Crystalline C3N3H3 tube (3,0) nanothreads.

Carbon nanothread (CNTh) is a "one-dimensional diamond polymer" that combines high tensile strength and flexibility, but it severely suffers from intrathread disorder. Here, by modifying the reactivity and the stacking ordering of the aromatic precursor, crystalline C3N3H3 CNTh with perfect hexagonal orientation and stacking was synthesized at 10.2 GPa and 573 K from s-triazine. By Rietveld refinement of X-ray diffraction data, gas chromatography mass spectrometry investigation, and theoretical calculation, we found that synthesized CNTh has a tube (3,0) structure, with the repeating s-triazine residue connected solely by C­N bonds along the thread. A "peri-cage" reaction, the concerted bonding between six C and N atoms, instead of [4 + 2] or [1,4] addition reactions, was concluded for the formation of CNThs, and the critical bonding distance between the nearest intermolecular C and N was ∼2.9 Å. The formation of a "structure-specific" crystalline CNTh with C and N orderly distributed highlighted the importance of reaction selectivity and stacking order of reactant molecules, which have great significance for understanding the polymerization of aromatic molecules under high pressure and developing new crystalline CNThs.

Ordered Van der Waals Hetero-nanoribbon from Pressure-Induced Topochemical Polymerization of Azobenzene.

Pressure-induced topochemical polymerization of molecular crystals with various stackings is a promising way to synthesize materials with different co-existing sub-structures. Here, by compressing the azobenzene crystal containing two kinds of intermolecular stacking, we synthesized an ordered van der Waals carbon nanoribbon (CNR) heterostructure in one step. Azobenzene polymerizes via a [4 + 2] hetero-Diels-Alder (HDA) reaction of phenylazo-phenyl in layer A and a para-polymerization reaction of phenyl in layer B at 18 GPa, as evidenced by in situ Raman and IR spectroscopies, X-ray diffraction, as well as gas chromatography-mass spectrometry and the solid-state nuclear magnetic resonance of the recovered products. The theoretical calculation shows that the obtained CNR heterostructure has a type II (staggered) band gap alignment. Our work highlights a high-pressure strategy to synthesize bulk CNR heterostructures.

Integrated variant allele frequency analysis pipeline and R package: easyVAF.

Somatic sequence variants are associated with cancer diagnosis, prognostic stratification, and treatment response. Variant allele frequency (VAF), the percentage of sequence reads with a specific DNA variant over the read depth at that locus, has been used as a metric to quantify mutation rates in these applications. VAF has the potential for feature detection by reflecting changes in tumor clonal composition across treatments or time points. Although there are several packages, including Genome Analysis Toolkit and VarScan, designed for variant calling and rare mutation identification, there is no readily available package for comparing VAFs among and between groups to identify loci of interest. To this end, we have developed the R package easyVAF, which includes parametric and nonparametric tests to compare VAFs among multiple groups. It is accompanied by an interactive R Shiny app. With easyVAF, the investigator has the option between three statistical tests to maximize power while maintaining an acceptable type I error rate. This paper presents our proposed pipeline for VAF analysis, from quality checking to group comparison. We evaluate our method in a wide range of simulated scenarios and show that choosing the appropriate test to limit the type I error rate is critical. For situations where data is sparse, we recommend comparing VAFs with the beta-binomial likelihood ratio test over Fisher's exact test and Pearson's χ2 test.

Instrumental variable analysis for cost outcome: Application to the effect of primary care visit on medical cost among low-income adults.

Medical cost data often consist of zero values as well as extremely right-skewed positive values. A two-part model is a popular choice for analyzing medical cost data, where the first part models the probability of a positive cost using logistic regression and the second part models the positive cost using a lognormal or Gamma distribution. To address the unmeasured confounding in studies on cost outcome under two-part models, two instrumental variable (IV) methods, two-stage residual inclusion (2SRI) and two-stage prediction substitution (2SPS) are widely applied. However, previous literature demonstrated that both the 2SRI and the 2SPS could fail to consistently estimate the causal effect among compliers under standard IV assumptions for binary and survival outcomes. Our simulation studies confirmed that it continued to be the case for a two-part model, which is another nonlinear model. In this article, we develop a model-based IV approach, Instrumental Variable with Two-Part model (IV2P), to obtain a consistent estimate of the causal effect among compliers for cost outcome under standard IV assumptions. In addition, we develop sensitivity analysis approaches to allow the evaluation of the sensitivity of the causal conclusions to potential quantified violations of the exclusion restriction assumption and the randomization of IV assumption. We apply our method to a randomized cash incentive study to evaluate the effect of a primary care visit on medical cost among low-income adults newly covered by a primary care program.

