Spectrum of brain malformations in fetuses with mild tubulinopathy.

OBJECTIVE: To report on a large cohort of fetuses with mild forms of tubulinopathy and to define prenatal ultrasound and magnetic resonance imaging (MRI) features that can facilitate prenatal diagnosis. METHODS: This was a retrospective multicenter study of fetuses diagnosed between January 2007 and February 2022 with a mild tubulinopathy (without lissencephaly or microlissencephaly). We collected and reviewed brain imaging and genetic data, and defined major criteria as findings observed in ≥ 70% of the patients and minor criteria as those observed in ≥ 50% but < 70% of the patients. RESULTS: Our cohort included 34 fetuses. The mean gestational age at ultrasound screening, when suspicion of a central nervous system anomaly was first raised, was 24.2 (range, 17-33) weeks. Callosal anomalies (n = 19 (56%)) and abnormal ventricles (n = 18 (53%)) were the main reasons for referral. The mean gestational age at neurosonography was 28.3 (range, 23-34) weeks and that at MRI was 30.2 (range, 24-35) weeks. Major ultrasound criteria were midline distortion, ventricular asymmetry, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation. Minor ultrasound criteria were distortion of the cavum septi pellucidi, abnormal corpus callosum, absent or asymmetric olfactory sulci, ventriculomegaly and basal ganglia dysmorphism. Major MRI criteria were midline distortion, distortion of the cavum septi pellucidi, ventricular asymmetry, dilatation (generally unilateral) and/or distortion, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation (mainly dysgyria). Minor MRI criteria were absent or asymmetric olfactory sulci, abnormal bulge of the pons, anteroposterior diameter of the pons ≤ 5th centile and brainstem asymmetry. A mutation was found in TUBB3 (44.1% of cases), TUBB (23.5%), TUBB2B (14.7%) or TUBA1A (17.6%). The mutation was inherited from a parent in 18/34 cases. The pregnancy was terminated in 23/34 cases. CONCLUSIONS: Prenatal diagnosis of mild forms of tubulinopathy is possible but challenging. We have defined, in this large series of fetuses, major and minor criteria that can help identify this entity in utero. Most findings can be visualized on ultrasound. This evaluation is also important for prenatal counseling. Once a prenatal diagnosis of mild tubulinopathy is suspected, the family members should be referred for exome sequencing and MRI. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Surgical outcomes in survivors of childhood cancer undergoing thyroidectomy: A single-institution experience.

BACKGROUND: Childhood cancer survivors (CCS) are at increased risk for thyroid disease, and many require definitive management with thyroid surgery. Despite this, there is limited evidence on surgical outcomes among CCS. We sought to evaluate postoperative outcomes at our institution among CCS undergoing thyroid surgery compared to patients without a history of primary childhood malignancy. PROCEDURE: Medical records were reviewed for 638 patients treated at the Children's Hospital of Philadelphia Pediatric Thyroid Center between 2009 and 2020. Rates of surgical complications, including recurrent laryngeal nerve (RLN) paralysis and hypoparathyroidism, among CCS were compared to patients with sporadic/familial thyroid cancer, Graves' disease, and other benign thyroid conditions. Operative time and intraoperative parathyroid hormone levels were also evaluated. RESULTS: There were no significant differences in long-term surgical complication rates, such as permanent RLN paralysis and hypoparathyroidism, between CCS and patients without a history of primary childhood malignancy (all p > .05). For all surgical outcomes, there were no significant differences in complication rates when CCS were compared to those undergoing surgery for sporadic/familial thyroid cancer or Graves' disease (all p > .05). CCS with benign final pathology had significantly higher rates of transient hypoparathyroidism compared to patients with benign thyroid conditions (p < .001). CONCLUSIONS: Our study suggests that CCS are not at higher risk of long-term complications from thyroid surgery when treated by high-volume surgeons within a multidisciplinary team.

Prevalence of COL4A1 and COL4A2 mutations in severe fetal multifocal hemorrhagic and/or ischemic cerebral lesions.

