ABSTRACT
Children with Down syndrome are at increased risk of sleep disordered breathing (SDB). SDB is associated with significant morbidity including neurocognitive impairment, cardiometabolic disease and systemic inflammation. The identification of clinical markers that may predict SDB is critical in facilitating early diagnosis and treatment, and ultimately, preventing morbidity. The objective of this systematic review was to identify predictors of SDB in patients with Down syndrome. A search was conducted using MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Cumulative Index to Nursing and Allied Health Literature. A meta-analysis was performed according to the Meta-analyses of Observational Studies in Epidemiology checklist. Our review of the literature identified inconsistent associations between a variety of variables and SDB in children with Down syndrome, although the quality of evidence was poor. Meta-analysis of age and sex identified that children with OSA were older than those without OSA, and there was a similar risk of OSA in males and females, although risk favoured males. Currently, the American Academy of Pediatrics guidelines recommend that children with Down syndrome undergo polysomnography by the age of 4â years. Our review supports the recommendation for routine screening of children with Down syndrome. However, results from our meta-analysis suggest a need for longitudinal screening to diagnose children who may develop SDB as they get older.
Subject(s)
Down Syndrome , Sleep Apnea Syndromes , Sleep Apnea, Obstructive , Child , Child, Preschool , Down Syndrome/complications , Down Syndrome/diagnosis , Down Syndrome/epidemiology , Female , Humans , Male , Polysomnography , Sleep Apnea Syndromes/diagnosis , Sleep Apnea Syndromes/epidemiologyABSTRACT
Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and noncoding cancer driver plexuses from somatic mutations. However, differentiating driver from passenger events among noncoding genetic variants remains a challenge. Herein, we reveal cancer-driver cis-regulatory elements linked to transcription factors previously shown to be involved in development of luminal breast cancers by defining a tumor-enriched catalogue of approximately 100,000 unique cis-regulatory elements from 26 primary luminal estrogen receptor (ER)+ progesterone receptor (PR)+ breast tumors. Integrating this catalog with somatic mutations from 350 publicly available breast tumor whole genomes, we uncovered cancer driver cistromes, defined as the sum of binding sites for a transcription factor, for ten transcription factors in luminal breast cancer such as FOXA1 and ER, nine of which are essential for growth in breast cancer with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of noncoding mutations over cis-regulatory elements concatenated into a functional unit. IMPLICATIONS: Mapping the accessible chromatin of luminal breast cancer led to discovery of an accumulation of mutations within cistromes of transcription factors essential to luminal breast cancer. This demonstrates coopting of regulatory networks to drive cancer and provides a framework to derive insight into the noncoding space of cancer.
Subject(s)
Breast Neoplasms/genetics , Chromatin/metabolism , Gene Expression Regulation, Neoplastic/genetics , Whole Genome Sequencing/methods , Breast Neoplasms/pathology , Female , Humans , MutationABSTRACT
Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Circulating Tumor DNA/genetics , Neoplasms/drug therapy , Neoplasms/genetics , BRCA2 Protein/genetics , BRCA2 Protein/immunology , Circulating Tumor DNA/metabolism , DNA Copy Number Variations , Drug Resistance, Neoplasm , Group II Phospholipases A2/genetics , Group II Phospholipases A2/immunology , Humans , Neoplasms/immunology , Prospective Studies , Tumor Burden , Tumor Escape/drug effects , Exome SequencingABSTRACT
We report on the case of a 61-year-old male who initially presented with a progressive myoclonus and an intention tremor and was subsequently diagnosed with celiac disease. His neurological symptoms improved with anti-epileptic therapy and a gluten-free diet. Possible explanations include a milder disease phenotype or an epileptic component to his myoclonic movement disorder. This case highlights findings of a progressive myoclonic movement disorder, likely linked to celiac disease, and stresses the importance of a gluten-free diet in the management of the neurological manifestations of celiac disease.
