[THE RISK FOR CLINICALLY SIGNIFICANT COPY NUMBER VARIANTS IN PREGNANCIES WITH TWO SOFT MARKERS].

INTRODUCTION: Soft sonographic markers, such as an intracardiac echogenic focus, are demonstrated in one out of 150 live births and are associated with a slightly increased risk of trisomy 21 and 18. In the case of an isolated soft marker, the recommendation to perform invasive tests such as amniocentesis or placental cyst testing depends to a large extent on the results of biochemical first and second trimester maternal serum screening. In the case of two soft markers, the women are referred to genetic counseling, and invasive testing is funded by the Ministry of Health. OBJECTIVES: To estimate the risk for clinically significant copy number variants (CNVs) in pregnancies with two soft markers. METHODS: This retrospective cohort study included all prenatal microarray tests performed during 2013-2021, due to demonstration of two soft markers (namely: echogenic intracardiac foci, choroid plexus cyst, single umbilical artery and mild pyelectasis). The rates of clinically significant (pathogenic and likely pathogenic) microarray findings were compared to a previously published cohort of 7235 pregnancies with normal ultrasound, in which 87 (1.2%) abnormal CNVs were noted. RESULTS: Of the 150 pregnancies with two soft markers, two (1.3%) clinically significant CNVs were found. The rate of abnormal microarray findings did not differ from baseline risk in pregnancies with normal ultrasound - relative risk of 1.11 (95% confidence interval 0.28-4.40). CONCLUSIONS: The risk for abnormal microarray findings in pregnancies with two soft markers was not significantly increased in comparison to control group of pregnancies with normal sonography. DISCUSSION: These results undermine the current national policy of genetic counseling and Ministry of Health-funded invasive testing in pregnancies with a combination of two soft markers. These findings are important for additional countries with similar management, and may facilitate the genetic counseling and informed decision-making in such cases.

Hepatitis C and Cigarette Smoking Behavior: Themes From Focus Groups.

INTRODUCTION: People with chronic hepatitis C virus (HCV; PWHC) use cigarettes at a much higher prevalence than other individuals, and smoking can exacerbate the harms specifically related to HCV (eg, hepatocellular carcinoma). Little is known about factors related to cigarette use among PWHC. AIMS AND METHODS: This study examined focus group data to explore beliefs and behaviors related to cigarette use among PWHC. Qualitative data from two focus groups of PWHC reporting current cigarette smoking (n = 15, 60% male) were collected using a semi-structured interview guide. Participants were asked about reasons for smoking, barriers to quitting smoking, and the relationship of HCV to smoking. Focus groups were transcribed verbatim and coded in NVivo 12. Four coders examined themes that arose in the focus groups. Common themes are described and supported with quotes. RESULTS: Reasons for smoking included addiction to cigarettes, stress, substituting cigarettes for other drugs, and social norms, while reasons for quitting included health and being free from the use of all drugs. Barriers to quitting included concerns about coping with stress, weight gain, and having a lack of support for and education about quitting. Many participants believed there was a link between smoking and HCV and discussed smoking in relation to the stress of an HCV diagnosis. CONCLUSIONS: Participants identified both HCV-related and non-HCV-related aspects of cigarette smoking and cessation-related behaviors that could be targeted in cessation treatment. More research is needed to identify the best treatment approaches that reduce the significant medical consequences of cigarette use among PWHC. IMPLICATIONS: People with chronic hepatitis C virus (HCV; PWHC) smoke cigarettes at a high prevalence, yet little is known about their smoking behaviors. Moreover, there are no cessation treatments targeting PWHC. This is the first study to collect focus group data from PWHC who smoke in order to identify reasons for cigarette use (HCV-related and non-HCV-related), and motivators and barriers to quitting cigarettes. PWHC reports using cigarettes to cope with the stress of an HCV diagnosis and to celebrate HCV cure. These findings suggest there are specific times during the HCV care continuum where providers can aid with cessation efforts.

National Rapid Genome Sequencing in Neonatal Intensive Care.