Equivocal end-of-therapy imaging findings do not predict a higher risk of local relapse after definitive radiotherapy in pediatric Ewing sarcoma and rhabdomyosarcoma.

BACKGROUND: Posttherapy imaging studies can provide reassurance or induce anxiety regarding risk of recurrence for patients and their families. In some cases, it is difficult to determine if imaging findings represent posttreatment changes or residual disease. Equivocal radiographic findings can occur due to therapy-related inflammation or residual, inactive soft tissue masses, but it is unknown if such findings indicate an increased likelihood of local recurrence. The aim of this study was to assess the value of initial posttherapy scans for predicting local relapse in patients with Ewing sarcoma (EWS) or rhabdomyosarcoma (RMS) who received radiotherapy (RT) for local control. These findings are critical to inform clinicians' surveillance recommendations and ability to accurately counsel patients and their families. PROCEDURE: The primary endpoint was time to local progression (LP). Patients were classified as having posttherapy scans that were "positive" (residual disease within the RT field), "negative" (no evidence of residual disease within the RT field), or "equivocal" (no determination could be made). The value of initial posttreatment scans for predicting LP was assessed using positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Negative imaging findings (n = 51) had an NPV of 88%, and positive imaging findings (n = 1) had a PPV of 100%. When equivocal findings (n = 16) were categorized with negative results (i.e., positive vs. equivocal/negative), the NPV was 90%. When equivocal findings were categorized with positive results (equivocal/positive vs. negative), the PPV was 12%. CONCLUSION: Equivocal findings within the RT field on end-of-therapy imaging studies indicate no higher risk of local recurrence than negative findings. These results may contribute to appropriate surveillance schedules and accurate counseling of patients with RMS and EWS who have received RT for local control.

Adoption of Optimal Small (6-9 mm) Colorectal Polyp Resection Technique Over Time.

BACKGROUND: Cold snare polypectomy (CSP) is the preferred resection technique for small (6-9 mm) polyps due to lower rate of incomplete resection compared to cold forceps polypectomy (CFP) and improved safety profile over hot snare polypectomy (HSP). AIMS: To describe resection techniques for small (6-9 mm) polyps and determine factors associated with sub-optimal technique. METHODS: This was retrospective cohort study of colonoscopies performed by gastroenterological and surgical endoscopists from 2012 to 2019 where at least one 6-9 mm polyp was removed. Patient, provider, and procedure characteristics were collected. Univariate and multivariate regression analyses were performed to determine factors associated with sub-optimal technique. RESULTS: In total, 773 colonoscopies where 1,360 6-9 mm polyps removed by 21 endoscopists were included. CSP was used for 1,122 (82.5%), CFP for 61 (4.5%), and HSP for 177 (13.0%). Surgeon specialty was associated with CFP use (aOR 7.81; 95% CI 3.02-20.16). Polyp location in left colon (aOR 1.65; 95% CI 1.17-2.33) and pedunculated morphology (aOR 12.76; 95% CI 7.24-22.50) were associated with HSP. There was a significant increase in overall CSP use from 30.4% in 2012 to 96.8% in 2019. CONCLUSIONS: 82.5% of all 6-9 mm polyps removed from 2012 to 2019 were removed using a cold snare with significant increase in CSP from 2012 to 2019. Differences in how optimal technique was adopted over time based on specialty highlight the need for standardized practice guidelines and quality monitoring.

From Biomass to Functional Crystalline Diamond Nanothread: Pressure-Induced Polymerization of 2,5-Furandicarboxylic Acid.