ABSTRACT
PURPOSE: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC. PATIENTS AND METHODS: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%-49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684). RESULTS: Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%-41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients. CONCLUSIONS: Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , B7-H1 Antigen/genetics , Interferon-gamma/genetics , Neoplasm Recurrence, Local/drug therapy , Squamous Cell Carcinoma of Head and Neck/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , B7-H1 Antigen/immunology , Chemotherapy, Adjuvant/adverse effects , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/virology , Papillomaviridae/immunology , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/virologyABSTRACT
BACKGROUND: Recent clinical practice changes in neonatal care resulted in higher, narrower oxygen saturation target ranges for preterm infants. The effect of targeting higher or lower oxygen saturations on respiratory outcomes of preterm infants and duration of hospitalization has not been extensively reviewed in the context of current care, but could have significant implications. METHODS: A multicentre retrospective cohort of 145 preterm infants was conducted; 105 had lower oxygen saturation targets (88 to 92%), 40 had higher targets (90 to 95%). The primary outcome was bronchopulmonary dysplasia (BPD). Secondary outcomes included duration of invasive/noninvasive respiratory support, oxygen therapy, and hospitalization. The primary outcome was compared using Fisher's exact test. Secondary outcomes were evaluated with survival analysis and Wilcoxon rank sum test. RESULTS: The difference in incidence of BPD in the lower (N=56, 53.3%) and higher saturation groups (N=14, 35.0%) was not statistically significant (relative risk [RR]=0.66 [0.41, 1.04], P=0.06). The difference in duration of mechanical ventilation in the lower (median 7.8 days, interquartile range [IQR] 3.7 to 15.9) and higher saturation groups (median 4.5, IQR 1.9 to 12.3) approached statistical significance (P=0.05). There were no statistically significant differences in the durations of other respiratory supports or hospital stay between the two groups. CONCLUSIONS: The results of this study approached statistical significance and suggest that higher, narrower oxygen saturation targets may result in a clinically important reduction in BPD incidence and duration of mechanical ventilation. These results require validation in a larger sample to refine optimal targets.
ABSTRACT
BACKGROUND: Pancreatic neuroendocrine tumors (PANETs) are rare, slow growing cancers that often present with local and distant metastasis upon detection. PANETS contain distinct karyotypes, epigenetic dysregulation, and recurrent mutations in MEN1, ATRX, and DAXX (MAD+); however, the molecular basis of disease progression remains uncharacterized. METHODS: We evaluated associations between aneuploidy and the MAD+ mutational state of 532 PANETs from 11 published genomic studies and 19 new cases using a combination of exome, targeted panel, shallow WGS, or RNA-seq. We mapped the molecular timing of MAD+ PANET progression using cellular fractions corrected for inferred tumor content. RESULTS: In 287 PANETs with mutational data, MAD+ tumors always exhibited a highly recurrent signature of loss of heterozygosity (LOH) and copy-number alterations affecting 11 chromosomes, typically followed by genome doubling upon metastasis. These LOH chromosomes substantially overlap with those that undergo non-random mis-segregation due to ectopic CENP-A localization to flanking centromeric regions in DAXX-depleted cell lines. Using expression data from 122 PANETs, we found decreased gene expression in the regions immediately adjacent to the centromere in MAD+ PANETs. Using 43 PANETs from AACR GENIE, we inferred this signature to be preceded by mutations in MEN1, ATRX, and DAXX. We conducted a meta-analysis on 226 PANETs from 8 CGH studies to show an association of this signature with metastatic incidence. Our study shows that MAD+ tumors are a genetically diverse and aggressive subtype of PANETs that display extensive chromosomal loss after MAD+ mutation, which is followed by genome doubling. CONCLUSIONS: We propose an evolutionary model for a subset of aggressive PANETs that is initiated by mutation of MEN1, ATRX, and DAXX, resulting in defects in centromere cohesion from ectopic CENP-A deposition that leads to selective loss of chromosomes and the LOH phenotype seen in late-stage metastatic PANETs. These insights aid in disease risk stratification and nominate potential therapeutic vulnerabilities to treat this disease.
Subject(s)
Co-Repressor Proteins/genetics , Molecular Chaperones/genetics , Neuroendocrine Tumors/genetics , Pancreatic Neoplasms/genetics , Proto-Oncogene Proteins/genetics , X-linked Nuclear Protein/genetics , Aneuploidy , Centromere , Chromosomes, Human , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Humans , Mutation , Phenotype , Exome SequencingABSTRACT
Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB.
Subject(s)
Circulating Tumor DNA , Neoplasms , Antibodies, Monoclonal, Humanized , Biomarkers , Circulating Tumor DNA/genetics , Humans , Neoplasms/drug therapy , Prospective StudiesABSTRACT
OBJECTIVE: Determine whether higher targeted oxygen levels are associated with reduced incidence of pulmonary hypertension (PH) and elevated pulmonary vascular resistance (PVR) in extremely premature infants. STUDY DESIGN: Retrospective chart review of 252 extremely preterm infants (<29 weeks), who underwent echocardiogram prior to discharge. PH rates were compared during periods (June 2012-May 2015 and June 2015-April 2016) when lower (88-92%) or higher (90-95%) oxygen saturation targets were used. PH was determined on echocardiography. The ratio of pulmonary artery acceleration time to right ventricular ejection time was computed, with values <0.31 indicative of elevated PVR. Survival analysis compared the effects of oxygen saturation group on development/resolution of PH and elevated PVR. RESULTS: The higher saturation group had significantly lower risk of developing PH (hazard ratio (HR) = 0.50, 95%CI 0.26-0.95; P = 0.03) or elevated PVR (HR = 0.55, 95%CI 0.38-0.81; P = 0.002), compared to the lower oxygen saturation group. Median time to PH development was significantly shorter in the lower saturation group than in the higher saturation group (5 days vs 12 days; P = 0.02), as was time to development of elevated PVR (4 days vs 6 days; P < 0.001). Duration of PH (P = 0.12) and elevated PVR (P = 0.86) did not differ significantly between groups. Cumulative incidence of PH (P = 0.04) and elevated PVR (P = 0.01) at 36 weeks post-menstrual age was significantly lower in the high saturation group compared to the lower saturation group. CONCLUSION: Higher targeted oxygen saturation was associated with reduced risk of PH or elevated PVR in extremely preterm infants compared to lower oxygen saturation target.