OBJECTIVE: To establish the prevalence of COL4A1 and COL4A2 gene mutations in fetuses presenting with a phenotype suggestive of cerebral injury. METHODS: This was a single-center retrospective analysis of all cases of fetal cerebral anomalies suggestive of COL4A1 or COL4A2 gene mutation over the period 2009-2018. Inclusion criteria were: (1) severe and/or multifocal hemorrhagic cerebral lesions; (2) multifocal ischemic-hemorrhagic cerebral lesions. These anomalies could be of different ages and associated with schizencephaly or porencephaly. Between fetuses with and those without a mutation, we compared gestational age at the time of diagnosis, parity and fetal gender. RESULTS: Among the 956 cases of cerebral anomaly diagnosed in our center during the 10-year study period, 18 fetuses were identified for inclusion. A pathogenic COL4A1 gene mutation was found in five of these cases, among which four were de-novo mutations. A variant of unknown significance was found in four fetuses: in the COL4A1 gene in one case and in the COL4A2 gene in three cases. No COL4A1 or COL4A2 mutation was found in the remaining nine fetuses. The median (interquartile range) gestational age at diagnosis was significantly lower in cases with a mutation (24 (22-26) weeks) than in cases without a mutation (32 (29.5-34.5) weeks) (P = 0.03). CONCLUSIONS: A phenotype suggestive of cerebral injury was found in 18 of the 956 (1.9%) cases in our population, in 28% of which there was an associated COL4A1 or COL4A2 mutation. COL4A1 and COL4A2 gene mutations should be sought systematically in cases of severe and/or multifocal hemorrhagic or ischemic-hemorrhagic cerebral lesions, with or without schizencephaly or porencephaly. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Deciphering the natural history of SCA7 in children.

BACKGROUND AND PURPOSE: Childhood-onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. METHODS: We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion > 100 CAG. RESULTS: We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. CONCLUSION: SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.

Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.

A Rabbit Model for Optimization of Amniotic Fluid Components in the EXTrauterine Environment for Newborn Development (EXTEND) System.

In this model article, we present a protocol for continuous amniotic fluid exchange in rabbits using a novel system to test the effects of growth factor-deficient, artificial amniotic fluid on bowel development. BACKGROUND: Ideally, the EXTrauterine Environment for Neonatal Development (EXTEND) will provide physiologic support to the extreme premature infant. An important component of that environment is the amniotic fluid. Thus, we developed an animal model to study the growth factors found within amniotic fluid and inform design of a synthetic fluid to optimize fetal development. METHODS: We designed a model of amniotic fluid exchange within the pregnant rabbit, continuously removing the natural fluid from around 2 fetuses per doe and replacing it with a physiologic electrolyte solution during the final 100 h of gestation. Two fetuses from the contralateral uterine horn were used as sham-operated controls. Thirty-eight fetuses were analyzed, 19 in each group. We analyzed the fetal growth and bowel development. RESULTS: Ultrasound after 100 h of exchange showed equivalent fluid volumes, p = 0.63. Cultures were negative for bacterial colonization. Final fluid protein concentrations were 11.6% that of control fluid (mean 1,451 ± 224.2 vs. 12,491 ± 849.2 µg/mL). There was no significant difference in fetal growth, with experimental weights 91.4% of control weights, p = 0.07. Fetal bowel weights (90.1%, p = 0.16) and lengths (94.2%, p = 0.49) were also not significantly less compared to controls. There was no significant difference in villous height or crypt depth measurements between the groups, and absorptive capacity of the bowel was not different between groups, p = 0.44. CONCLUSION: This animal model allows for manipulation of the components of amniotic fluid. Marked reduction of natural amniotic fluid proteins during gestation does not appear to significantly impair fetal growth or bowel development. Further work with this model will assess the importance of amniotic fluid components for normal development to inform design of a synthetic fluid for use during EXTEND.

Preemptive Delivery and Immediate Resection for Fetuses with High-Risk Sacrococcygeal Teratomas.

INTRODUCTION: Fetuses with "high-risk" sacrococcygeal teratoma (SCT) have a mortality rate of 40-50%. While fetal surgery may benefit select fetuses prior to 27 weeks' gestation, many fetuses die due to consequences of rapid tumor growth after 27 weeks. Here we report our experience applying "preemptive" delivery to fetuses who manifest signs of decompensation between 27 and 32 weeks. METHODS: A retrospective review of SCT fetuses delivered between 2010 and 2016 at ≤32 weeks' gestation was performed. Patients who decompensated prior to 27 weeks and were treated with fetal surgery or neonatal palliation were excluded. RESULTS: Forty-two SCT fetuses were evaluated, and 11 were preemptively delivered in response to impending fetal or maternal decompensation. Nine (81.8%) survived. One death was due to pulmonary hypoplasia in a neonate with significant intra-abdominal tumor burden, and the other was due to in utero tumor rupture. There were no deaths related to prematurity in this cohort. CONCLUSIONS: Many fetuses with SCT manifest signs of decompensation between 27 and 32 weeks. In the absence of fetal hydrops prior to 27 weeks or tumor rupture in utero, early delivery is associated with favorable outcomes. Our single-center experience supports a management algorithm change to incorporate "preemptive" delivery for selected cases.