2,5-Furandicarboxylic acid (FDCA) is one of the top-12 value-added chemicals from sugar. Besides the wide application in chemical industry, here we found that solid FDCA polymerized to form an atomic-scale ordered sp3-carbon nanothread (CNTh) upon compression. With the help of perfectly aligned π-π stacked molecules and strong intermolecular hydrogen bonds, crystalline poly-FDCA CNTh with uniform syn-configuration was obtained above 11 GPa, with the crystal structure determined by Rietveld refinement of the X-ray diffraction (XRD). The in situ XRD and theoretical simulation results show that the FDCA experienced continuous [4 + 2] Diels-Alder reactions along the stacking direction at the threshold C···C distance of ∼2.8 Å. Benefiting from the abundant carbonyl groups, the poly-FDCA shows a high specific capacity of 375 mAh g-1 as an anode material of a lithium battery with excellent Coulombic efficiency and rate performance. This is the first time a three-dimensional crystalline CNTh is obtained, and we demonstrated it is the hydrogen bonds that lead to the formation of the crystalline material with a unique configuration. It also provides a new method to move biomass compounds toward advanced functional carbon materials.

Early-Age Onset Colorectal Neoplasia in Average-Risk Individuals Undergoing Screening Colonoscopy: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Incidence and mortality associated with early-age onset colorectal cancer (EAO-CRC) is increasing, prompting professional society recommendations to lower the screening age in average-risk individuals. The yield of screening individuals younger than 50 years is not known. METHODS: A systematic review of 3 databases from inception through July 2020 was performed in all languages that reported colonoscopy findings in average-risk individuals younger than 50 years. The primary outcomes were EAO colorectal neoplasia (CRN) and advanced colorectal neoplasia (aCRN) prevalence. Subgroup analyses were performed based on sex, geographic location, time period, and age, including comparison with those aged 50-59 years. Generalized linear mixed model with random intercept logistic regression and fixed subgroup effects were performed. RESULTS: Of 10,123 unique articles, 17 studies published between 2002 and 2020, including 51,811 average-risk individuals from 4 continents, were included. The pooled rate of EAO-CRN was 13.7% (95% confidence interval [CI], 0.112%-0.168%) and EAO-aCRN was 2.2% (95% CI, 0.016%-0.031%). Prevalence of CRC was 0.05% (95% CI, 0.00029%-0.0008%). Rates of EAO-CRN were higher in men compared with women (relative risk, 1.71%; 95% CI, 1.49%-1.98%), and highest in the United States (15.6%; 95% CI, 12.2%-19.7%) compared with Europe (14.9%; 95% CI, 6.9%-29.3%), East Asia (13.4%; 95% CI, 10.3%-17.2%), and the Middle East (9.8%; 95% CI, 7.8%-12.2%) (P = .04) The rate of EAO-CRN in age groups 45-49 years and 50-59 years was 17.8% (95% CI, 14.5%-21.6%) and 24.8% (95% CI, 19.5%-30.8%), respectively (P = .04). The rate of EAO-aCRN in age group 45-49 years was 3.6% (95% CI, 1.9%-6.7%) and 4.2% (95% CI, 3.2%-5.7%), respectively (P = .69). CONCLUSIONS: The rate of aCRN in individuals aged 45-49 years was similar to the rate observed in individual aged 50-59 years, suggesting that expanding screening to this population could yield a similar impact on colorectal cancer risk reduction.

A prospective survey study of lower urinary tract dysfunction in childhood cancer survivors after vincristine and/or doxorubicin chemotherapy.

BACKGROUND: Two chemotherapeutic agents used widely in pediatric oncology are vincristine (VCR) and doxorubicin (DOX), which may cause neuropathy and myopathy, respectively. The study hypothesis is that neurotoxic effects of VCR and/or myotoxic effects of DOX affect bladder physiology and manifest clinically as lower urinary tract dysfunction (LUTD). PROCEDURE: Based on a priori power analysis, 161 children divided evenly by gender were recruited. Children aged 5-10 years completed the dysfunctional voiding scoring system (DVSS) survey. The study cohort comprised cancer survivors treated with VCR and/or DOX. Healthy controls were recruited from well-child clinic visits. Exclusion criteria included pelvic-based malignancy, pelvic irradiation, pre-existing LUTD, neurologic abnormalities, and treatment with cyclophosphamide/ifosfamide. DVSS scores and presence of LUTD, defined as DVSS scores above gender-specific thresholds (males ≥9, females ≥6), were compared across cohorts. RESULTS: Median DVSS scores were higher in the study cohort (6 vs. 4, p = .003). Moreover, children in the study cohort were more likely to exceed threshold scores for LUTD (38.8% vs. 21%, p = .014; OR 1.8). Subanalysis by gender revealed female cancer survivors are more likely to report LUTD than controls (57.5% vs. 30%, p = .013, OR 1.9). This did not hold true for males (20% vs. 12.2%, p = .339). CONCLUSIONS: Childhood cancer survivors who received VCR and/or DOX reported higher rates of LUTD than controls. Female cancer survivors appear more likely to suffer from LUTD than males. Further study with a positive control cohort of cancer survivors who received non-VCR, non-DOX chemotherapy is underway to elucidate the contribution of a cancer diagnosis to LUTD.

