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Objectives: This study assessed overall quality of life (QoL) over time in youth with cleft lip and palate (CLP) undergoing maxillary protraction treatment or orthognathic surgery for class III malocclusion to identify any differences in QoL based on treatment group and outcome success., Materials and Methods: A prospective longitudinal cohort study was conducted in two pediatric hospitals. The Short Form Health Survey (SF-12) measured physical and mental QoL prior to treatment, at maximal correction, at treatment completion, and at 1-year post treatment. Analyses included one-sample, two-sample, and paired t-tests and analyses of variance and covariance., Results: Participants (N = 91) either completed protraction (n = 53) at age 11-14 or surgery (n = 38) at age 16-21. Participants were mostly Latinx (67%) males (55%) born with unilateral CLP (81%) and there were no demographic differences between the two groups other than age. The total sample's QoL was in the average range and significantly higher than national norms. No significant differences were found in QoL-based outcome success; however, the protraction group showed a gradual physical QoL improvement over time, while the surgery group experienced a temporary drop in physical QoL postoperatively. At treatment completion, higher physical QoL was associated with higher socioeconomic status. At a year post treatment, mental QoL was significantly higher for males., Conclusion: Both protraction and surgery appear to be acceptable treatment options in terms of overall QoL for youth with CLP. While treatment success did not impact QoL, there were some differences in physical QoL coinciding with the treatment phase as well as individual factors., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Craniofacial microsomia (CFM) is a broad clinical term used to describe a congenital condition most commonly involving the underdevelopment of the external ear, mandible, soft tissues, and facial nerve. Despite medical advances, understanding of the psychological health and healthcare experiences of individuals with CFM and their caregivers remains limited. This article describes a research program designed to address these knowledge gaps, and identify opportunities for psychosocial intervention and improved healthcare provision., Design: The Craniofacial microsomia: Accelerating Research and Education (CARE) research program aims to: 1) Conduct up to 160 narrative interviews with individuals and caregivers to validate a conceptual framework; 2) Administer an online international survey of up to 800 individuals with CFM and caregivers to identify predictors of psychological distress; 3) Perform up to 60 semi-structured interviews with healthcare providers and advocacy leaders to examine the extent to which current healthcare provisions address identified patient needs; and 4) Establish a participant registry to build a longitudinal database and develop an international community., Results: Teams in the USA and UK have been established, alongside an international, interdisciplinary Advisory Committee. Data analysis for Aim 1 is ongoing and informing the delivery of Aims 2-3. Aim 4 is also in development. A dedicated website serves as a recruitment tool, educational resource, and mechanism for engaging with the CFM community., Conclusions: The CARE program provides a comprehensive approach to understanding the experiences of individuals with CFM and their caregivers. Challenges encountered and lessons learned are shared for the benefit of the community., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Craniosynostosis is a common diagnosis requiring early referral to a pediatric plastic surgeon; however, disparities in healthcare may influence presentation timing and affect treatment options and outcomes. This study aimed to explore sociodemographic factors contributing to delay in craniosynostosis surgical consultation., Methods: A retrospective cohort study of 694 California-based craniosynostosis patients at a tertiary children's hospital was performed from 2006 to 2023. State-specific Area Deprivation Index (ADI) and distance to the hospital were calculated using ZIP codes. Multivariate linear and logistic regressions considered race, insurance type, syndromic status, suture type, and ZIP code-based socioeconomic factors., Results: Median age of presentation was 4.5 [interquartile range: 2.6-7.6] months with racial/ethnic breakdown of Hispanic/Latinx (41.2%), White (23.6%), Asian (3.7%), Black/African American (2.0%), or other/unreported (29.5%) with 58.4% having public insurance and an average distance to the hospital of 48.3 km. Median ADI was 5.4 [interquartile range: 4.0-7.1]. By linear regression, public insurance ( P < 0.001) and higher ADI decile ( P < 0.001) independently contributed to an older age of presentation. Patients with public insurance (odds ratio 1.90; P = 0.002) were more likely to present after 4 months of age., Conclusions: Patients who had public insurance or resided in more disadvantaged areas presented later for craniosynostosis surgical consultation. Eliminating disparities in these populations ensures more equitable access to surgical options and can improve patient outcomes., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Children born with a cleft palate with or without a cleft lip (CP±L) are at risk for sleep-disordered breathing, particularly obstructive sleep apnea (OSA). While OSA and CP±L have both been associated with higher risk for psychosocial and academic concerns, their combined risk has been understudied. This paper aimed to describe polysomnography findings and psychosocial and academic concerns among children with isolated (iCP±L) and syndrome-associated (sCP±L) clefts who had undergone primary palatoplasty. Medical records were reviewed from 2004 to 2022 for demographics, medical history, polysomnography results, and family-reported psychosocial and academic variables. Of the 694 patients with CP±L who had a palatoplasty, 147 had a polysomnogram and 82 had at least one follow-up polysomnogram. Across time points, only 19% to 27% of participants had normal polysomnograms and the most frequent finding was mild OSA for 30% to 35% of patients. For children with iCP±L, more frequent oxygen desaturations were significantly associated with receiving special education services and family-reported academic concerns and OSA was associated with a history of receiving mental health services. Children with sCP±L had a significantly higher Obstructive Apnea-Hypopnea Index and a greater proportion of all-day special education classroom placements relative to youth with iCP±L. Study results suggest that cleft providers should monitor for OSA and sleep-disordered breathing symptoms, collaborate with pulmonologists for evaluation and treatment of sleep concerns, and address possible sleep-associated psychosocial and academic issues., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

