While subcutaneous metastases are often observed with stage MS neuroblastoma, an entity that usually resolves spontaneously, skeletal muscle metastases (SMM) have been rarely described. The purpose ...of this retrospective study was to investigate the significance of SMM in neuroblastoma.
Seventeen patients with neuroblastoma SMM were diagnosed at a median age of 4.3 (0.1-15.6) months. All had SMM at diagnosis and metastases at other sites. Fifteen (88%) had ≥ 2 SMM in disparate muscle groups. One, 14, and 2 patients had low, intermediate, and high-risk disease respectively. Fifteen tumors had favorable histology without MYCN amplification, and 2 were MYCN-amplified. Most SMM (80%; n=12/15 evaluated) were MIBG-avid.
Only 1 patient (with MYCN-non-amplified neuroblastoma) had disease progression. All survive at median follow-up of 47.9 (16.9-318.9) months post-diagnosis. Biological markers (histology, chromosomal and genetic aberrations) were not prognostic. Whole genome sequencing of 3 matched primary and SMM lesions suggested that both primary and metastatic tumors arose from the same progenitor. SMM completely resolved in 10 patients by 12 months post-diagnosis. Of 4 patients managed with watchful observation alone without any cytotoxic therapy, 3 maintain complete remission with SMM resolving by 5, 13, and 21 months post-diagnosis respectively.
Children with neuroblastoma SMM have an excellent prognosis, with a clinical course suggestive of stage MS disease. Based on these results, the initial management of infants with non-MYCN-amplified NB with SMM could be watchful observation, which could eliminate or reduce exposure to genotoxic therapy.
Objectives
Both the immune system of human milk and milk cortisol have complex short‐ and long‐term effects on child health and development. As understanding continues to grow of the independent ...effects of each of these components of milk, it is also important to investigate their intersection, including how milk cortisol affects the immune system of milk. We began this important endeavor through secondary analyses of archived milk specimens.
Methods
Participants were 31 lactating mothers from upstate New York. We estimated milk cortisol concentrations via enzyme immunoassay. We assessed milk proinflammatory cytokine (interleukin‐6, IL‐6) responses to pathogenic (Salmonella) and commensal (Escherichia, Lactobacillus, Bifidobacterium) bacteria via in vitro stimulation. We estimated ordered logistic regression models to assess associations between milk cortisol and IL‐6 responses to bacteria.
Results
Milk cortisol ranged from 0.098 to 1.007 μg/dL. Milk cortisol was positively associated with IL‐6 responses to S. enterica (B: 4.035; 95% CI: 0.674, 7.395) and B. breve (B: 3.675; 95% CI: 0.426, 6.924); this association persisted after controlling for child age. Results were less clear for associations between milk cortisol and IL‐6 responses to L. acidophilus (B: 2.318; 95% CI: −1.224, 5.859) and E. coli (B: 2.366; 95% CI: −0.960, 5.692).
Conclusions
Complex interactions between cortisol and the immune system extend to milk. Milk cortisol was positively associated with proinflammatory responses to some bacteria in vitro. This may suggest that milk cortisol is causally upstream of protective immune activity.
Predictors of milk cortisol in North American women Anyim, Rachael; Li, Shanita; Armstrong, Daniel ...
American journal of human biology,
February 2024, 2024-Feb, 2024-02-00, 20240201, Letnik:
36, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Objectives
Human milk content varies across mother–child dyads, environments, and populations. Among the hormones in milk is cortisol, a glucocorticoid; its impact on the breastfeeding child is ...unknown. Milk cortisol may constitute a signal to the child's developing physiology which can shape characteristics (e.g., growth, temperament) to prevailing environmental conditions. This exploratory study evaluated the maternal, breastfeeding, and infant characteristics associated with milk cortisol.
Methods
We evaluated archived milk specimens for cortisol using enzyme immunoassay and employed an information‐theoretic approach to assess associations between milk cortisol and participant characteristics with linear regression modeling. Because we employed secondary data, information for some variables likely to impact milk cortisol variation (e.g., time of day, socioeconomic status, maternal or infant body mass index, milk energy density) was unavailable.
