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  • Venous malformations. Seminars in pediatric surgery Cooke-Barber, J., Kreimer, S., Patel, M., Dasgupta, R., Jeng, M. 2020; 29 (5): 150976

    Abstract

    Venous malformations include a spectrum of slow-flow malformations that together are the most common forms of vascular anomalies. Care of these patients requires a multi-disciplinary approach. Goals of care are to ameliorate symptoms and to preserve function. Use of therapeutic compression garments remains the mainstay of therapy. There are new and promising therapies over the last few years that will be invaluable tools for optimal care of this complex patient population. Advances in medical therapy through inhibition of the mTOR/PI3K/AKT pathway with Sirolimus and more proximal targeted drugs along with advances in sclerotherapy techniques are promising for the long-term improvement and amelioration of symptoms in patients with venous malformations.

    View details for DOI 10.1016/j.sempedsurg.2020.150976

    View details for PubMedID 33069284

  • A somatic activating NRAS variant associated with kaposiform lymphangiomatosis GENETICS IN MEDICINE Barclay, S. F., Inman, K. W., Luks, V. L., McIntyre, J. B., Al-Ibraheemi, A., Church, A. J., Perez-Atayde, A. R., Mangray, S., Jeng, M., Kreimer, S. R., Walker, L., Fishman, S. J., Alomari, A. I., Chaudry, G., Trenor, C. C., Adams, D., Kozakewich, H. W., Kurek, K. C. 2019; 21 (7): 1517–24
  • Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Science translational medicine Lin, G. L., Wilson, K. M., Ceribelli, M., Stanton, B. Z., Woo, P. J., Kreimer, S., Qin, E. Y., Zhang, X., Lennon, J., Nagaraja, S., Morris, P. J., Quezada, M., Gillespie, S. M., Duveau, D. Y., Michalowski, A. M., Shinn, P., Guha, R., Ferrer, M., Klumpp-Thomas, C., Michael, S., McKnight, C., Minhas, P., Itkin, Z., Raabe, E. H., Chen, L., Ghanem, R., Geraghty, A. C., Ni, L., Andreasson, K. I., Vitanza, N. A., Warren, K. E., Thomas, C. J., Monje, M. 2019; 11 (519)

    Abstract

    Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.

    View details for DOI 10.1126/scitranslmed.aaw0064

    View details for PubMedID 31748226

  • A somatic activating NRAS variant associated with kaposiform lymphangiomatosis. Genetics in medicine : official journal of the American College of Medical Genetics Barclay, S. F., Inman, K. W., Luks, V. L., McIntyre, J. B., Al-Ibraheemi, A., Church, A. J., Perez-Atayde, A. R., Mangray, S., Jeng, M., Kreimer, S. R., Walker, L., Fishman, S. J., Alomari, A. I., Chaudry, G., Trenor Iii, C. C., Adams, D., Kozakewich, H. P., Kurek, K. C. 2018

    Abstract

    PURPOSE: Kaposiform lymphangiomatosis (KLA) is a rare, frequently aggressive, systemic disorder of the lymphatic vasculature, occurring primarily in children. Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions, and systemic involvement. We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development.METHODS: We performed exome sequencing of tumor samples from five individuals with KLA, along with samples from uninvolved control tissue in three of the five. We used digital polymerase chain reaction (dPCR) to validate the exome findings and to screen KLA samples from six other individuals.RESULTS: We identified a somatic activating NRAS variant (c.182 A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1% to 28%, that was absent from the tested control tissues.CONCLUSION: The activating NRAS p.Q61R variant is a known "hotspot" variant, frequently identified in several types of human cancer, especially melanoma. KLA, therefore, joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signaling pathways. This discovery will expand treatment options for these high-risk patients as there is potential for use of targeted RAS pathway inhibitors.

    View details for PubMedID 30542204

  • HDAC INHIBITION IN THALAMIC AND SPINAL CORD H3K27M+DIFFUSE MIDLINE GLIOMA Kreimer, S., Lin, G., Woo, P., Monje-Deisseroth, M. OXFORD UNIV PRESS INC. 2018: 50
  • ANTICOAGULATION FOR TREATMENT OF PAIN IN VENOUS MALFORMATIONS Chien, M., Kreimer, S., Teng, J., Marqueling, A., Jeng, M. WILEY. 2018
  • HDAC INHIBITION IN THALAMIC AND SPINAL CORD H3K27M+DIFFUSE MIDLINE GLIOMA Kreimer, S., Woo, P., Monje-Deisseroth, M. WILEY. 2018

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