Purpose: Craniofacial microsomia (CFM) is a congenital condition that can be associated with feeding challenges in infants. As part of the larger 'Craniofacial microsomia: Accelerating Research and Education (CARE)' program, this study described caregivers' early feeding experiences., Design and Materials: US-based caregivers of 34 children with CFM participated in remote narrative interviews. Two authors completed inductive thematic analysis in an iterative process until consensus was reached., Results: Caregivers' narratives outlined the inherent challenges of feeding an infant with special healthcare needs. The first theme 'Navigating Challenges and Managing Expectations' describes the distress participants experienced when they were unable to breastfeed and the negative emotional effect of switching to formula. The second theme 'Making Adaptations' outlines the methods participants tried, including breast pumps and feeding tubes. The third theme 'Accessing Support' describes participants' interactions with healthcare providers and challenges accessing feeding support. The final theme 'Growing from Adversity' recounts participants' relief once their child established a feeding pattern and the personal growth gained from their experiences., Conclusions: Caregivers reported several feeding related challenges associated with CFM, many of which negatively affected their wellbeing. Negative consequences were particularly pronounced in cases where caregivers' feeding experiences differed from their expectations. Participants identified challenges in accessing reliable feeding information and support. Despite difficult experiences, caregivers cited some positive outcomes, including increased confidence and resilience., Practice Implications: Holistic feeding information and support for families affected by CFM should be inclusive of several feeding methods to improve care delivery, child health, and the caregiver experience., Competing Interests: Declaration of competing interest No known conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Children with cleft palate, with or without cleft lip (CP±L), exhibit language delays on average compared to children without clefts. Interventions to address these disparities are scarce. In this multi-center study, Book Sharing for Toddlers with Clefts (BOOST), we will test a remote, parent-focused intervention to promote language development in children with CP±L., Objectives: The study will test two primary hypotheses. First, toddlers randomized to BOOST will exhibit better language outcomes than children receiving standard-of-care (SOC). Second, we hypothesize that the BOOST program's effect on language outcomes is mediated by the frequency and quality of parent-child reading interactions., Methods: The study is a randomized-controlled trial comparing the BOOST group to a SOC comparison group. We will enroll N = 320 English and/or Spanish-speaking children ages 24-32 months with isolated CP±L (n = 160 per group). Both groups will receive children's books, and parents will record and upload videos of themselves reading the books with their children using a smartphone app developed for the study. Parents will also complete surveys asking whether they read to their children on five randomly selected days each week. In addition, the BOOST group will participate in 3 remote dialogic book-sharing intervention sessions via Zoom. We will code book-sharing videos to assess parents' target skill usage and children's expressive language. End-of-study assessments will include measures of child language outcomes (e.g., clinician-administered measures, parent reports, and naturalistic child language samples)., Results: Enrollment began in April 2024 and will continue through approximately April 2028., Conclusion: The BOOST study will address a critical gap in the literature on interventions to improve language in children with CP±L. The results will inform the care for toddlers with oral clefts and have potential applications for other populations., Competing Interests: No authors have competing interests., (Copyright: © 2024 Collett et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Craniofacial microsomia (CFM) and microtia psychosocial research in the US is primarily with English-speaking participants. Given that 19% of the US is Latino, and there is a higher prevalence of CFM in Latino populations, this study aims to describe psychosocial experiences related to CFM among Spanish-speaking Latino caregivers to better inform health care. Narrative interviews (mean 73±17 min) were completed in Spanish with parents of children with CFM aged 3 to 17 (mean age 10.8±4.8 years). Transcripts were analyzed using quantitative linguistic analyses and reflexive thematic analysis. Participants (N=12) were mostly mothers (83%) who had immigrated to the US and had low socioeconomic status. Based upon analysis of grouped word counts, participants spent approximately half of their narratives discussing the first two years of their child's life. Themes selected based on US Latino sociodemographics and cultural values included the Impact of Language, Healthcare Challenges, Supportive Healthcare Experiences, Caregiver Coping with CFM, Family Roles, and Addressing Social Implications of CFM. Results highlighted that the first years of care are of critical importance to parents and suggest this is an optimal time to focus on education and support services for families. Additional treatment suggestions include providing interpretation and informational materials in Spanish, addressing care barriers, supporting familial and child coping, accounting for the role of extended family, and helping address social concerns. Ongoing research with Latino families can further assist in guiding culturally sensitive CFM health care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Objective: To describe the early health care experiences of parents of children with craniofacial microsomia (CFM), a congenital diagnosis often identified at birth., Design: Qualitative descriptive., Setting: Homes of participants., Participants: Parents of 28 children with CFM from across the United States., Methods: We interviewed participants (27 mothers individually and one mother and father together) via telephone or teleconference and used reflexive thematic analysis to derive themes that represented early health care experiences of parents of children with CFM., Results: Participants' narratives included detailed recounting of their birth and early care experiences. We identified two overarching themes. The first overarching theme, Stressors, included four subthemes that represented difficulties related to emotional reactions and negative experiences with health care providers. The second overarching theme, Finding Strength, included four subthemes that represented participants' positive adjustment to stressors through independent information seeking about CFM, adaptive coping, positive experiences with health care providers, and drawing on external supports., Conclusion: Participants often described early experiences as challenging. Findings have implications for improving early care, including increasing open and supportive communication by health care professionals, expanding access to CFM information, screening for mental health concerns among parents, strengthening coping among parents, and linking families to resources such as reliable online CFM information and early intervention programs., Competing Interests: Conflict of Interest The authors report no conflicts of interest or relevant financial relationships., (Copyright © 2024 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses. Published by Elsevier Inc. All rights reserved.)