Importance: National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates. Objective: To evaluate the feasibility, diagnostic efficacy, and clinical utility of rtGS in neonatal intensive care units (NICUs) throughout Israel. Design, Setting, and Participants: This prospective, public health care-based, multicenter cohort study was conducted from October 2021 to December 2022 with the Community Genetics Department of the Israeli Ministry of Health and all Israeli medical genetics institutes (n = 18) and NICUs (n = 25). Critically ill neonates suspected of having a genetic etiology were offered rtGS. All sequencing, analysis, and interpretation of data were performed in a central genomics center at Tel-Aviv Sourasky Medical Center. Rapid results were expected within 10 days. A secondary analysis report, issued within 60 days, focused mainly on cases with negative rapid results and actionable secondary findings. Pathogenic, likely pathogenic, and highly suspected variants of unknown significance (VUS) were reported. Main Outcomes and Measures: Diagnostic rate, including highly suspected disease-causing VUS, and turnaround time for rapid results. Clinical utility was assessed via questionnaires circulated to treating neonatologists. Results: A total of 130 neonates across Israel (70 [54%] male; 60 [46%] female) met inclusion criteria and were recruited. Mean (SD) age at enrollment was 12 (13) days. Mean (SD) turnaround time for rapid report was 7 (3) days. Diagnostic efficacy was 50% (65 of 130) for disease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidate (1%). Disease-causing variants included 12 chromosomal and 52 monogenic disorders as well as 1 neonate with uniparental disomy. Overall, the response rate for clinical utility questionnaires was 82% (107 of 130). Among respondents, genomic testing led to a change in medical management for 24 neonates (22%). Results led to immediate precision medicine for 6 of 65 diagnosed infants (9%), an additional 2 (3%) received palliative care, and 2 (3%) were transferred to nursing homes. Conclusions and Relevance: In this national cohort study, rtGS in critically ill neonates was feasible and diagnostically beneficial in a public health care setting. This study is a prerequisite for implementation of rtGS for ill neonates into routine care and may aid in design of similar studies in other public health care systems.

Long-Lived Squeezed Ground States in a Quantum Spin Ensemble.

We generate spin squeezed ground states in an atomic spin-1 Bose-Einstein condensate tuned near the quantum-critical point separating the different spin phases of the interacting ensemble using a novel nonadiabatic technique. In contrast to typical nonequilibrium methods for preparing atomic squeezed states by quenching through a quantum phase transition, squeezed ground states are time stationary with a constant quadrature squeezing angle. A squeezed ground state with 6-8 dB of squeezing and a constant squeezing angle is demonstrated. The long-term evolution of the squeezed ground state is measured and shows gradual decrease in the degree of squeezing over 2 s that is well modeled by a slow tuning of the Hamiltonian due to the loss of atomic density. Interestingly, modeling the gradual decrease does not require additional spin decoherence models despite a loss of 75% of the atoms.

Lessons learned from the first national population-based genetic carrier-screening program for Duchenne muscular dystrophy.

PURPOSE: To summarize the results of first year implementation of pan-ethnic screening testing for Duchenne muscular dystrophy (DMD) and present the ensuing challenges. METHODS: Data acquisition for this study was performed by retrospective search of Ministry of Health registry for reports of all laboratories performing genetic screening tests. DMD testing was performed by multiplex ligation-dependent probe amplification technology. In case of single-exon deletion, sequencing of the specific exon was performed to rule out underlying single-nucleotide variant. RESULTS: Of overall 85,737 DMD tests, 82 clinically significant findings were noted (0.095%, or 1:1,046 women). In addition, 80 findings with uncertain clinical significance were detected (0.093%, or 1:1072), as well as 373 cases (0.4%, or 1:230) of single-exon deletions subsequently identified as false positives because of underlying single-nucleotide variant, mostly variants in exon 8 in North African Jewish population, and in exon 48 in Arab Muslim population. CONCLUSION: Interpretation of population-based DMD carrier screening is complex, occasionally requiring additional genetic testing methods and ethical considerations. Multicenter data registry, including ethnic origin and familial segregation in selected cases, is crucial for optimal definition of the results during genetic counseling and informed decisions regarding prenatal testing.