Phase transition and chemical reactivity of 1H-tetrazole under high pressure up to 100 GPa.

The pressure-induced phase transition and polymerization of nitrogen-rich molecules are widely focused on due to their extreme importance for the development of green high-energy-density materials. Here, we present a study of the phase-transition behaviour and chemical reaction of 1H-tetrazole up to 100 GPa using in situ Raman, IR, X-ray diffraction, neutron diffraction techniques and theoretical calculations. A phase transition above 2.6 GPa was identified and the high-pressure structure was determined with one molecule in a unit cell instead of two molecules as reported before. The 1H-tetrazole polymerized reversibly below 100 GPa, probably through carbon-nitrogen bonding instead of nitrogen-nitrogen bonding. Our studies update the structure model of the high-pressure phase of 1H-tetrazole, and present the possible intermolecular bonding route for the first time, which gives new insights to understand the phase transition and chemical reaction of nitrogen-rich compounds, and is of benefit for designing new high-energy-density materials.

Design and analysis of a 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria: Small sample considerations for cluster-randomized trials with count data.

BACKGROUND: Cluster-randomized trials allow for the evaluation of a community-level or group-/cluster-level intervention. For studies that require a cluster-randomized trial design to evaluate cluster-level interventions aimed at controlling vector-borne diseases, it may be difficult to assess a large number of clusters while performing the additional work needed to monitor participants, vectors, and environmental factors associated with the disease. One such example of a cluster-randomized trial with few clusters was the "efficacy and risk of harms of repeated ivermectin mass drug administrations for control of malaria" trial. Although previous work has provided recommendations for analyzing trials like repeated ivermectin mass drug administrations for control of malaria, additional evaluation of the multiple approaches for analysis is needed for study designs with count outcomes. METHODS: Using a simulation study, we applied three analysis frameworks to three cluster-randomized trial designs (single-year, 2-year parallel, and 2-year crossover) in the context of a 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria. Mixed-effects models, generalized estimating equations, and cluster-level analyses were evaluated. Additional 2-year parallel designs with different numbers of clusters and different cluster correlations were also explored. RESULTS: Mixed-effects models with a small sample correction and unweighted cluster-level summaries yielded both high power and control of the Type I error rate. Generalized estimating equation approaches that utilized small sample corrections controlled the Type I error rate but did not confer greater power when compared to a mixed model approach with small sample correction. The crossover design generally yielded higher power relative to the parallel equivalent. Differences in power between analysis methods became less pronounced as the number of clusters increased. The strength of within-cluster correlation impacted the relative differences in power. CONCLUSION: Regardless of study design, cluster-level analyses as well as individual-level analyses like mixed-effects models or generalized estimating equations with small sample size corrections can both provide reliable results in small cluster settings. For 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria, we recommend a mixed-effects model with a pseudo-likelihood approximation method and Kenward-Roger correction. Similarly designed studies with small sample sizes and count outcomes should consider adjustments for small sample sizes when using a mixed-effects model or generalized estimating equation for analysis. Although the 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria is already underway as a parallel trial, applying the simulation parameters to a crossover design yielded improved power, suggesting that crossover designs may be valuable in settings where the number of available clusters is limited. Finally, the sensitivity of the analysis approach to the strength of within-cluster correlation should be carefully considered when selecting the primary analysis for a cluster-randomized trial.

Advanced adenomas may be a red flag for hereditary cancer syndromes.