Chronically Hypoxic Fetal Lambs Supported by an Extra-Uterine Device Exhibit Mitochondrial Dysfunction and Elevations of Hypoxia Inducible Factor 1-Alpha.

INTRODUCTION: We have recently developed an extra-uterine environment for neonatal development (EXTEND) capable of supporting premature fetal lambs and have been able to replicate hypoxic in utero conditions by controlling fetal oxygen delivery. In this study, we investigated the fetal mitochondrial response to hypoxia. METHODS: Eight premature fetal lambs were delivered via hysterotomy and transitioned to extra-uterine support for 3 weeks. The lambs were divided into 2 groups: normoxic fetuses which maintained physiologic oxygen delivery and hypoxic fetuses in which oxygen delivery was significantly reduced. Control fetuses were delivered via hysterotomy but not cannulated. Measurements of mitochondrial membrane potential (MMP) were performed in peripheral blood mononuclear cells. RESULTS: There were no significant differences in MMP between normoxic EXTEND fetuses and controls. Hypoxic fetuses had significantly more depolarized mitochondria compared to normoxic fetuses overall, and these changes were specifically appreciated in weeks 1 and 2, but not by week 3. Hypoxic fetuses had significantly elevated levels of HIF-1α compared to normoxic fetuses in the first 2 weeks. DISCUSSION: Normoxic fetal lambs supported by EXTEND demonstrate normal mitochondrial function as evidenced by equivalent membrane potentials compared to control fetuses. Hypoxic fetuses exhibit mitochondrial dysfunction, though they do show evidence of adaptation after 3 weeks of hypoxic exposure.

Premature Lambs Exhibit Normal Mitochondrial Respiration after Long-Term Extrauterine Support.

BACKGROUND: In an effort to mitigate the major morbidities and mortality associated with extreme prematurity, we have developed an EXTrauterine Environment for Neonatal Development (EXTEND) designed to provide physiologic support of extremely premature infants. OBJECTIVES: We have previously shown that long-term, physiologic support of premature fetal lambs is possible with EXTEND, but in this study, we sought to demonstrate bioenergetic equipoise at the tissue level. METHODS: Four premature fetal lambs were delivered by hysterotomy at gestational ages (GA) of 105-107 days (term ∼145 days), cannulated via the umbilical vessels, and transitioned to support on EXTEND for 3-4 weeks. Five control fetuses were age-matched to the GA of experimental fetuses at the time of study end (128-134 days GA) and immediately sacrificed after hysterotomy. Mitochondria were isolated from the heart, liver, kidney, and skeletal muscle of fetuses at the time of sacrifice, and oxygen consumption rates (OCRs) were measured. RESULTS: There were no differences in basal mitochondrial OCR between EXTEND and control fetuses for heart, kidney, or skeletal muscle. For liver, the basal OCR was higher in EXTEND fetuses compared to controls. There were no differences in physiologic maximal OCR or reserve capacity for any tissue analyzed. CONCLUSIONS: Fetal lambs supported by EXTEND demonstrate physiologic mitochondrial function as evidenced by adequate basal and physiologic maximal cellular respiration as well as preserved reserve capacity.

Erythropoietin Prevents Anemia and Transfusions in Extremely Premature Lambs Supported by an EXTrauterine Environment for Neonatal Development (EXTEND).