Subject(s)
Cardiovascular Abnormalities/diagnosis , Hypertension, Pulmonary/diagnosis , Vascular Resistance , Cardiovascular Abnormalities/complications , Echocardiography , Female , Humans , Hypertension, Pulmonary/complications , Incidence , Infant , Infant, Extremely Premature , Infant, Newborn , Male , Oxygen/chemistry , Patient Discharge , Proportional Hazards Models , Retrospective StudiesABSTRACT
Mature T-cell lymphomas consisting of an expanded clonal population of T cells that possess common rearrangements of the T-cell receptor (TCR) encoding genes can be identified and monitored using molecular methods of T-cell repertoire analysis. We have developed a hybrid-capture method that enriches DNA sequencing libraries for fragments encoding rearranged TCR genes from all 4 loci in a single reaction. We use this method to describe the TCR repertoires of 63 putative lymphoma clinical isolates, 7 peripheral blood mononuclear cell (PBMC) populations, and a collection of tumor infiltrating lymphocytes. Dominant Variable (V) and Joining (J) gene pair rearrangements in cancer cells were confirmed by polymerase chain reaction (PCR) amplification and Sanger sequencing; clonality assessment of clinical isolates using BIOMED-2 methods showed agreement for 73% and 77% of samples at the ß and γ loci, respectively, whereas ß locus V and J allele prevalence in PBMCs were well correlated with results from commercial PCR-based DNA sequencing assays (r 2 = 0.94 with Adaptive ImmunoSEQ, 0.77-0.83 with Invivoscribe LymphoTrack TRB Assay). CapTCR-seq allows for rapid, high-throughput and flexible characterization of dominant clones within TCR repertoire that will facilitate quantitative analysis of patient samples and enhance sensitivity of tumor surveillance over time.
Subject(s)
Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, gamma-delta/genetics , Sequence Analysis, DNA/methods , Gene Library , Gene Rearrangement, T-Lymphocyte/genetics , Genetic Loci , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Lymphoma, T-Cell/diagnosis , Lymphoma, T-Cell/genetics , Polymerase Chain Reaction , Receptors, Antigen, T-Cell, alpha-beta/chemistry , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Receptors, Antigen, T-Cell, gamma-delta/chemistry , Receptors, Antigen, T-Cell, gamma-delta/metabolismABSTRACT
BACKGROUND: Patients diagnosed with high-grade serous ovarian cancer (HGSOC) who received initial debulking surgery followed by platinum-based chemotherapy can experience highly variable clinical responses. A small percentage of women experience exceptional long-term survival (long term (LT), 10+ years), while others develop primary resistance to therapy and succumb to disease in less than 2 years (short term (ST)). To improve clinical management of HGSOC, there is a need to better characterize clinical and molecular profiles to identify factors that underpin these disparate survival responses. METHODS: To identify clinical and tumor molecular biomarkers associated with exceptional clinical response or resistance, we conducted an integrated clinical, exome, and transcriptome analysis of 41 primary tumors from LT (n = 20) and ST (n = 21) HGSOC patients. RESULTS: Younger age at diagnosis, no residual disease post debulking surgery and low CA125 levels following surgery and chemotherapy were clinical characteristics of LT. Tumors from LT survivors had increased somatic mutation burden (median 1.62 vs. 1.22 non-synonymous mutations/Mbp), frequent BRCA1/2 biallelic inactivation through mutation and loss of heterozygosity, and enrichment of activated CD4+, CD8+ T cells, and effector memory CD4+ T cells. Characteristics of ST survival included focal copy number gain of CCNE1, lack of BRCA mutation signature, low homologous recombination deficiency scores, and the presence of ESR1-CCDC170 gene fusion. CONCLUSIONS: Our findings suggest that exceptional long- or short-term survival is determined by a concert of clinical, molecular, and microenvironment factors.