BACKGROUND: 16-25% of colorectal cancers (CRCs) diagnosed under age 50 are associated with hereditary cancer syndromes. Advanced adenomas are considered precursors to CRC. Although polyp removal prevents cancer, polypectomy does not change underlying genetic risk. Patients with isolated advanced polyps do not currently qualify for genetic testing unless they have a personal or family history of cancer. AIM: Describe the prevalence of hereditary cancer syndromes among patients with advanced colorectal polyps. METHODS: We performed a single center retrospective review from 2015 to 2019 of patients who underwent germline genetic testing with indication for testing listed as colorectal polyp. We excluded patients with a personal history of CRC and those with ≥10 cumulative polyps. We collected patient demographics, polyp characteristics, family history data and genetic testing results from the medical record. Discrete variables were reported as frequency and percentages and continuous variables reported as mean with range. RESULTS: A total of 42 patients underwent genetic testing due to a personal history of advanced adenoma. 17% of patients met current genetic testing criteria. All patients underwent multi-gene panel testing. Two patients (4.8%) had a germline pathogenic mutation (one in MLH1 and one in CHEK2). The patient with an MLH1 mutation met current criteria for genetic testing (PREMM5 score 5.8), however the patient with the CHEK2 mutation did not. Both mutation carriers had a personal history of synchronous or metachronous advanced adenomas. 38% had a variant of uncertain significance. CONCLUSIONS: 5% of patients with advanced adenomas in our retrospective series had a pathogenic germline mutation in a cancer predisposition gene. Though the patient with a pathogenic mutation in MLH1 met current clinical criteria for genetic testing, this was not recognized prior to referral; he was referred based on a personal history of advanced adenoma. Advanced polyps may be a red flag to identify patients who are at risk for hereditary cancer syndromes.

Distance-Selected Topochemical Dehydro-Diels-Alder Reaction of 1,4-Diphenylbutadiyne toward Crystalline Graphitic Nanoribbons.

Solid-state topochemical polymerization (SSTP) is a promising method to construct functional crystalline polymeric materials, but in contrast to various reactions that happen in solution, only very limited types of SSTP reactions are reported. Diels-Alder (DA) and dehydro-DA (DDA) reactions are textbook reactions for preparing six-membered rings in solution but are scarcely seen in solid-state synthesis. Here, using multiple cutting-edge techniques, we demonstrate that the solid 1,4-diphenylbutadiyne (DPB) undergoes a DDA reaction under 10-20 GPa with the phenyl as the dienophile. The crystal structure at the critical pressure shows that this reaction is "distance-selected". The distance of 3.2 Å between the phenyl and the phenylethynyl facilitates the DDA reaction, while the distances for other DDA and 1,4-addition reactions are too large to allow the bonding. The obtained products are crystalline armchair graphitic nanoribbons, and hence our studies open a new route to construct the crystalline carbon materials with atomic-scale control.

The impact of age at orchiopexy on testicular cancer outcomes.

PURPOSE: To estimate how many boys with UDT must undergo orchiopexy to prevent one case of TC, one death from TC and one exposure to TC treatment beyond radical orchiectomy as compared to being treated at an older age. METHODS: This retrospective study utilized data from a 2007 Swedish study of males who underwent orchiopexy for UDT (Pettersson et al.). TC incidence for boys undergoing orchiopexy for UDT was assessed based on the age at orchiopexy (0-6 years, 7-9 years, 10-12 years, 13-15 years). The incidence of TC in each age cohort was calculated and used to determine the number needed to treat (NNT) for each age group using assumptions based on published TC outcomes. RESULTS: For an index patient ≤ 6 years, 372 boys need to undergo orchiopexy to prevent a single case of TC, 1488 boys to prevent exposure to TC therapy beyond radical orchiectomy, and 5315 boys to prevent a single TC-related death compared to treatment at an older age. CONCLUSION: While there is evidence supporting benefits of early orchiopexy, the NNT to affect TC outcomes is very high. Even those with delayed orchiopexies have low risk for TC poor outcomes. This information can be used when counseling patients and families faced with UDT about the risks related to TC, especially with comorbidities.

Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15+ Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma.

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs.

Interleukin-37 is highly expressed in regulatory T cells of melanoma patients and enhanced by melanoma cell secretome.