Objective: Children with craniofacial microsomia (CFM) have complex healthcare needs, resulting in evaluations and interventions from infancy onward. Yet, little is understood about families' treatment experiences or the impact of CFM on caregivers' well-being. To address this gap, the NIH-funded 'Craniofacial microsomia: Accelerating Research and Education (CARE)' program sought to develop a conceptual thematic framework of caregiver adjustment to CFM., Design: Caregivers reported on their child's medical and surgical history. Narrative interviews were conducted with US caregivers ( n  = 62) of children aged 3-17 years with CFM. Transcripts were inductively coded and final themes and subthemes were identified., Results: Components of the framework included: 1) Diagnostic Experiences, including pregnancy and birth, initial emotional responses, communication about the diagnosis by healthcare providers, and information-seeking behaviors; 2) Child Health and Healthcare Experiences, including feeding, the child's physical health, burden of care, medical decision-making, surgical experiences, and the perceived quality of care; 3) Child Development, including cognition and behavior, educational provision, social experiences, and emotional well-being; and 4) Family Functioning, including parental well-being, relationships, coping strategies, and personal growth. Participants also identified a series of "high" and "low" points throughout their journey and shared their priorities for future research., Conclusions: Narrative interviews provided rich insight into caregivers' experiences of having a child with CFM and enabled the development of a conceptual thematic framework to guide clinical care and future research. Information gathered from this study demonstrates the need to incorporate evidence-based psychological support for families into the CFM pathway from birth onward., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Caring for patients with congenital upper limb differences (CULD) requires an understanding of unique psychosocial challenges. The study purpose was to describe the needs of children with CULD and their caregivers to develop a group curriculum. This mixed-method study included 13 mothers and one father of children with CULD (age 3 months to 14 years; mean 7.2 ± 4.3 years) using Patient-Reported Outcomes Measurement Information System Parent Proxy Reports and caregiver interviews. Patient-Reported Outcomes Measurement Information System Peer Relationships (M = 48.1 ± 10.9) and Pain Interference (M = 44.5 ± 7.5) T-scores were average with below average scores for Physical Function: Upper Extremity (M = 31.9 ± 12.1). Caregivers expressed high interest in groups to create community and mutual support covering themes of responding to questions from strangers, social and coping skills, building self-confidence, accessing resources, advocacy skills, and advice from adults with CULD. Access to a support group with a curriculum addressing CULD-related patient and family needs may improve care., Competing Interests: The authors has disclosed no conflicts of interest., (Copyright © 2024 by National Association of Orthopaedic Nurses.)