BACKGROUND: We recently developed an EXTrauterine Environment for Neonatal Development (EXTEND) that provides physiologic support for premature lambs. Here, we assess the efficacy of exogenous erythropoietin (EPO) to prevent anemia and transfusions on EXTEND. MATERIALS AND METHODS: Lambs were cannulated at 0.7 gestation and supported on EXTEND for up to 4 weeks. The lambs were divided into three groups: (1) No EPO, (2) Low EPO (300 U kg-1 per day), and (3) High EPO (800 U kg-1 per day). Daily hematocrit and weekly complete blood count were assessed. RESULTS: The mean percentage change in hematocrit from baseline was significantly different between the groups (No EPO -23.6 ± 7.8% vs. Low EPO -16.6 ± 6.4% vs. High EPO +2.6 ± 6.6%; p = 0.02). This occurred despite a greater median number of blood transfusions in the No EPO group (5 vs. 1 vs. 0; p = 0.02). EPO administration was associated with a higher mean corpuscular volume (MCV; p < 0.01) and reticulocyte count (p = 0.02). The High EPO group was comparable to in utero control fetuses with respect to hematocrit (p = 0.49), MCV (p = 0.24), and reticulocyte count (p = 0.68). CONCLUSIONS: EPO (800 U kg-1 per day) prevents anemia, eliminates transfusions, and restores normal red blood cell indices in premature lambs supported by EXTEND.

Oil spill cleanup employing magnetite nanoparticles and yeast-based magnetic bionanocomposite.

Oil spill is a serious environmental concern, and alternatives to remove oils from water involving biosorbents associated to nanoparticles is an emerging subject. Magnetite nanoparticles (MNP) and yeast magnetic bionanocomposite (YB-MNP) composed by yeast biomass from the ethanol industry were produced, characterized, and tested to remove new motor oil (NMO), mixed used motor oil (MUMO) and Petroleum 28 °API (P28API) from water following the ASTM F726-12 method, which was adapted by insertion of a lyophilization step to ensure the accuracy of the gravimetric approach. Temperature, contact time, the type and the amount of the magnetic material were the parameters evaluated employing a fractional factorial design. It was observed the removal of 89.0 ±â€¯2.6% or 3522 ±â€¯118 g/kg (NMO) employing MNP; 69.1 ±â€¯6.2% or 2841 ±â€¯280 g/kg (MUMO) with YB-MNP; and 55.3 ±â€¯8.2% or 2157 ±â€¯281 g/kg (P28API) using MNP. The temperature was the most significant parameter in accordance with the Pareto's graphics (95% confidence) for all oil samples considered in this study as well as the two magnetic materials. Contact time and the interaction between the materials and temperature were also relevant. The D-Optimals designs showed that the NMO and P28API responded in a similar way for all evaluated parameters, while the uptake of MUMO was favored at higher temperatures. These behaviors demonstrate the influence of oil characteristics and the intermolecular forces between the oil molecules on the mechanism dragging process performed by the attraction between magnetite nanoparticles and a 0.7 T magnet. It was clear that this kind of experiment is predominantly a physic phenomenon which cannot be described as adsorption process.

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype.

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.

Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients.

Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.

Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

Phase II trial of post-operative radiotherapy with concurrent cisplatin plus panitumumab in patients with high-risk, resected head and neck cancer.

BACKGROUND: Treatment intensification for resected, high-risk, head and neck squamous cell carcinoma (HNSCC) is an area of active investigation with novel adjuvant regimens under study. In this trial, the epidermal growth-factor receptor (EGFR) pathway was targeted using the IgG2 monoclonal antibody panitumumab in combination with cisplatin chemoradiotherapy (CRT) in high-risk, resected HNSCC. PATIENTS AND METHODS: Eligible patients included resected pathologic stage III or IVA squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or human-papillomavirus (HPV)-negative oropharynx, without gross residual tumor, featuring high-risk factors (margins <1 mm, extracapsular extension, perineural or angiolymphatic invasion, or ≥2 positive lymph nodes). Postoperative treatment consisted of standard RT (60-66 Gy over 6-7 weeks) concurrent with weekly cisplatin 30 mg/m2 and weekly panitumumab 2.5 mg/kg. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-six patients were accrued; 44 were evaluable and were analyzed. The median follow-up for patients without recurrence was 49 months (range 12-90 months). The probability of 2-year PFS was 70% (95% CI = 58%-85%), and the probability of 2-year OS was 72% (95% CI = 60%-87%). Fourteen patients developed recurrent disease, and 13 (30%) of them died. An additional five patients died from causes other than HNSCC. Severe (grade 3 or higher) toxicities occurred in 14 patients (32%). CONCLUSIONS: Intensification of adjuvant treatment adding panitumumab to cisplatin CRT is tolerable and demonstrates improved clinical outcome for high-risk, resected, HPV-negative HNSCC patients. Further targeted monoclonal antibody combinations are warranted. REGISTERED CLINICAL TRIAL NUMBER: NCT00798655.

Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer.

BACKGROUND: We previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF). PATIENTS AND METHODS: Patients with previously untreated stage III-IVB SCCHN were randomized to receive: conventionally fractionated radiation (70 Gy), concurrent cetuximab, and concurrent pemetrexed (arm A); or the identical regimen plus concurrent bevacizumab followed by bevacizumab maintenance for 24 weeks (arm B). The primary end point was 2-year progression-free survival (PFS), with each arm compared with historical control. Exploratory analyses included the relationship of established prognostic factors to PFS and quality of life (QoL). RESULTS: Seventy-eight patients were randomized: 66 oropharynx (42 HPV-positive, 15 HPV-negative, 9 unknown) and 12 larynx; 38 (49%) had heavy tobacco exposure. Two-year PFS was 79% [90% confidence interval (CI) 0.69-0.92; P < 0.0001] for arm A and 75% (90% CI 0.64-0.88; P < 0.0001) for arm B, both higher than historical control. No differences in PFS were observed for stage, tobacco history, HPV status, or type of center (community versus academic). A significantly increased rate of hemorrhage occurred in arm B. SCCHN-specific QoL declined acutely, with marked improvement but residual symptom burden 1 year post-treatment. CONCLUSIONS: RT with a concurrent non-platinum regimen of cetuximab and pemetrexed is feasible in academic and community settings, demonstrating expected toxicities and promising efficacy. Adding bevacizumab increased toxicity without apparent improvement in efficacy, countering the hypothesis that dual EGFR-VEGF targeting would overcome radiation resistance, and enhance clinical benefit. Further development of cetuximab, pemetrexed, and RT will require additional prospective study in defined, high-risk populations where treatment intensification is justified.

Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome.

Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array-comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management.

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.

Post-operative Opioid Reduction Protocol Reduces Racial Disparity in Clinical Outcomes in Children.

INTRODUCTION: Racial disparities in health outcomes continue to exist for children requiring surgery. Previous investigations suggest that clinical protocols may reduce racial disparities. A post-operative opioid reduction protocol was implemented in children undergoing abdominal surgery who were less than 1 years old at a tertiary level hospital. The purpose of this investigation was to determine if the clinical protocol was associated with a reduction in racial disparity in post-operative opioid prescribing patterns and associated clinical outcomes. METHODS: A post-operative opioid reduction protocol based on standing intravenous acetaminophen, educational sessions with nursing staff, and standardized post-operative sign-out between the surgical and NICU teams was implemented in children under 1 year old in 2016. A time series and before and after analysis was conducted using a historical pre-intervention cohort (Jan 2011-Dec 2015) and prospectively collected post-intervention cohort (Jan 2016-Jan 2021). Primary outcomes included post-operative opioid use and post-operative pain scores stratified by race. Secondary outcomes included associated clinical outcomes also stratified by race. RESULTS: A total of 249 children were included in the investigation, 117 in the pre-intervention group and 132 in the post intervention group. The majority of patients in both cohorts were either White or Black. The two cohorts were equally matched in terms of pre-operative clinical variables. In the pre-intervention cohort, the median post-operative morphine equivalents in White children was 2.1 mg/kg (IQR 0.2, 11.1) while in Black children it was 13.1 mg/kg (IQR 2.4, 65.3), p-value = 0.0352. In the post-intervention cohort, the median value for White children and Black children was statistically identical (0.05 mg/kg (IQR 0, 0.5) and 0.0 mg/kg (IQR 0, 0.3), respectively, p-value = 0.237). This pattern was also demonstrated in clinical variables including length of stay, intubation length and total parenteral nutrition use. In the pre-intervention cohort, the total length of stay for white children was 16 days while for black children it was 45 days (p = 0.007). In the postintervention cohort the length of stay for both White and Black children were identical at 8 days (p = 0.748). CONCLUSION: The use of a clinical opioid reduction protocol implemented at a tertiary medical center was associated with a reduction in racial disparity in opioid prescribing habits in children. Prior to the protocol, there was a racial disparity in clinical variables associated with prolonged opioid use including length of stay, TPN use, and intubation length. The clinical protocol reduced variability in opioid prescribing patterns in all racial groups which was associated with a reduction in variability in associated clinical variables. LEVEL OF EVIDENCE: Level III.