Immune suppression is one of the 10 hallmarks of cancer. Interleukin-37 (IL-37), a member of the IL-1 family, inhibits both innate and adaptive immunity, and has been shown to modulate immune responses in various disease conditions. Yet, IL-37 has rarely been investigated in cancer patients, and its biological role in cancer remains to be elucidated. In this study, we investigated the gene expression of IL-37 in age- and sex-matched blood samples of healthy individuals and melanoma patients, and demonstrated upregulation of IL-37 messenger RNA (mRNA) in the blood samples of melanoma patients. By further analyzing immune cell subsets responsible for the upregulated IL-37 expression, we discovered that IL-37 mRNA was highly expressed in T cells and granulocytes, with the highest expression in regulatory T (Treg ) cells in healthy individuals, and that IL-37 mRNA was upregulated in lymphocytes (T, B, and natural killer cells) in melanoma patient blood. Among all cell subsets, Treg cells from melanoma patients exhibited the highest IL-37 gene expression levels. We provided evidence that melanoma-conditioned media induces IL-37 mRNA and protein expression in multiple lymphocyte populations, particularly in Treg cells. We further confirmed that the IL-1-mediated secretome from human melanoma cells, specifically transforming growth factor-ß, induces IL-37 mRNA expression in human Treg cells. Our results suggest a potential immunosuppressive role for IL-1 and IL-37 in melanoma tumorigenesis. Highly elevated IL-37 in specific lymphocyte populations could serve as a biomarker for tumor-induced immunosuppression.

Does Tonsillectomy Increase Obesity Risk in Children with Down Syndrome?

OBJECTIVES: To examine weight changes relative to surgical success in children with Down syndrome and obstructive sleep apnea (OSA). STUDY DESIGN: Retrospective chart review of children with Down syndrome undergoing tonsillectomy from 2005 to 2016 for OSA at a tertiary care children's hospital. Only patients with pre-and postoperative polysomnogram within 6 months of tonsillectomy were included. Demographics, weight, height, and polysomnogram data were collected. Body mass index (BMI), expressed as a percentage of the 95th percentile (%BMIp95), was calculated for 24 months prior to and following surgery. Pre-and postoperative OSA severity were also recorded. The postoperative obstructive/hypopnea index identified subjects with resolution of obstruction (obstructive/hypopnea index <2 events/hour) or persistent mild/moderate/severe obstructive apnea. Regression analyses were used to compare %BMIp95 pre- and post-tonsillectomy with %BMIp95 by OSA status following tonsillectomy. RESULTS: A total of 78 patients with Down syndrome whose mean age was 5.29 years at time of tonsillectomy were identified. There was no difference between best-fit curves of %BMI p95 pre-and post-tonsillectomy. There was no difference between best-fit curves of %BMI p95 in patients who saw resolution of OSA after tonsillectomy vs patients with residual OSA. CONCLUSIONS: Tonsillectomy neither alters the BMI trajectory of children with Down syndrome, nor changes differentially the risk for obesity in children whose OSA did or did not resolve after surgery.

Obstructive Sleep Apnea and Sleep Position: Does It Matter for Infants With a Cleft Palate?

OBJECTIVE: To determine whether nonsupine sleep improves obstructive sleep apnea (OSA) in infants with cleft palate undergoing polysomnography (PSG). DESIGN: Retrospective chart review. SETTING: Tertiary care pediatric hospital. PATIENTS: Twenty-seven infants (1 month to 1 year) with cleft palate with or without cleft lip (CP ± L) undergoing PSG testing for suspected OSA were included. MAIN OUTCOME MEASURES: Polysomnography measures included obstructive apnea-hypopnea index (OAHI), central apnea-hypopnea index (CAHI), oxygen saturation (SpO2) nadir, SpO2, and end-tidal carbon dioxide (ETCO2). RESULTS: Twenty-three PSGs with at least 20 minutes of sleep in both the supine and the nonsupine positions were analyzed. The supine OAHI (mean: 16.8 events/hour; standard deviation [SD]: 18.5) and nonsupine OAHI (mean: 12.6 events/hour; SD: 12.6) did not differ significantly (P = .10). The supine CAHI (mean: 1.9 events/hour; SD: 2.7) and nonsupine CAHI (mean: 3.1 events/hour; SD: 3.7; P = .15), the supine SpO2 nadir (mean: 81.2%; SD: 6.3) and nonsupine SpO2 nadir (mean: 81.8%; SD: 5.3; P = .70), the supine mean SpO2 (mean: 95.5%; SD: 1.9) and nonsupine mean SpO2 saturation (mean: 95.3%; SD: 2.4; P = .34), and the supine ETCO2 (mean: 45.4 mm Hg; SD: 5.3) and nonsupine ETCO2 (mean: 42.5 mm Hg; SD: 10.1; P = .24) were also similar. CONCLUSIONS: There were no significant improvements in OSA metrics during nonsupine sleep in infants with CP ± L. Prior to recommending nonsupine positioning which increases infant's exposure to sudden infant death syndrome risk, we advocate obtaining a PSG to verify an objective improvement in OSA.