[MOH SCREENING FOR TBCD IN COCHIN JEWS: COLLABORATION BETWEEN MEDICAL, RESEARCH AND COMMUNITY MEMBERS IN ACHIEVING PUBLIC HEALTH GOALS].

INTRODUCTION: PEBAT (Progressive Encephalopathy, Early-Onset, with Brain Atrophy and Thin Corpus Callosum) is a rare disease characterized by a significant and progressive, neurological deficit. The disease has autosomal recessive etiology and is caused by bi-allelic variants in the gene TBCD (Tubulin-Specific Chaperone D). In 2017 the disease was diagnosed in two sisters from Jewish Cochin ethnicity (originating in Karela in south India) in Israel. Genetic testing for the girls revealed the homozygous TBCD variant c.1423G>A (p.Ala475Thr). This variant was reported simultaneously in another unrelated patient of Cochin origin.

[SUMMARY AND UPDATES IN THE FIELD OF GENETIC TESTING IN ISRAEL - AS OF 2022].

INTRODUCTION: Considerable progress has been observed in the field of genetic counseling and testing in Israel, including the availability and funding of services. The purpose of the article is to summarize the management and present the updates in the field of genetic testing in Israel, as of 2022. The progress in the field of pregnancy-related genetic testing includes an ancestry-based annually updated genetic screening, which has significantly reduced the incidence of several severe and common hereditary diseases. A comprehensive and uniform genetic screening test was submitted for approval by the next basket committee.

Community data-driven approach to identify pathogenic founder variants for pan-ethnic carrier screening panels.

BACKGROUND: The American College of Medical Genetics and Genomics (ACMG) recently published new tier-based carrier screening recommendations. While many pan-ethnic genetic disorders are well established, some genes carry pathogenic founder variants (PFVs) that are unique to specific ethnic groups. We aimed to demonstrate a community data-driven approach to creating a pan-ethnic carrier screening panel that meets the ACMG recommendations. METHODS: Exome sequencing data from 3061 Israeli individuals were analyzed. Machine learning determined ancestries. Frequencies of candidate pathogenic/likely pathogenic (P/LP) variants based on ClinVar and Franklin were calculated for each subpopulation based on the Franklin community platform and compared with existing screening panels. Candidate PFVs were manually curated through community members and the literature. RESULTS: The samples were automatically assigned to 13 ancestries. The largest number of samples was classified as Ashkenazi Jewish (n = 1011), followed by Muslim Arabs (n = 613). We detected one tier-2 and seven tier-3 variants that were not included in existing carrier screening panels for Ashkenazi Jewish or Muslim Arab ancestries. Five of these P/LP variants were supported by evidence from the Franklin community. Twenty additional variants were detected that are potentially pathogenic tier-2 or tier-3. CONCLUSIONS: The community data-driven and sharing approaches facilitate generating inclusive and equitable ethnically based carrier screening panels. This approach identified new PFVs missing from currently available panels and highlighted variants that may require reclassification.

Associations between illness burden and care experiences among Medicare beneficiaries before or after a cancer diagnosis.

INTRODUCTION: To understand associations between a new measure of illness burden and care experiences in a large, national sample of Medicare beneficiaries surveyed before or after a cancer diagnosis. MATERIALS AND METHODS: The SEER-CAHPS Illness Burden Index (SCIBI) was previously developed using Surveillance, Epidemiology, and End Results (SEER)-Consumer Assessment of Healthcare Providers and Systems (CAHPS) linked data. The SCIBI provides a standardized morbidity score based on self- and other-reported information from 8 domains and proxies relative risk of 12-month, all-cause mortality among people surveyed before or after a cancer diagnosis. We analyzed a population of Medicare beneficiaries (n = 116,735; 49% fee-for-service and 51% Medicare Advantage [MA]; 73% post-cancer diagnosis) surveyed 2007-2013 to understand how their SCIBI scores were associated with 12 different care experience measures. Frequentist and Bayesian multivariable regression models adjusted for standard case-mix adjustors, enrollment type, timing of cancer diagnoses relative to survey, and survey year. RESULTS AND DISCUSSION: SCIBl scores were associated (P < .001) in frequentist models with better ratings of Health Plan (coefficient ± standard error: 0.33 ± 0.08) and better Getting Care Quickly scores (0.51 ± 0.09). In Bayesian models, individuals with higher illness burden had similar results on the same two measures and also reported reliably worse Overall Care experiences (coefficient ± posterior SD: -0.17 ± 0.06). Illness burden may influence how people experience care or report those experiences. Individuals with greater illness burdens may need intensive care coordination and multilevel interventions before and after a cancer diagnosis.