Class III malocclusion for individuals with cleft lip and palate has historically been managed with surgery. Orthodontic protraction is a noninvasive alternative that may be associated with lower costs. This analysis investigated the budget impact of protraction versus surgery from an institutional perspective. Using a decision tree, analysis was conducted using costs derived from Medicaid reimbursement codes and using actual institutional reimbursement. Probabilities of success, failure, and complications were based on a clinical trial comparing the 2 treatment modalities. One-way and probabilistic sensitivity analyses tested the robustness of results to model parameters. Based on Medicaid fee schedules and failure rates requiring additional surgery, the total cost of protraction was $79,506 versus $172,807 for surgery, resulting in $93,302 cost-savings per patient. The cost and probability of surgery success, as well as the cost of surgery failure and repeat surgery, had the largest impact on these cost-savings. Probabilistic sensitivity analysis showed cost-savings of nearly $92,000 or higher in >50% of simulations. This study showed that protraction is associated with lower costs than surgery and may present a cost-effective alternative to surgery in eligible, appropriate patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma., (© 2023. The Author(s).)

This paper describes 20 years of microtia and craniofacial microsomia (CFM) psychosocial and healthcare studies and suggests directions for clinical care and research., A narrative review of papers January 2000 to July 2021 related to psychosocial and healthcare experiences of individuals with microtia and CFM and their families., Studies (N = 64) were mainly cross-sectional (69%), included a range of standardized measures (64%), and were with European (31%), American (27%), or multinational (23%) samples. Data were generally collected from both patients and caregivers (38%) or patient self-report (35%). Sample sizes were 11 to 25 (21%), 26 to 50 (19%), 51 to 100 (22%), or over 100 (38%). Studies addressed 5 primary topics: (1) Healthcare Experiences, including Medical Care, Hearing Loss/Amplification, Diagnostic Experiences, and Information Preferences; (2) Psychosocial Experiences, including Teasing, Behavioral Adjustment, Psychosocial Support, and Public Perception; (3) Neurocognitive Functioning and Academic Assistance; (4) Pre- and Post-Operative Psychosocial Outcomes of Ear Reconstruction/Canaloplasty; and (5) Quality of Life and Patient Satisfaction., Care involved multiple specialties and was often experienced as stressful starting at diagnosis. Psychosocial and neurocognitive functioning were generally in the average range, with possible risk for social and language concerns. Coping and resiliency were described into adulthood. Satisfaction and positive benefit of ear reconstruction/canaloplasty were high. Care recommendations include increasing: hearing amplification use, microtia and CFM knowledge among providers, efficient treatment coordination, psychosocial support, academic assistance, and advances to minimize surgical scarring. This broad literature overview informs clinical practice and research to improve psychosocial outcomes.

Craniosynostosis (CS) occurs 1 in 2500 births and surgical intervention is indicated partly due to risk for elevated intracranial pressure (EICP). Ophthalmological examinations help identify EICP and additional vision concerns. This study describes preoperative and postoperative ophthalmic findings in CS patients (N=314) from chart review. Patients included nonsyndromic CS: multisuture (6.1%), bicoronal (7.3%), sagittal (41.4%), unicoronal (22.6%), metopic (20.4%), and lambdoidal (2.2%). Preoperative ophthalmology visits were at M =8.9±14.1 months for 36% of patients and surgery was at M =8.3±4.2 months. Postoperative ophthalmology visits were at age M =18.7±12.6 months for 42% with follow-up at M =27.1±15.1 months for 29% of patients. A marker for EICP was found for a patient with isolated sagittal CS. Only a third of patients with unicoronal CS had normal eye exams (30.4%) with hyperopia (38.2%) and anisometropia (16.7%) at higher rates than the general population. Most children with sagittal CS had normal exams (74.2%) with higher than expected hyperopia (10.8%) and exotropia (9.7%). The majority of patients with metopic CS had normal eye exams (84.8%). About half of patients with bicoronal CS had normal eye exams (48.5%) and findings included: exotropia (33.3%), hyperopia (27.3%), astigmatism (6%), and anisometropia (3%). Over half of children with nonsyndromic multisuture CS had normal exams (60.7%) with findings of: hyperopia (7.1%), corneal scarring (7.1%), exotropia (3.6%), anisometropia (3.6%), hypertropia (3.6%), esotropia (3.6%), and keratopathy (3.6%). Given the range of findings, early referral to ophthalmology and ongoing monitoring is recommended as part of CS care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Competing Interests: We declare no competing interests. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/WHO.