Results
Participants were 48 lactating mothers from upstate New York, aged 21–40 years. Milk cortisol ranged from 0.098 to 1.007 μg/dL. Child age ranged from 1 to 26 months. In linear regression employing best fit modeling criteria, milk cortisol increased with child age (B: 0.069; p: .000; a 7.1% increase in milk cortisol for each month of child age), while child symptoms of illness (B: −0.398; p: .057; a 33% decrease) and consumption of complementary foods (B: −.525; p: .020; a 41% decrease) were associated with lower milk cortisol.
Conclusions
We speculate that increasing milk cortisol with child age plays a role in signaling development (e.g., as increasing independence increases risk for injury and other negative health outcomes), independent of the maternal stressors we could capture.
Clonal hematopoiesis in survivors of childhood cancer Friedman, Danielle Novetsky; Chan, Irenaeus Chi-Chung; Moskowitz, Chaya S. ...
Journal of clinical oncology,
06/2023, Letnik:
41, Številka:
16_suppl
Journal Article
Recenzirano
10014
Background: Subsequent malignancies and cardiovascular (CV) disease are the leading cause of premature death in childhood cancer survivors, a population also at risk for premature aging. Clonal ...hematopoiesis (CH), the age-related clonal expansion of mutated hematopoietic stem cells, is a prominent risk factor for early-onset malignant and CV disease. Data are lacking on the prevalence of CH in childhood cancer survivors. Methods: We evaluated the prevalence of CH in a retrospective case-control study of childhood cancer survivors and matched controls (all ≥13 years of age). Cases included individuals diagnosed with a solid tumor or lymphoma at age ≤25 years who were ≥6-months from completion of chemotherapy and/or radiotherapy. Age-matched controls (5-year age bins) with and without a history of cancer were included, given evidence of shared genomic risk factors between cancer and CH. Samples were batched and sequenced at an average depth of 19,830x using a custom, targeted amplicon-based UMI sequencing platform (ArcherDX), which included full exons of DMNT3A, TET2, ASXL1, TP53, CHEK2 and targeted regions of PPM1D, SRSF2, SF3B1, JAK2. Mutations at a variant allelic frequency (VAF) ≥ 0.02% were identified with VAF > 2% considered clinically significant. Logistic regression adjusted for age, gender, and race was used to test for an association between CH and case-control status. Results: Samples were analyzed from 104 childhood cancer survivors (median age 19 years y, range, 13-49y; median time since end-of-therapy: 10y, range 0.5-39y), 71 controls with untreated, newly diagnosed cancer (median age 25y, range 8-48y), and 68 healthy controls (median age 23y, range, 15-51y). The frequency of CH was higher in childhood cancer survivors compared to controls across ages with CH detected in 36.5% of survivors and 20.1% of controls (OR 3.2, 95% CI, 1.6-6.1). The enrichment of CH in survivors was observed both relative to healthy controls (OR 2.3, 95% CI 1.1-5.3) and treatment-naïve solid tumor controls (OR 5.0, 95% CI, 2.1-13.7). A trend toward a stronger association for CH mutations with VAF > 2% (OR 10.9, 95% CI, 1.9-60.7) compared to VAF < 2% (OR 2.7, 95% CI, 1.4-5.2) was observed. The most commonly mutated genes were in the DTA ( DNMT3A, TET2 and ASXL1) and DDR ( PPM1D, TP53 and CHEK2) classes. While a higher proportion of both DTA and DDR mutations was noted among survivors compared to controls, the enrichment of DDR mutations was stronger than DTA (OR 7.1, 95% CI 2.8-18.3 for DDR; OR 2.3, 95% CI 1.1-4.6 for DTA). A sub-analysis of 5 year survivors showed a higher frequency of CH in this cohort compared to controls (OR 2.8, 95% CI, 1.3-5.9). Conclusions: Childhood cancer survivors have higher frequencies of CH than age-matched controls, which persists for years after treatment. These data suggest that CH may, in part, drive the long-term premature multimorbidity seen in survivors. Longitudinal assessment of CH among survivors may be indicated to elucidate these associations.
Background
The immune system of milk protects against infections and guides immune system development. A system-level understanding of milk immune activity is critical for research into infant ...infectious disease risk and lifelong health.
Research aim
To describe a protocol to characterize immune activity in human milk via in vitro stimulation for use in population-based (rather than clinical) research.
Methods
This study proceeded in two phases, each with a cross-sectional design. Human milk specimens were incubated for 24 hr at 37 °C in mammalian cell culture medium with stimuli (e.g., Salmonella enterica) in a CO2-enriched environment. Immune responses to stimuli were characterized as the change in cytokine: stimulated/baseline. Predictors of cytokine responses were evaluated with generalized linear models.