Unique Transcriptomic Changes Underlie Hormonal Interactions During Mammary Histomorphogenesis in Female Pigs.

Successful lactation and the risk for developing breast cancer depend on growth and differentiation of the mammary gland (MG) epithelium that is regulated by ovarian steroids (17ß-estradiol [E] and progesterone [P]) and pituitary-derived prolactin (PRL). Given that the MG of pigs share histomorphogenic features present in the normal human breast, we sought to define the transcriptional responses within the MG of pigs following exposure to all combinations of these hormones. Hormone-ablated female pigs were administered combinations of E, medroxyprogesterone 17-acetate (source of P), and either haloperidol (to induce PRL) or 2-bromo-α-ergocryptine. We subsequently monitored phenotypic changes in the MG including mitosis, receptors for E and P (ESR1 and PGR), level of phosphorylated STAT5 (pSTAT5), and the frequency of terminal ductal lobular unit (TDLU) subtypes; these changes were then associated with all transcriptomic changes. Estrogen altered the expression of approximately 20% of all genes that were mostly associated with mitosis, whereas PRL stimulated elements of fatty acid metabolism and an inflammatory response. Several outcomes, including increased pSTAT5, highlighted the ability of E to enhance PRL action. Regression of transcriptomic changes against several MG phenotypes revealed 1669 genes correlated with proliferation, among which 29 were E inducible. Additional gene expression signatures were associated with TDLU formation and the frequency of ESR1 or PGR. These data provide a link between the hormone-regulated genome and phenome of the MG in a species having a complex histoarchitecture like that in the human breast, and highlight an underexplored synergy between the actions of E and PRL during MG development.

Factors That Affect Emergency Responder Wellbeing: Considerations for Public Health Responders.

PURPOSE: The purpose of this study is to identify key risk factors that could negatively affect public health emergency responders' health and wellbeing. We seek to use this information to provide recommendations and strategies to mitigate such risks. DESIGN/METHODOLOGY/APPROACH: A narrative review of the peer-reviewed literature on wellbeing of military personnel and other responders was conducted. Data was grouped and categorized according to overarching domains. FINDINGS: Factors associated with wellbeing were categorized into 5 domains: (1) demographics; (2) mental health concerns; (3) social networks; (4) work environment; and (5) postdeployment life. The strategies identified to promote wellbeing included mental health assessments, preparedness trainings, debriefs in the field, postdeployment debriefs, resources in the field, and further postdeployment decompression strategies. ORIGINALITY/VALUE: This study provides a unique understanding of the risk factors associated with poor health and wellbeing outcomes in public health emergency response work by extending the body of knowledge that focuses on other types of emergency and military response.

A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies.

Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018-2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p < 0.05). Other factors, including MCA and coexistence of epilepsy, autism spectrum disorder, microcephaly or abnormal brain magnetic resonance imaging findings, were not associated with the yield. To conclude, our findings support the utility of clinical ES in a real-world setting, as part of a publicly funded genetic workup for individuals with GDD/ID and/or MCA.

Associations between shared care and patient experiences among older cancer survivors.