Background: The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains suboptimal largely due to the absence of consideration of aggressive tumor biology., Objective: The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes., Methods: Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype., Results: TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status., Conclusions: Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some research participants suggest that researchers should be returning actionable IRRs to participants., Competing Interests: The authors have declared that no competing interests exist.

Abstract: Children with craniofacial microsomia (CFM) are at increased risk for educational and social concerns. This study describes intervention services and frequency of teasing in a multinational population of children with CFM. Caregivers of children with CFM ages 3 to 18 years in the US and South America were administered a questionnaire. Additional information was gathered from medical charts and photographs. Participants (N = 169) had an average age of 10.1 ± 6.2 years, were primarily male (60%), and from the US (46%) or Colombia (32%). Most participants had microtia and mandibular hypoplasia (70%). They often had unilateral (71%) or bilateral (19%) hearing loss and 53% used a hearing aid. In the US, special education services were provided for 48% of participants enrolled in school; however, similar services were rare (4%) in South America and reflect differences in education systems. Access to any intervention service was higher in the US (80%) than in South America (48%). Caregivers reported children showed diagnosis awareness by an average age of 4.4 ± 1.9 years. Current or past teasing was reported in 41% of the children, starting at a mean age of 6.0 ± 2.4 years, and most often took place at school (86%). As half of the US participants received developmental and academic interventions, providers should screen for needs and facilitate access to services. Given diagnosis awareness at age 4 and teasing at age 6, providers are encouraged to assess for psychosocial concerns and link to resources early in treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by Mutaz B. Habal, MD.)

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Förster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micropatterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow–induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy.

Objective: To examine neurodevelopment in preschool-aged children with craniofacial microsomia (CFM) relative to unaffected peers., Design: Multisite, longitudinal cohort study., Setting: Tertiary care centers in the United States., Participants: We included 92 children with CFM ("cases") through craniofacial centers and clinics. Seventy-six children without CFM (controls) were included from pediatric practices and community advertisements. This study reports on outcomes assessed when participants were an average age of 38.4 months (SD = 1.9)., Main Outcome Measures: We assessed cognitive and motor skills using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), and language function using subtests from the Clinical Evaluation of Language Fundamentals-Preschool, second edition (CELF-P2)., Results: Case-control differences were negligible for Bayley-III cognitive (effect sizes [ES] = -0.06, P = .72) and motor outcomes (ES = -0.19, P = .25). Cases scored lower than controls on most scales of the CELF-P2 (ES = -0.58 to -0.20, P = .01 to .26). Frequency counts for "developmental delay" (ie, one or more scores > 1 SD below the normative mean) were higher for cases (39%) than controls (15%); however, the adjusted odds ratio = 1.73 ( P = 0.21) was not significant. Case-control differences were most evident in children with microtia or other combinations of CFM-related facial features., Conclusions: Cognitive and motor scores were similar for preschool-aged children with and without CFM. However, children with CFM scored lower than controls on language measures. We recommend early monitoring of language to identify preschoolers with CFM who could benefit from intervention.

Background: Survivors of childhood acute lymphoblastic leukemia and lymphoma (ALL/LL) are at risk for cognitive dysfunction, but little is known about its relationship with language proficiency and sociodemographics., Procedure: In this cross-sectional cohort study of Latino survivors of childhood ALL/LL, English and Spanish language proficiency and cognitive and academic functioning were measured and their associations determined using paired t-tests, Pearson correlations, and linear regressions., Results: Participants (N = 57; 50.9% female) had mean ages (years ± SD) of 4.3 ± 2.6 at diagnosis and 10.6 ± 2.9 at testing (range 6-16); mean time post treatment was 3.7 ± 2.6 years. The majority (73.7%) had low socioeconomic status (SES). Most (78.8%) were dual-language learners in English and Spanish. English proficiency was graded as limited-to-fluent and was significantly higher than Spanish (p < .001). Higher SES was correlated with higher English proficiency (r = 0.31, p = .020). Males had higher Spanish proficiency (r = -0.32, p = .034). Controlling for SES and sex, English proficiency accounted for 43% of cognitive functioning variance (F = 14.86, p < .001), 55% of reading comprehension variance (F = 22.14, p < .001), and 21% of mathematics variance (F = 5.76, p = .002)., Conclusions: Low language proficiency correlated with SES but was independently associated with lower cognitive and academic functioning. Research and surveillance for neurocognitive late effects in Latino ALL/LL survivors should incorporate measures of language proficiency and SES to account for their effects on cognitive and academic functioning., (© 2021 Wiley Periodicals LLC.)

