“My Home Away From Home”: Community Support for International Pediatric and Young Adult Patients and Their Families in End-of-Life Care and Bereavement
Journal of Palliative Medicine
View details for DOI 10.1089/jpm.2023.0370
Case Report: Castleman Disease With an Associated Stromal Spindle Cell Proliferation, PDGFRB Mutation and p53 Expression: Clonal Origins of a Rare Disease.
Frontiers in oncology
2022; 12: 857606
Castleman disease (CD) is a rare lymphoproliferative disorder with distinct clinical subtypes. However, our understanding of the underlying pathogenesis of particular subtypes of CD remains unclear. While the characteristic morphologic changes within UCD, including occasional cases of overgrowth of spindled stromal and follicular dendritic cells have been described, the nature and origin of these spindle cells remain elusive. Few reports have suggested that underlying stromal cells in UCD are clonally neoplastic and may be of fibroblastic reticular cell (FRC) or follicular dendritic cell (FDC) origins given their close clonal relationship. Although certain histomorphologic features may aid diagnosis, there are no specific biomarkers that can differentiate a reactive process mimicking UCD from true UCD. Hence, we describe an index case with morphology consistent with the hyaline vascular subtype of UCD with concomitant atypical smooth muscle actin (SMA)-positive stromal spindle cell proliferation containing a recurrent PDGFRB N666S mutation and upregulation of p53 expression. Further analysis of 21 additional cases of UCD identified increased p53 expression by digital image analysis and SMA positive stromal cells predominantly within the paracortical and intrafollicular areas further strengthening the hypothesis of the stromal cellular derivation and origins of UCD.
View details for DOI 10.3389/fonc.2022.857606
View details for PubMedID 35494027
View details for PubMedCentralID PMC9043324
Leiomyomatosis in an Infant With a SUFU Splice Site Variant: Case Report.
Journal of pediatric hematology/oncology
Heterozygous loss-of-function variants in the suppressor of fused protein gene (SUFU) can result in Gorlin syndrome, which is characterized by an increased frequency of basal cell carcinoma, medulloblastoma, odontogenic keratocysts, as well as other tumors. We describe a case of a 5-month-old female who presented with multiple intra-abdominal leiomyomata and was found to have a likely pathogenic splice site variant in the SUFU gene. This is the first reported case of leiomyomatosis secondary to a pathogenic SUFU variant in an infant and may represent an early, atypical presentation of Gorlin syndrome.
View details for DOI 10.1097/MPH.0000000000002454
View details for PubMedID 35398865
Treatment at Specialized Cancer Centers Is Associated with Improved Survival in Adolescent and Young Adults with Soft Tissue Sarcoma.
Journal of adolescent and young adult oncology
Background: Soft tissue sarcomas (STS) are a heterogeneous group of tumors whose management benefits from a multidisciplinary therapeutic approach. Published data suggest that cancer treatment at a specialized cancer center (SCC) can improve survival in other cancers. Therefore, we examined the impact of the location of treatment on survival in children and adolescents and young adults (AYAs) with STS. Methods: We performed a population-based analysis of children and AYAs hospitalized within 1 year of diagnosis with first primary STS (2000-2014) using the California Cancer Registry linked with hospitalization data. Patients were categorized based on receiving all inpatient treatments at a SCC versus part/none. Multivariable Cox proportional hazards regression identified factors associated with overall and STS-specific survival by age group. Results are presented as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Of the 1,674 patients with STS, 142 were children (0-14) and 1,532 were AYAs (15-39) and 89.4% and 40.4% received all inpatient treatments at a SCC, respectively. Overall, the 5-year survival was improved for patients who received all inpatient care at a SCC (59.8% vs. those who received part/none, 50.7%). Multivariable regression analysis found that having all treatments at a SCC was associated with better overall survival (HR, 0.79, CI: 0.65-0.95) in AYAs, but not in children. Conclusions: Our findings demonstrate that treatment for STS at a SCC is associated with better survival in AYAs. Eliminating barriers to treatment of AYAs with STS at SCCs could improve survival in this population.
View details for DOI 10.1089/jayao.2021.0110
View details for PubMedID 34910881
Seminars in pediatric surgery
2020; 29 (5): 150976
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 2019; 21 (7): 1517–24
Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening.
Science translational medicine
2019; 11 (519)
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
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
OXFORD UNIV PRESS INC. 2018: 50
View details for Web of Science ID 000438339000104
ANTICOAGULATION FOR TREATMENT OF PAIN IN VENOUS MALFORMATIONS
View details for Web of Science ID 000428851200243
HDAC INHIBITION IN THALAMIC AND SPINAL CORD H3K27M+DIFFUSE MIDLINE GLIOMA
View details for Web of Science ID 000428851200424
- Risk group accurately predicts outcome in primary extremity non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in patients < 30 years of age: Findings from Children's Oncology Group study ARST0332. AMER SOC CLINICAL ONCOLOGY. 2018