Stage 4S neuroblastoma (4SNB) is associated with spontaneous tumor regression and an excellent prognosis. However, a small group of the patients have a poor prognosis. One hundred eighty-five stage ...4SNB cases filed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory were studied. MYCN oncogene status non-amplified (NA) vs. Amplified (A) determined by fluorescence in situ hybridization, MYC-family (MYCN/MYC) protein expression no-overexpression(-)/(+/-) vs. overexpression(+) by immunohistochemistry and histopathology by International Neuroblastoma Pathology Classification Favorable Histology (FH) vs. Unfavorable Histology (UH) with particular attention to nucleolar hypertrophy NH(-) vs. (+) were assessed with patient survival. One hundred forty-seven (79.5%) tumors were MYCN-NA, FH, MYC-family protein(-)/(+/-), and NH(-) with a good prognosis 88.5±3.1% 3-y event-free survival (EFS); 94.1±2.3% 3-y overall survival (OS). Among MYCN-NA tumors, 11 demonstrated MYCN protein(+) with a moderate and uniform (M/U) staining pattern: they were FH(10/11), NH(-), 1 showed MYC protein(+) simultaneously, and all patients are alive. Also found were 5 MYC protein(+) and MYCN(-)/(+/-) tumors; they were FH without NH (4/5), and all patients are alive. Among MYCN-A tumors, 18 had MYCN protein(+) with a strong and heterogeneous (S/H) staining pattern, 9 had UH (44.4±23.4% EFS/OS) and 9 had FH (68.6±19.2% EFS/OS), and 15 showed NH(+). Two tumors had MYCN protein(-)/(+/-) despite MYCN-A; both were FH and NH(-), and 1 patient died. S/H staining pattern of MYCN protein overexpression by immunohistochemistry was associated with MYCN amplification, NH(+) and a poor prognosis. In contrast, the M/U staining pattern was associated with MYCN nonamplification and NH(-), and had no adverse prognostic effects for the stage 4SNB patients.
Summary
Over 50% of patients with systemic LCH are not cured with front‐line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with ...clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long‐term efficacy, late toxicities, relative cost and patient‐reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.
MYCN is an oncogenic driver of childhood neuroblastoma, a frequently lethal pediatric tumor. In a recent paper in Science Translational Medicine, Chanthery and colleagues demonstrate that PI3K ...inhibition leads to the dual therapeutic benefits of enhanced MYCN degradation and loss of a paracrine angiogenic signal mediated by MYCN.
The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive ...neuroblastoma.Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines.We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK.Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%.Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression.Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants.In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.
Neuroblastomas with a high mitosis-karyorrhexis index (High-MKI) are often associated with
amplification, MYCN protein overexpression and adverse clinical outcome. However, the prognostic effect of ...MYC-family protein expression on these neuroblastomas is less understood, especially when
is not amplified. To address this, MYCN and MYC protein expression in High-MKI cases (120
amplified and 121 non-
amplified) was examined by immunohistochemistry. The majority (101) of
-amplified High-MKI tumors were MYCN(+), leaving one MYC(+), 2 both(+), and 16 both(-)/(+/-), whereas non-
-amplified cases appeared heterogeneous, including 7 MYCN(+), 36 MYC(+), 3 both(+), and 75 both(-)/(+/-) tumors. These MYC-family proteins(+), or MYC-family driven tumors, were most likely to have prominent nucleolar (PN) formation (indicative of augmented rRNA synthesis). High-MKI neuroblastoma patients showed a poor survival irrespective of
amplification. However, patients with MYC-family driven High-MKI neuroblastomas had significantly lower survival than those with non-MYC-family driven tumors. MYCN(+), MYC-family protein(+), PN(+), and clinical stage independently predicted poor survival. Specific inhibition of hyperactive rRNA synthesis and protein translation was shown to be an effective way to suppress MYC/MYCN protein expression and neuroblastoma growth. Together, MYC-family protein overexpression and PN formation should be included in new neuroblastoma risk stratification and considered for potential therapeutic targets.