Background: The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment., Methods: Individuals aged 40-80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel., Results: Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment., Conclusion: Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted., (© 2021. The Author(s).)

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

Objective: The study aim was to assess behavioral adjustment in preschool children with and without craniofacial microsomia (CFM)., Design: Multisite cohort study of preschoolers with CFM ("cases") or without CFM ("controls")., Participants: Mothers (89%), fathers (9%), and other caregivers (2%) of 161 preschoolers., Outcome Measure: Child Behavior Check List (CBCL 1.5-5); linear regressions with standardized effect sizes (ES) adjusted for sociodemographic confounds., Results: Child Behavior Check Lists for 89 cases and 72 controls (average age 38.3 ± 1.9 months). Children were male (54%), white (69%), and of Latino ethnicity (47%). Cases had microtia with mandibular hypoplasia (52%), microtia only (30%), or other CFM-associated features (18%). Nearly 20% of cases had extracranial anomalies. Composite CBCL scores were in the average range compared to test norms and similar for cases and controls. On the subscales, cases' parents reported higher Anxious/Depressed scores (ES = 0.35, P = .04), Stress Problems (ES = 0.40, P = .04), Anxiety Problems (ES = 0.34, P = .04), and Autism Spectrum Problems (ES = 0.41, P = .02); however, the autism subscale primarily reflected speech concerns. Among cases, more problems were reported for children with extracranial anomalies and certain phenotypic categories with small ES., Conclusions: Behavioral adjustment of preschoolers with CFM was comparable to peers. However, parental reports reflected greater concern for internalizing behaviors; thus, anxiety screening and interventions may benefit children with CFM. Among cases, more problems were reported for those with more complex presentations of CFM. Craniofacial microsomia-related speech problems should be distinguished from associated psychosocial symptoms during developmental evaluations.

Objective: An increasing number of patients use social media for health-related information and social support. This study's objective was to describe the content posted on Facebook groups for individuals with microtia and/or craniofacial microsomia (CFM) and their families in order for providers to gain insight into patient and family needs and experiences to inform clinical care., Methods: Two months of posts, images, comments, and "like" responses from two Facebook groups in the US and the UK were recorded and analyzed using content analysis. A secondary analysis identified statements of emotion., Results: Posts (N = 254) had a total of 7912 "like" responses, 2245 comments, and 153 images. There were three categories of posts: seeking guidance (43%; 9 themes), promoting events/news (33%; 5 themes), and sharing experiences (24%; 3 themes). Across categories, 16% of posts had emotional content. Most comments were responding to posts seeking guidance, including medical care (20%), surgical care (9%), and hearing aids (5%). Promotional posts often aimed to increase CFM awareness. Posts sharing experiences were generally positive, with the highest number of "likes"., Conclusions: Facebook groups members frequently exchanged health-related information, suggesting value placed on input from other families and the convenience of seeking information online. Posts also promoted awareness and shared experiences. Clinical care implications include the need for easily accessible accurate and tailored CFM-related health education. Additionally, providers should demonstrate awareness of health information on social media and may address the potential emotional impact of CFM by facilitating access to resources for social support., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection., Background: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease., Method: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram., Results: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables., Conclusions: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour's molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.

Objective: The Craniofacial microsomia: Longitudinal Outcomes in Children pre-Kindergarten (CLOCK) study is a longitudinal cohort study of neurobehavioral outcomes in infants and toddlers with craniofacial microsomia (CFM). In this article, we review the data collection and methods used to characterize this complex condition and describe the demographic and clinical characteristics of the cohort., Setting: Craniofacial and otolaryngology clinics at 5 study sites., Participants: Infants with CFM and unaffected infants (controls) ages 12 to 24 months were recruited from the same geographical regions and followed to age 36 to 48 months., Methods: Phenotypic, neurodevelopmental, and facial expression assessments were completed during the first and third waves of data collection (time 1 and time 3, respectively). Medical history data were taken at both of these time points and during an intermediate parent phone interview (time 2)., Results: Our cohort includes 108 cases and 84 controls. Most cases and controls identified as white and 55% of cases and 37% of controls identified as Hispanic. Nearly all cases had microtia (95%) and 59% had mandibular hypoplasia. Cases received extensive clinical care in infancy, with 59% receiving care in a craniofacial clinic and 28% experiencing at least one surgery. Study visits were completed at a study site (92%) or at the participant's home (8%)., Conclusions: The CLOCK study represents an effort to overcome the challenges of characterizing the phenotypic and neurodevelopmental outcomes of CFM in a large, demographically and geographically diverse cohort.