Results
Patterns were detectable across mother–child dyads: Interleukin-6 responses to stimuli were generally positively associated with child age and with maternal autoimmune disease.
Conclusions
Our method allows characterization of pro-inflammatory milk immune activity in vitro in population-based (rather than clinical) research settings. In vitro activity has a system-level interpretation and is likely to be of broad utility in global health research in settings with high infectious disease risk, where understanding the immune system of milk is critical to understanding maternal and child health.
Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and ...temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease.
The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.
Abstract
Intrinsic brainstem tumors arising in pediatric, adolescent, and young adult patients comprise a spectrum of entities, predominantly diffuse midline gliomas (DMG) and IDH mutant ...astrocytomas. Accurate molecular diagnosis is essential for prognostication and optimal therapy. Therapeutic considerations include inclusion (in IDH mutant) or exclusion (in H3K27M) of adjuvant Temozolomide post radiotherapy and use of molecular targeted therapy (IDH inhibitors). Surgical biopsy, however, is associated with increased risk of permanent neurological deficits and may yield insufficient or non-diagnostic tissue. We hypothesized that minimally-invasive “liquid biopsy” of cerebrospinal fluid (CSF) could represent a superior diagnostic modality in this patient population, employing molecular analysis of cell free DNA (cfDNA). We analyzed 44 CSF samples from 38 unique patients for recurrent driver mutations in brainstem gliomas, including H3K27M, IDH1, and IDH2. MSK-IMPACT, a NY state-authorized hybridization capture-based next-generation panel DNA sequencing assay, was used for analysis. Samples without a detectable driver mutation by MSK-IMPACT testing were further subjected to gene targeted testing by droplet digital PCR. In all, 10/44 (22.7%) samples had mutations detected by MSK-IMPACT using standard calling criteria and 13 of the remaining 34 samples (38.2%) had supporting evidence of a mutation based on manual review. Further testing by ddPCR was performed on a subset of cases (based on DNA availability) which confirmed 7 of the previous low-level mutations and uncovered 4 additional mutations. Overall, 27/44 (61.4%) of cases had detectable evidence of a mutation, and of the 23 patients without a known tissue diagnosis, a driver in the CSF was identified for 47.8% of patients (11/23). Minimally-invasive analysis of CSF cfDNA in patients with intrinsic brainstem tumors has a high diagnostic yield and may obviate the need for tissue biopsy in a majority of patients. Testing with high sensitivity assays is valuable to maximize the rate of detection.
Abstract
PURPOSE: A subset of pediatric, adolescent and young adult (AYA) gliomas are located in the brainstem, eloquent locations, or present with diffuse/leptomeningeal disease, and are associated ...with high risk and low yield of biopsy. At the same time, accurate molecular diagnosis is necessary to direct optimal therapy. In such cases, analysis of cell free DNA (cfDNA) form cerebral spinal fluid (CSF) may represent a diagnostic alternative to biopsy. METHODS: We investigated the utility of CSF cfDNA sequencing through a stepwise approach, using clinically validated, targeted molecular assays. Testing was performed using a broad hybrid capture next generation sequencing assay (MSK-IMPACT) and subsequent targeted digital droplet PCR in a subset of cases. RESULTS: We analyzed 17 CSF samples from 17 pediatric (n=6) and AYA (n=11) glioma patients with primary or recurrent disease. Thirteen had tumors located within the brainstem, and four had leptomeningeal involvement. Somatic alterations were detected in 12/17 samples (71%). In 3/4 patients with leptomeningeal involvement, cfDNA testing revealed a BRAF fusion consistent with the diagnosis of diffuse leptomeningeal glioneuronal tumor (DLGNT). Among the 13 patients with brainstem involvement, four had somatic H3 K27M mutations, three had IDH mutations, and one had TP53 and ATRX mutations; five patients had no detectable mutations. CONCLUSION: In our analysis, we found that established glioma hotspot mutations were able to be detected within the CSF. We propose that in patients for whom tissue biopsy is high risk, not feasible, or tissue was nondiagnostic, CSF cfDNA sequencing has a substantial diagnostic yield and should be considered as a valuable novel diagnostic tool. Ongoing research is aiming to further increase the sensitivity of cfDNA testing, especially in patients with very low levels of CSF cfDNA.
