding the pathophysiology, some patients can be successfully managed with a staged plan in our practice. Therefore, recognizing the pathophysiologies of gastrointestinal involvement is needed to evaluate, prevent pitfalls, and determine adequate managements for practitioners. Because of the complexity and rarity of this condition, prospective controlled study or a large cohort of patients is impossible. Based on literature review and our practice, we discuss pathophysiologies, evaluation, pitfalls, and treatment strategies for gastrointestinal involvement in Klippel-Trénaunay syndrome.

2023: Hemifacial myohyperplasia: a study describes the mechanism of this rare facial malformation and proposes a medicinal treatment

  • Hemifacial myohyperplasia (HFMH) is a rare cause of asymmetry involving exclusively the facial muscles. This disorder is reported in very few patients in the literature. The genetic causes and mechanisms of progression of HFMH have hitherto been unknown.

    To date, its management has been punctuated by diagnostic errors and inadequate strategies, including aggressive attempts at surgical correction (muscle remodelling surgery). The results were always disappointing, with significant sequelae.

    The recent discovery of the role played by somatic mutation of genes activating the PIK3CA/AKT/mTOR pathway has opened up new therapeutic prospects for patients.

    In particular, gain-of-function PIK3CA mutations explain the vast majority of proliferation syndromes.

    Canaud and Khonsari research teams and clinicians hypothesised that the PIK3CA/AKT/mTOR pathway was abnormally affected in patients with HFMH.

    Five patients with HFMH were included in this study.

    A gain-of-function mutation in the PIK3CA gene was found in the facial muscles of these five patients. It resulted in striated muscle cell hypertrophy, mitochondrial dysfunction and hypoglycaemia with low circulating insulin levels.

    To understand the pathophysiology of muscle hypertrophy, Prof Canaud’s research team created a mouse model specifically carrying a PIK3CA mutation in skeletal muscle.

    Treatment with alpelisib, an approved PIK3CA inhibitor, was able to prevent and reduce muscle hypertrophy in the mouse model with correction of the endocrine abnormalities.

    Pr Canaud’s team obtained authorisation to treat the five patients with alpelisib and observed a clear improvement in muscle hypertrophy in all patients, associated with progressive symmetrisation of the face. Response to treatment was assessed and confirmed using innovative imaging methods, including 3D photography and analysis of 2D photographs using artificial intelligence. These morphological approaches were confirmed by cellular and molecular methods which demonstrated that alpelisib had a positive and prolonged action on the effects of the PIK3CA gene mutation.

    These results mean that we finally have a genetic explanation for patients with haemifacial myohyperplasia, an understanding of the mechanisms of the disease and the prospect of an effective therapeutic approach.

2023: Article on Alpelisib

  • Article looks at what is Alpelisib, what is PI3K & PIK3CA, how does Alpelisib work, side effects & more.

2023: Article on PIK3CA by Oliwia Mruk

2023: Low risk of embryonic and other cancers in PIK3CA ‐related overgrowth spectrum: Impact on screening recommendations

  • The PIK3CA ‐related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%–21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long‐term follow‐up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.

2023: PI3K signaling through a biochemical systems lens

  • Following 3 decades of extensive research into PI3K
    signaling, it is now evidently clear that the underlying network
    does not equate to a simple ON/OFF switch. This is best
    illustrated by the multifaceted nature of the many diseases
    associated with aberrant PI3K signaling, including common
    cancers, metabolic disease, and rare developmental disorders.
    However, we are still far from a complete understanding of the
    fundamental control principles that govern the numerous
    phenotypic outputs that are elicited by activation of this well-
    characterized biochemical signaling network, downstream of
    an equally diverse set of extrinsic inputs. At its core, this is a
    question on the role of PI3K signaling in cellular information
    processing and decision making. Here, we review the de-
    terminants of accurate encoding and decoding of growth factor
    signals and discuss outstanding questions in the PI3K signal
    relay network. We emphasize the importance of quantitative
    biochemistry, in close integration with advances in single-cell
    time-resolved signaling measurements and mathematical
    modeling.

2023: New Insight Into Hyperglycemia Risk With PI3K Inhibitor for Breast Cancer

  • Severe hyperglycemia has emerged as a common side effect among patients with PIK3CA-mutated breast cancer treated with the PI3K inhibitor alpelisib (Piqray), especially patients treated outside a clinical trial, a retrospective study showed.

2023: Mutant PIK3CA is a targetable driver alteration in histiocytic neoplasms

  • Activation of PI3K signaling is sufficient to induce a histiocytosis-like disease in vivo at the monocyte/dendritic cell precursors level.

  • The PI3Kα-specific inhibitor alpelisib shows promising clinical efficacy in PIK3CA-mutant Langerhans cell histiocytosis.
Key Points:

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by the accumulation of clonal mononuclear phagocyte system cells expressing CD1a and CD207. In the past decade, molecular profiling of LCH, as well as other histiocytic neoplasms demonstrated that these diseases are driven by MAP kinase (MAPK) activating alterations, with somatic BRAFV600E mutations in >50% of LCH patients, and clinical inhibition of MAPK signaling has demonstrated remarkable clinical efficacy. At the same time, activating alterations in kinase-encoding genes such as PIK3CA, ALK, RET, and CSF1R which can activate mitogenic pathways independent from the MAPK pathway have been reported in a subset of histiocytic neoplasms with anecdotal evidence of successful targeted treatment of histiocytoses harboring driver alterations in RET, ALK, and CSF1R. However, evidence supporting the biological consequences of expression of PIK3CA mutations in hematopoietic cells has been lacking, and whether targeted inhibition of PI3K is clinically efficacious in histiocytic neoplasms is unknown. Here, we provide evidence that activating mutations in PIK3CA can drive histiocytic neoplasms in vivo using a conditional knock-in mouse expressing mutant PIK3CAH1047R in monocyte/dendritic cell progenitors. In parallel, we demonstrate successful treatment of PIK3CA-mutated, multisystemic LCH using alpelisib, an inhibitor of the alpha catalytic subunit of PI3K. Alpelisib demonstrated a tolerable safety profile at a dose of 750mg/week and clinical and metabolic complete remission in a PIK3CA-mutated LCH patient. These data demonstrate PIK3CA as a targetable non-canonical driver of LCH and underscore the importance of mutational analysis-based personalized treatment in histiocytic neoplasms.

2023: Successful Treatment of Hypoglycemia With Alpelisib in Pediatric Patients With PIK3CA-Related Overgrowth Spectrum

  • Activating mutations in the PIK3CA gene, causing phosphoinositide 3-kinase (PI3K) hyperactivation, are rare causes of hypoglycemia. We report the novel use of alpelisib (a PI3K inhibitor) for the treatment of hypoketotic, hypoinsulinemic hypoglycemia in 2 children with PIK3CA-related overgrowth spectrum (PROS). Patient 1 was a 7-month-old girl who presented with a hypoglycemic seizure. Despite nutritional management including continuous feeds, she continued to have frequent hypoglycemia. At age 2.8 years, alpelisib was started at 50 mg daily and titrated to 100 mg daily. She was weaned off nocturnal continuous feeds by 8 months. She developed colitis when the alpelisib dose was increased to 125 mg, but this resolved with a dose decrease and medical management. At age 5.3 years, she was doing well with rare hypoglycemia. Her accelerated growth stabilized. Patient 2 was a 3-year-old boy who developed hypoglycemia in early infancy. Alpelisib 50 mg daily was started due to recurrent hypoglycemia despite nutritional management. He came off continuous feeds after 4 months, with decreased hypoglycemia frequency. At age 4.5 years, he had not experienced side effects from treatment. In conclusion, alpelisib appears to be effective in decreasing PROS-related hypoglycemia frequency and severity and should be considered for refractory hypoglycemia in this condition.

2023: PI3K signaling through a biochemical systems lens

  • Following 3 decades of extensive research into PI3K signaling, it is now evidently clear that the underlying network does not equate to a simple ON/OFF switch. This is best illustrated by the multifaceted nature of the many diseases associated with aberrant PI3K signaling, including common cancers, metabolic disease, and rare developmental disorders. However, we are still far from a complete understanding of the fundamental control principles that govern the numerous phenotypic outputs that are elicited by activation of this well-characterized biochemical signaling network, downstream of an equally diverse set of extrinsic inputs. At its core, this is a question on the role of PI3K signaling in cellular information processing and decision making. Here, we review the determinants of accurate encoding and decoding of growth factor signals and discuss outstanding questions in the PI3K signal relay network. We emphasize the importance of quantitative biochemistry, in close integration with advances in single-cell time-resolved signaling measurements and mathematical modeling.

2023: Fibro-adipose vascular anomaly (FAVA) – diagnosis, staging and management

Background

The diagnosis and treatment of fibro-adipose vascular anomaly (FAVA) of the limb remains challenging since this entity is rare and complex. This paper is aimed to describe the clinical and imaging features, staging and management of this underrecognized disease of the limb.

Material and method

Patients diagnosed with FAVA and managed between September 2019 and May 2022 in department of pediatric surgery & vascular anomalies of Xi’an international medical center hospital were retrospectively reviewed. Data extracted include age at presentation, previous diagnosis, affected muscles, symptoms, previous treatment, our management, and follow-up.

Results

Thirty-two patients with FAVA were diagnosed and managed in our center. There was a female sex predominance, with 23 female (72%) and 9 male (28%) in the cohort. Only one lesion was noticed during infancy; the remaining presented at age 1 to 20 years (median, 7 years). The most commonly involved muscles were gastrocnemius (14/32, 44%) and soleus (13/32, 40%). Swelling (mass), pain and contractures were the most common presentations. MRI featured a heterogeneous and ill-defined intramuscular high signal intensity. Diseases were staged according to clinical features: stage I (pain stage, n = 4), stage II (contracture stage, n = 20) and stage III (deformity stage, n = 8). Patients with stage I disease underwent radical resection and obtained a cure. Patients with stage II disease received radical resection and possible Achilles lengthening, having an outcome of cure. Personalized treatment was required in patients with stage III disease, including radical/partial/staged resection, Achilles lengthening/tenotomy, joint capsulotomy, neurolysis/neurectomy, tendon transfer, stretching exercises, and oral sirolimus/alpelisib. Significant improvement of symptoms was achieved in most.

Conclusion

The most distinct features of FAVA include enlarging mass, severe pain and contracture. Based on distinct clinical and radiologic features, it is not difficult to make the diagnosis of FAVA. Earlier awareness of this disease can reduce misdiagnoses. Surgery-based comprehensive management can typically improve pain and contracture. Oral sirolimus or alpelisib plays an important role in treatment of unresectable lesions and major nerve involvement. Surgery alone can be curative in early stage FAVA.

2023: Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations

  • BACKGROUND. Slow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.

    METHODS. The Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.

    RESULTS. Thirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3–4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.

    CONCLUSION. Sirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.