Objectives: Craniofacial microsomia (CFM) is a congenital condition that typically involves hypoplasia of the ear and jaw. It is often associated with adverse effects such as hearing loss and sleep-disordered breathing. There is little research on its etiology., Methods: We conducted a case-control study from maternal interview data collected from mothers of infants with and without CFM. The study included 108 children with and 84 children without CFM. Logistic regression with adjustment for demographic factors was used to evaluate associations between maternal exposures of interest and risk for CFM overall, as well as for different phenotypic sub-groups of children on the CFM spectrum., Results: We found a statistically significant association between diabetes mellitus (DM) and CFM (OR 4.01, 95% CI 1.6-10.5). The association was slightly attenuated after adjustment for BMI. Higher parity was also associated with increased risk for CFM (OR 2.0, 95% CI 1.0-4.0). Vitamin A consumption and/or liver consumption was associated with a 70% lower risk compared with non-users (OR 0.3, 95% 0.1-0.8). Maternal age at the time of pregnancy was not associated with CFM., Conclusions: These analyses contribute evidence linking maternal DM with an elevated risk of having an infant with CFM, which is consistent with previous research and adds to the body of knowledge about the strength of this association. Further study is warranted to understand the potential mechanisms underlying the effect of DM in the developing embryo., (© 2019 Wiley Periodicals, Inc.)

Objective: To describe psychosocial functioning before and after participation in support groups for pediatric patients with craniofacial diagnoses and their families., Design: Baseline and postgroup outcomes and comparison to test norms., Setting: Urban children's hospital., Participants: Patients (N = 138) were 54% female, primarily Latino (83%), aged 7 to 18 years (mean = 10.4, standard deviation = 2.8), and had public insurance (72%). Patients had isolated cleft lip/palate (54%), craniofacial syndromes (19%), craniofacial microsomia/microtia (14%), or other diagnoses (12%). Caregivers (n = 138) were mostly mothers (80%)., Intervention: Support groups focused on peer normalization, social skills, and coping for patients with craniofacial diagnoses., Main Outcome Measure: Selected scales of the Behavior Assessment System for Children-Second Edition completed by patients and caregivers (51% Spanish; 49% English)., Results: While in the average range, caregivers reported significantly higher baseline clinical concerns and patients and caregivers reported lower positive scales compared to test norms. Postgroup, patients reported significantly lower social stress than peer norms. Caregivers reported higher postgroup clinical scales, but no differences from test norms in the positive scales. In comparing pre to postgroup means, all but one scale showed significant improvement. The largest effect sizes were for higher self-reported self-esteem ( d = 0.49) and lower caregiver-reported depression ( d = 0.54) in their children., Conclusions: Although greater clinical concerns were reported compared to test norms, baseline and postgroup functioning was in the average range. Patients and caregivers reported significantly improved psychosocial functioning following group participation, particularly for adaptive skills and self-esteem.

Background: Some patients with isolated sagittal craniosynostosis have demonstrated mild neurodevelopmental delays. This study examined potential preoperative risk factors for developmental delay., Methods: Patients completed preoperative Bayley Scales of Infant and Toddler Development, Third Edition, and medical records were reviewed. Multivariate analyses of covariance and correlations were calculated., Results: Participants (n = 77) were predominantly male (77.9 percent) and were aged 2 to 12 months (mean, 5.1 ± 2.3 months). Patients were classified with no delays [n = 63 (82 percent)] or delays [n = 14 (18 percent)] in one or more developmental area(s). There were no group sociodemographic differences. Prenatally, patients with delays versus no delays had lower mean gestational age in weeks (36.9 ± 2.8 weeks versus 39.1 ± 1.7 weeks; p = 0.001) with higher rates of gestational diabetes (36 percent versus 5 percent; p = 0.006) and premature rupture of membranes (14 percent versus 2 percent; p = 0.026). At birth, patients with delays had lower mean birth weight (2982 ± 714 g versus 3374 ± 544 g; p = 0.053), higher rates of respiratory distress (29 percent versus 5 percent; p = 0.005), additional medical diagnoses (57 percent versus 13 percent; p = 0.001), and longer mean neonatal intensive care unit stays (1.4 ± 1.8 weeks versus 0.2 ± 0.9 week; p = 0.002). Variables differing by group had moderate correlations., Conclusions: Patients with nonsyndromic sagittal craniosynostosis that had delays in development had lower gestational age and birth weight, with more prenatal and birth complications. These factors can help identify patients who might be at risk for delay and need close monitoring., Clinical Question/level of Evidence: Risk, III.