Perturbed epigenomic programs play key roles in tumorigenesis, and chromatin modulators are candidate therapeutic targets in various human cancer types. To define singular and shared dependencies on ...DNA and histone modifiers and transcription factors in poorly differentiated adult and pediatric cancers, we conducted a targeted shRNA screen across 59 cell lines of 6 cancer types. Here, we describe the TRPS1 transcription factor as a strong breast cancer-specific hit, owing largely to lineage-restricted expression. Knockdown of TRPS1 resulted in perturbed mitosis, apoptosis, and reduced tumor growth. Integrated analysis of TRPS1 transcriptional targets, chromatin binding, and protein interactions revealed that TRPS1 is associated with the NuRD repressor complex. These findings uncover a transcriptional network that is essential for breast cancer cell survival and propagation.
Abstract
Aims
We hypothesized left atrial (LA) stiffness may serve as a surrogate marker in children to differentiate elevated pulmonary capillary wedge pressure (PCWP) from normal and help detect ...diastolic dysfunction in myocardial injury due to multisystem inflammatory syndrome in children (MIS-C).
Methods and results
We validated LA stiffness in 76 patients (median age 10.5 years), 33 had normal PCWP (<12 mmHg) and 43 had elevated PCWP (≥12 mmHg). LA stiffness was applied to 42 MIS-C patients 28 with myocardial injury (+) and 14 without myocardial injury (−), defined by serum biomarkers. The validation group consisted of a group with and without cardiomyopathies, whose PCWP values ranged from normal to severely elevated. Peak LA strain was measured by speckle-tracking and E/e′ from apical four chamber views. Noninvasive LA stiffness was calculated as: LAStiffness=E/e′LAPeakStrain (%−1). Patients with elevated PCWP showed significantly elevated LA stiffness median 0.71%−1 vs. 0.17%−1, P < 0.001. Elevated PCWP group showed significantly decreased LA strain (median: 15.0% vs. 38.2%, P < 0.001). Receiver operator characteristic (ROC) curve for LA stiffness yielded an area under the curve (AUC) of 0.88 and cutoff value of 0.27%−1. In MIS-C group, ROC curve yielded an AUC of 0.79 and cutoff value of 0.29%−1 for identifying myocardial injury.
Conclusion
In children with elevated PCWP, LA stiffness was significantly increased. When applied to children with MIS-C, LA stiffness classified myocardial injury accurately. LA stiffness and strain may serve as noninvasive markers of diastolic function in the pediatric population.
Graphical Abstract
Graphical Abstract
The ACGME recently released its recommendation for updates to the program requirements for pediatrics. These updates proposed changes to allocation of resident clinical time and a greater emphasis on ...individualization. The potential impact of these changes on the training of physician-scientists is discussed.
Discussion of the proposed changes was held within the members of the National Pediatrician-Scientist Collaborative Workgroup, a group that represents scientists, trainees, program directors, chairs, and physician-scientist educators at nearly 30 residency programs from across the US with a focus on understanding and developing optimal approaches to physician-scientist training. Consideration was given to the both the personal and institutional impact of the proposal for physician-scientist development.
Both threats and opportunities were identified. Key opportunities include the enhanced individualized training time that could be used to explore research. Threats include re-allocation of clinical training time that may strain institutions financially, expand clinical service requirements for other early career stage individuals, and alter exposure to a broad range of pediatric specialists and sub-specialists that impact career development.
The NPSCW encourages consideration of the impact of changing program requirements on physician-scientist development to include ongoing discussion amongst mentors, programs, and trainees to understand and mitigate impact of new program requirements on the development of pediatrician-scientists.
Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF‐V600E mutation. Here, we identified two BRAF gene fusions (novel MTAP‐BRAF and MS4A6A‐BRAF) in two aggressive ...histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP‐BRAF and MS4A6A‐BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N‐terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF‐fusions respond similarly to BRAF‐inhibitors. As an alternative, we show suppression of fusion‐driven oncogenic growth with the pan‐RAFi LY3009120 and MEK inhibition.
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