PURPOSE: Cancer survivors have unique medical care needs. "Shared care," delivered by both oncologists and primary care providers (PCPs), may better address these needs. Little information is available on differences in outcomes among survivors receiving shared care versus oncologist-led or PCP-led care. This study compared experiences of care for survivors receiving shared care, oncologist-led, PCP-led, or other care patterns. METHODS: We used SEER-CAHPS data, including NCI's SEER registry data, Medicare claims, and Medicare Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey responses. Medicare Fee-for-Service beneficiaries age ≥ 65 years in SEER-CAHPS with breast, cervical, colorectal, lung, renal, or prostate cancers or hematologic malignancies who responded to a Medicare CAHPS survey ≥ 18 months post-diagnosis were included. CAHPS measures included ratings of overall care, personal doctor, specialist physician, health plan, prescription drug plan, and five composite scores. Survivorship care patterns were identified using proportions of oncologist, PCP, and other physician encounters. Multivariable regressions examined associations between care patterns and CAHPS outcomes. RESULTS: Among 10,132 survivors, 15% received shared care, 10% oncologist-led, 33% PCP-led, and 42% other. Compared with shared care, we found no significant differences in experiences of care except for getting needed drugs (lower scores for PCP-led and other care patterns). Sensitivity analyses using different patterns of care definitions similarly showed no associations between survivorship care pattern and experience of care. CONCLUSIONS: Within the limitations of the study dataset, survivors age 65+ receiving shared care reported similar experiences of care to those receiving oncologist-led, PCP-led, and other patterns of care. IMPLICATIONS FOR CANCER SURVIVORS: Shared care may not provide survivor-perceived benefits compared with other care patterns.

Random survival forests using linked data to measure illness burden among individuals before or after a cancer diagnosis: Development and internal validation of the SEER-CAHPS illness burden index.

PURPOSE: To develop and internally validate an illness burden index among Medicare beneficiaries before or after a cancer diagnosis. METHODS: Data source: SEER-CAHPS, linking Surveillance, Epidemiology, and End Results (SEER) cancer registry, Medicare enrollment and claims, and Medicare Consumer Assessment of Healthcare Providers and Systems (Medicare CAHPS) survey data providing self-reported sociodemographic, health, and functional status information. To generate a score for everyone in the dataset, we tabulated 4 groups within each annual subsample (2007-2013): 1) Medicare Advantage (MA) beneficiaries or 2) Medicare fee-for-service (FFS) beneficiaries, surveyed before cancer diagnosis; 3) MA beneficiaries or 4) Medicare FFS beneficiaries surveyed after diagnosis. Random survival forests (RSFs) predicted 12-month all-cause mortality and drew predictor variables (mean per subsample = 44) from 8 domains: sociodemographic, cancer-specific, health status, chronic conditions, healthcare utilization, activity limitations, proxy, and location-based factors. Roughly two-thirds of the sample was held out for algorithm training. Error rates based on the validation ("out-of-bag," OOB) samples reflected the correctly classified percentage. Illness burden scores represented predicted cumulative mortality hazard. RESULTS: The sample included 116,735 Medicare beneficiaries with cancer, of whom 73 % were surveyed after their cancer diagnosis; overall mean mortality rate in the 12 months after survey response was 6%. SEER-CAHPS Illness Burden Index (SCIBI) scores were positively skewed (median range: 0.29 [MA, pre-diagnosis] to 2.85 [FFS, post-diagnosis]; mean range: 2.08 [MA, pre-diagnosis] to 4.88 [MA, post-diagnosis]). The highest decile of the distribution had a 51 % mortality rate (range: 29-71 %); the bottom decile had a 1% mortality rate (range: 0-2 %). The error rate was 20 % overall (range: 9% [among FFS enrollees surveyed after diagnosis] to 36 % [MA enrollees surveyed before diagnosis]). CONCLUSIONS: This new morbidity measure for Medicare beneficiaries with cancer may be useful to future SEER-CAHPS users who wish to adjust for comorbidity.

Colchicine treatment increases the risk for fetal chromosomal aberrations-an observational study and systematic literature review.

OBJECTIVES: To examine the risk for chromosomal aberrations in fetuses of colchicine-treated patients in a large cohort, and to perform a systematic literature review on the subject. METHODS: For the observational study, a retrospective search was performed through the Ministry of Health computerized database, for all invasive tests performed due to parental colchicine treatment over the years 2003-19. The rate of aberrant karyotypes in pregnancies exposed to colchicine was compared with a local cohort of 2752 normal pregnancies, yielding six (0.2%) karyotype-detectable findings. In addition, a systematic literature search was conducted for studies examining the rate of chromosomal aberrations in pregnancies exposed to colchicine. RESULTS: The study group consisted of 755 pregnancies karyotyped due to colchicine exposure. A marked decrease due to this indication was noted over the years (i.e. 67 cases in 2003 vs 8 in 2019). Five (0.66%) chromosomal aberrations were noted: 47,XXY; 45,X0; 47,XYY; and two fetuses with trisomy 21. This rate was significantly increased compared with the control population [relative risk 2.2 (95% CI: 1.1, 4.2)]. Literature search yielded four studies encompassing 740 pregnancies. The rate of chromosomal aberrations ranged from 'none' (in three studies) up to 1.5%. Quality assessment of the evidence was defined as 'low'. CONCLUSION: The results of our observational study support the concern that colchicine treatment is associated with increased risk for fetal chromosomal aberrations; however, the absolute risk is relatively low (one in 151 pregnancies). This information should be taken into account when considering invasive testing in such pregnancies.

Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell-associated cytokine release syndrome (CRS) may present with tachycardia, hemodynamic instability and reduced cardiac function. Pediatric CAR studies examining cardiac toxicity are limited. METHODS: We report on cardiac toxicity observed in children and young adults with hematologic malignancies enrolled in a CD19-28ζ CAR T-cell phase I trial (NCT01593696). All patients had a formal baseline echocardiogram. Real-time studies included echocardiograms on intensive care unit (ICU) transfer, and serial troponin and pro-B-type natriuretic peptide (pro-BNP) in the select patients. RESULTS: From July 2012 to March 2016, 52 patients, with a median age of 13.4 years (range 4.2-30.3) were treated. CRS developed in 37/52 (71%), which was grade 3-4 CRS in nine patients (17%). The median prior anthracycline exposure was 205 mg/m2 (range 70-620 mg/m2) in doxorubicin equivalents. The median baseline left ventricle ejection fraction (LVEF) and baseline LV global longitudinal strain (GLS) were 60% (range 50%-70%) and 16.8% (range 14.1%-23.5%, n=37) respectively. The majority, 78% (29/37), of patients had a reduced GLS <19% at baseline, and 6% (3/52) of patients had baseline LVEF <53%. ICU transfers occurred in 21 patients, with nine requiring vasoactive hemodynamic support and three necessitating >1 vasopressor. Six (12%) patients developed cardiac dysfunction (defined by >10% absolute decrease in LVEF or new-onset grade 2 or higher LV dysfunction, per CTCAE v4), among whom 4 had grade 3-4 CRS. Troponin elevations were seen in 4 of 13 patients, all of whom had low LVEF. Pro-BNP was elevated from baseline in 6/7 patients at the onset of CRS, with higher levels correlating with more severe CRS. Cardiac dysfunction fully resolved in all but two patients by day 28 post-CAR. CONCLUSION: Cardiac toxicity related to CD19-28ζ CAR T-cell-associated CRS was generally reversible by day 28 postinfusion. Implementation of more frequent monitoring with formal echocardiograms incorporating systemic analysis of changes in GLS, and cardiac biomarkers (troponin and proBNP) may help to earlier identify those patients at highest risk of severe cardiac systolic dysfunction, facilitating earlier interventions for CRS to potentially mitigate acute cardiac toxicity.

A Systematic Review of Pediatric Phase I Trials in Oncology: Toxicity and Outcomes in the Era of Targeted Therapies.