This study describes stressors, resources, and recommendations related to craniofacial microsomia (CFM) care from the perspective of caregivers of children with CFM and adults with CFM to inform improved quality of healthcare delivery. A mixed method design was used with fixed-response and open-ended questions from an online survey in English. The survey included demographics, CFM phenotypic information, and items about CFM-related experiences across settings. Themes were identified by qualitative analysis of responses to open-ended questions. Respondents (n = 51) included caregivers (n = 42; 90% mothers) and adults with CFM (n = 9; 78% female), who had a mean age of 45 ± 6 years. Most children were male (71%) with an average age of 7 ± 4 years. Respondents were primarily white (80%), non-Hispanic (89%), from the United States (82%), had a college degree (80%), and had private health insurance (80%). Reflecting the high rate of microtia (84%) in the sample, themes centered on the impact of hearing difficulties across settings with related language concerns. Negative social experiences were frequently described and school needs outlined. Multiple medical stressors were identified and corresponding suggestions included: providers need to be better informed about CFM, treatment coordination among specialists, and preference for a family-centered approach with reassurance, empathy, and clear communication. Advice offered to others with CFM included positive coping strategies. Overall, caregivers' and patients' responses reflected the complexity of CFM treatment. Incorporating these perspectives into routine CFM care has the potential to reduce family distress while improving their healthcare.

Objectives: To determine whether infant cases with craniofacial microsomia (CFM) evidence poorer neurodevelopmental status than demographically similar infants without craniofacial diagnoses ("controls"), and to examine cases' neurodevelopmental outcomes by facial phenotype and hearing status., Study Design: Multicenter, observational study of 108 cases and 84 controls aged 12-24 months. Participants were assessed by the Bayley Scales of Infant and Toddler Development-Third Edition and the Preschool Language Scales-Fifth Edition (PLS-5). Facial features were classified with the Phenotypic Assessment Tool for Craniofacial Microsomia., Results: After adjustment for demographic variables, there was little difference in Bayley Scales of Infant and Toddler Development-Third Edition or Preschool Language Scales-Fifth Edition outcomes between cases and controls. Estimates of mean differences ranged from -0.23 to 1.79 corresponding to standardized effect sizes of -.02 to 0.12 (P values from .30 to .88). Outcomes were better among females and those with higher socioeconomic status. Among cases, facial phenotype and hearing status showed little to no association with outcomes. Analysis of individual test scores indicated that 21% of cases and 16% of controls were developmentally delayed (OR  0.68, 95% CI 0.29-1.61)., Conclusions: Although learning problems have been observed in older children with CFM, we found no evidence of developmental or language delay among infants. Variation in outcomes across prior studies may reflect differences in ascertainment methods and CFM diagnostic criteria., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study describes postpartum depression rates and risk factors for mothers with infants with cleft lip and/or palate as postpartum depression has been associated with a range of negative maternal and child outcomes. A retrospective chart review from August 2009 to May 2015 included medical diagnoses, demographics, receipt of prenatal diagnosis, and the Edinburgh Postnatal Depression Scale (EPDS). Mothers (N = 206) had infants (59.2% male; mean age in weeks 5.1 ± 6.9) with isolated cleft lip (18%), cleft palate (22.8%), or cleft lip and palate (59.2%). Mothers ranged from 16 to 45 years old (mean age 29 ± 6.2) and half had received a prenatal diagnosis. Patients mostly had public insurance (57.8%) and represented diverse ethnicities. Based on the EPDS, 11.7% of mothers met the depression cutoff of 10 or higher. The majority endorsed self-blame (68.9%), difficulty coping (59.2%), and feeling anxious (57.3%). Mothers of infants with cleft lip or cleft lip and palate who did not receive a prenatal diagnosis had higher total EPDS scores, anxiety, and incidence of feeling scared. Higher EPDS scores were predicted by not having a prenatal diagnosis and by older maternal age. Mothers of infants with a cleft had similar rates of postpartum depression as the general population; however, those who were older and who did not receive a prenatal diagnosis endorsed more symptoms. Prenatal diagnosis may contribute to positive maternal postpartum adjustment. Providers should incorporate screening for risk factors into their evaluation and treatment planning.