A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options. ENMD-2076 is a small-molecule inhibitor of Aurora and angiogenic kinases with proapoptotic and antiproliferative activity in preclinical models of TNBC. METHODS: This dual-institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC previously treated with one to three prior lines of chemotherapy in the advanced setting. Patients were treated with ENMD-2076 250 mg orally once daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary endpoint was 6-month clinical benefit rate (CBR), and secondary endpoints included progression-free survival, pharmacokinetic profile, safety, and biologic correlates in archival and fresh serial tumor biopsies in a subset of patients. RESULTS: Forty-one patients were enrolled. The 6-month CBR was 16.7% (95% CI, 6-32.8%) and included two partial responses. The 4-month CBR was 27.8% (95% CI, 14-45.2%), and the average duration of benefit was 6.5 cycles. Common adverse events included hypertension, fatigue, diarrhea, and nausea. Treatment with ENMD-2076 resulted in a decrease in cellular proliferation and microvessel density and an increase in p53 and p73 expression, consistent with preclinical observations. CONCLUSIONS: Single-agent ENMD-2076 treatment resulted in partial response or clinical benefit lasting more than 6 months in 16.7% of patients with pretreated, advanced, or metastatic TNBC. These results support the development of predictive biomarkers using archival and fresh tumor tissue, as well as consideration of mechanism-based combination strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01639248 . Registered on July 12, 2012.

Dual use of hematopoietic and mesenchymal stem cells enhances engraftment and immune cell trafficking in an allogeneic humanized mouse model of head and neck cancer.

In this report, we describe in detail the evolving procedures to optimize humanized mouse cohort generation, including optimal conditioning, choice of lineage for engraftment, threshold for successful engraftment, HNSCC tumor implantation, and immune and stroma cell analyses. We developed a dual infusion protocol of human hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stem cells (MSCs), leading to incremental human bone marrow engraftment, and exponential increase in mature peripheral human immune cells, and intratumor homing that includes a more complete lineage reconstitution. Additionally, we have identified practical rules to predict successful HSPC/MSC expansion, and a peripheral human cell threshold associated with bone marrow engraftment, both of which will optimize cohort generation and management. The tremendous advances in immune therapy in cancer have made the need for appropriate and standardized models more acute than ever, and therefore, we anticipate that this manuscript will have an immediate impact in cancer-related research. The need for more representative tools to investigate the human tumor microenvironment (TME) has led to the development of humanized mouse models. However, the difficulty of immune system engraftment and minimal human immune cell infiltration into implanted xenografts are major challenges. We have developed an improved method for generating mismatched humanized mice (mHM), using a dual infusion of human HSPCs and MSCs, isolated from cord blood and expanded in vitro. Engraftment with both HSPCs and MSCs produces mice with almost twice the percentage of human immune cells in their bone marrow, compared to mice engrafted with HSPCs alone, and yields 9- to 38-fold higher levels of mature peripheral human immune cells. We identified a peripheral mHM blood human B cell threshold that predicts an optimal degree of mouse bone marrow humanization. When head and neck squamous cell carcinoma (HNSCC) tumors are implanted on the flanks of HSPC-MSC engrafted mice, human T cells, B cells, and macrophages infiltrate the stroma of these tumors at 2- to 8-fold higher ratios. In dually HSPC-MSC engrafted mice we also more frequently observed additional types of immune cells, including regulatory T cells, cytotoxic T cells, and MDSCs. Higher humanization was associated with in vivo response to immune-directed therapy. The complex immune environment arising in tumors from dually HSPC-MSC engrafted mice better resembles that of the originating patient's tumor, suggesting an enhanced capability to accurately recapitulate a human TME.