BACKGROUND: Pediatric phase I oncology trials have historically focused on safety and toxicity, with objective response rates (ORRs) <10%. Recently, with an emphasis on targeted approaches, response rates may have changed. We analyzed outcomes of recent phase I pediatric oncology trials. MATERIALS AND METHODS: This was a systematic review of phase I pediatric oncology trials published in 2012-2017, identified through PubMed and EMBASE searches conducted on March 14, 2018. Selection criteria included full-text articles with a pediatric population, cancer diagnosis, and a dose escalation schema. Each publication was evaluated for patient characteristics, therapy type, trial design, toxicity, and response. RESULTS: Of 3,431 citations, 109 studies (2,713 patients) met eligibility criteria. Of these, 78 (72%) trials incorporated targeted therapies. Median age at enrollment/trial was 11 years (range 3-21 years). There were 2,471 patients (91%) evaluable for toxicity, of whom 300 (12.1%) experienced dose-limiting toxicity (DLT). Of 2,143 patients evaluable for response, 327 (15.3%) demonstrated an objective response. Forty-three (39%) trials had no objective responses. Nineteen trials (17%) had an ORR >25%, of which 11 were targeted trials and 8 were combination cytotoxic trials. Targeted trials demonstrated a lower DLT rate compared with cytotoxic trials (10.6% vs. 14.7%; p = .003) with similar ORRs (15.0% vs. 15.9%; p = .58). CONCLUSION: Pediatric oncology phase I trials in the current treatment era have an acceptable DLT rate and a pooled ORR of 15.3%. A subset of trials with target-specific enrollment or combination cytotoxic therapies showed high response rates, highlighting the importance of these strategies in early phase trials. IMPLICATIONS FOR PRACTICE: Enrollment in phase I oncology trials is crucial for development of novel therapies. This systematic review of phase I pediatric oncology trials provides an assessment of outcomes of phase I trials in children, with a specific focus on the impact of targeted therapies. These data may aid in evaluating the landscape of current phase I options for patients and enable more informed communication regarding risk and benefit of phase I clinical trial participation. The results also suggest that, in the current treatment era, there is a rationale to increase earlier access to targeted therapy trials for this refractory patient population.

Maternal depression in early childhood and child emotional and behavioral outcomes at school age: examining the roles of preschool childcare quality and current maternal depression symptomatology.

Recent studies have shown that the association between maternal depression and child outcome can be moderated by children's experience of childcare (e.g., daycare) during early childhood (0-5 years). We also know that maternal depression in the child's early years has long-term associations with child development. However, the moderating role of childcare quality on long-term associations between maternal depression and child outcome has not been thoroughly investigated. This article examined longitudinal associations between probable maternal depression (PMD) during early childhood (0-5 years) and childcare quality on children's emotional and behavioral development at the age of 7-8 years (N = 207). Childcare quality was evaluated through observations within the settings. PMD during early childhood was assessed using complementary information from interviews conducted with the mother and current maternal symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Internalizing and externalizing behaviors were reported by the mother, father and the child at age 7-8 years. Results indicate that when mothers reported clinically relevant depression in early childhood, 7-8-year-old children demonstrate fewer behavioral problems if they attended a higher quality childcare setting. The moderating role of childcare quality remained after considering current maternal depression symptoms. Therefore, it is important to ensure high-quality childcare during early childhood to optimize child development.

Cediranib phase-II study in children with metastatic alveolar soft-part sarcoma (ASPS).

BACKGROUND: Alveolar soft-part sarcoma (ASPS), a rare vascular sarcoma with a clinically indolent course, frequently presents with metastases. Vascular endothelial growth factor (VEGF) is a promising therapeutic target. In a phase-II trial of the VEGF receptor inhibitor cediranib for adults with ASPS, the partial response (PR) rate (response evaluation criteria in solid tumors [RECIST] v1.0) was 35% (15/43; 95% confidence interval: 21-51%). We evaluated cediranib in the pediatric population. PROCEDURE: Patients <16 years old with metastatic, unresectable ASPS received cediranib at the pediatric maximum tolerated dose of 12 mg/m2 (≈70% of the fixed adult phase-II dose orally daily). Tumor response was assessed every two cycles (RECIST v1.0). A Simon two-stage optimal design (target response rate 35%, rule out 5%) was used. RESULTS: Seven patients (four females), with a median age of 13 years, (range 9-15), were enrolled on stage 1. The most frequent grade 2 or 3 adverse events were neutropenia, diarrhea, hypertension, fatigue, and proteinuria. The best response was stable disease (SD) (median cycle number = 34). Three patients were removed from the study treatment for disease progression (cycles 4, 5, and 36). Five of seven patients had SD for ≥14 months. Two patients with SD remain on study (34-57+ cycles). CONCLUSIONS: Cediranib did not reach the target response rate in this small pediatric cohort, in contrast to the adult 35% PR rate. The pediatric dosing was 30% lower compared to the adult dosing, which may have contributed to response differences. Prolonged SD was observed in five patients, but given the indolent nature of ASPS, SD cannot be clearly attributed to cediranib. Cediranib has an acceptable safety profile.