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.

Medullary Tegmental Cap Dysplasia: Fetal and Postnatal Presentations of a Unique Brainstem Malformation.

BACKGROUND AND PURPOSE: Medullary tegmental cap dysplasia is a rare brainstem malformation, first described and defined by James Barkovich in his book Pediatric Neuroimaging from 2005 as an anomalous mass protruding from the posterior medullary surface. We describe the neuroimaging, clinical, postmortem, and genetic findings defining this unique malformation. MATERIALS AND METHODS: This is a multicenter, international, retrospective study. We assessed the patients' medical records, prenatal ultrasounds, MR images, genetic findings, and postmortem results. We reviewed the medical literature for all studies depicting medullary malformations and evaluated cases in which a dorsal medullary protuberance was described. RESULTS: We collected 13 patients: 3 fetuses and 10 children. The medullary caps had multiple characteristics. Associated brain findings were a rotated position of the medulla, a small and flat pons, cerebellar anomalies, a molar tooth sign, and agenesis of the corpus callosum. Systemic findings included the following: polydactyly, hallux valgus, large ears, and coarse facies. Postmortem analysis in 3 patients revealed that the cap contained either neurons or white matter tracts. We found 8 publications describing a dorsal medullary protuberance in 27 patients. The syndromic diagnosis was Joubert-Boltshauser syndrome in 11 and fibrodysplasia ossificans progressiva in 14 patients. CONCLUSIONS: This is the first study to describe a series of 13 patients with medullary tegmental cap dysplasia. The cap has different shapes: distinct in Joubert-Boltshauser syndrome and fibrodysplasia ossificans progressive. Due to the variations in the clinical, imaging, and postmortem findings, we conclude that there are multiple etiologies and pathophysiology. We suggest that in some patients, the pathophysiology might be abnormal axonal guidance.

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.

Late Toxicity and Long-Term Local Control in Patients With Ultra-Central Lung Tumours Treated by Intensity-Modulated Radiotherapy-Based Stereotactic Ablative Body Radiotherapy With Homogenous Dose Prescription.

AIMS: To report late toxicity and long-term outcomes of intensity-modulated radiotherapy (IMRT)-based stereotactic ablative body radiotherapy (SABR) in patients with ultra-central lung tumours. MATERIALS AND METHODS: This is a single-institution retrospective analysis of patients treated with SABR for ultra-central tumours between May 2008 and April 2016. Ultra-central location was defined as tumour (GTV) abutting or involving trachea, main or lobar bronchi. Respiratory motion management and static-field dynamic-IMRT were used, with dose prescribed homogeneously (maximum <120%). Descriptive analysis, Kaplan-Meier method, log-rank test and Cox regression were used to assess outcomes. RESULTS: Sixty-five per cent of patients had inoperable primary non-small cell lung cancer and 35% had lung oligometastases. The median age was 72 (range 34-85) years. The median gross tumour volume and planning target volume (PTV) were 19.6 (range 1.7-203.3) cm3 and 57.4 (range 7.7-426.6) cm3, respectively. The most commonly used dose fractionation was 60 Gy in eight fractions (n = 51, 87.8%). Median BED10 for D98%PTV and D2%PTV were 102.6 Gy and 115.06 Gy, respectively. With a median follow-up of 26.5 (range 3.2-100.5) months, fatal haemoptysis occurred in five patients (8.7%), of which two were directly attributable to SABR. A statistically significant difference was identified between median BED3 for 4 cm3 of airway, for patients who developed haemoptysis versus those who did not (147.4 versus 47.2 Gy, P = 0.005). At the last known follow-up, 50 patients (87.7%) were without local recurrence. Freedom from local progression at 2 and 4 years was 92 and 79.8%, respectively. The median overall survival was 34.3 (95% confidence interval 6.1-61.6) months. Overall survival at 2 and 4 years was 55.1 and 41.2%, respectively. CONCLUSION: In patients with high-risk ultra-central lung tumours, IMRT-based SABR with homogenous dose prescription achieves high local control, similar to that reported for peripheral tumours. Although fatal haemoptysis occurred in 8.7% of patients, a direct causality with SABR was evident in only 3%. Larger studies are warranted to ascertain factors associated with outcomes, especially toxicity, and identify patients who would probably benefit from this treatment.

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.

Fetoscopic insufflation modeled in the extrauterine environment for neonatal development (EXTEND): Fetoscopic insufflation is safe for the fetus.

BACKGROUND: Minimally invasive fetal surgery, or fetoscopy, is an alternative to open fetal surgery to repair common birth defects like myelomeningocele. Although this hysterotomy-sparing approach reduces maternal morbidity, the effects of in utero insufflation on the fetus are poorly understood. Our purpose was to determine the optimal fetal insufflation conditions. METHODS: Fetal sheep at gestational age 104 to 107 days were studied under insufflation conditions in utero and ex utero. The ex utero fetuses were cannulated via their umbilical vessels into a support device, the EXTra-uterine Environment for Neonatal Development (EXTEND). EXTEND fetuses were exposed to four different insufflation conditions for four hours: untreated carbon dioxide (CO2) (n=5), warm humidified (whCO2) (n=4), whCO2 with the umbilical cord exposed (n=3), and whCO2 without amniotic fluid (skin and cord exposed) (n=3). RESULTS: In utero insufflation led to significant increases in fetal CO2 and reductions in fetal pH. Ex utero insufflation with whCO2 did not lead to changes in fetal blood gas measurements or cerebral perfusion parameters. Insufflation with whCO2 with an exposed umbilical cord led to reduced umbilical blood flow. CONCLUSIONS: Insufflation with warm humidified CO2 with an amniotic fluid covered umbilical cord is well tolerated by the fetus without significant changes in hemodynamics or cerebral perfusion parameters. TYPE OF STUDY: Basic science LEVEL OF EVIDENCE: N/A.

Positive Predictive Value of Neck Imaging Reporting and Data System Categories 3 and 4 Posttreatment FDG-PET/CT in Head and Neck Squamous Cell Carcinoma.

BACKGROUND AND PURPOSE: The Neck Imaging Reporting and Data System is a standardized reporting system intended to risk stratify patients treated for head and neck squamous cell carcinoma. The purpose of this study is to investigate the positive predictive value of the Neck Imaging Reporting and Data System categories 3 and 4 on posttreatment PET/CT in patients treated definitively for head and neck squamous cell carcinoma. MATERIALS AND METHODS: We retrospectively identified patients treated definitively for head and neck squamous cell carcinoma between 2006 and 2018. Patients whose posttreatment PET/CT scans were interpreted as Neck Imaging Reporting and Data System 3 (suspicious) or 4 (definitive recurrence) at the primary site, regional nodes, or at distant sites were included. The reference standard was histopathology or unequivocal imaging or clinical evidence of treatment failure. The positive predictive values of Neck Imaging Reporting and Data System 3 and 4 posttreatment PET/CT were calculated. RESULTS: Seventy-two of 128 patients with posttreatment PET/CT interpreted as Neck Imaging Reporting and Data System 3 at the primary site, regional nodes, or distant sites were proved to have treatment failure at the suspicious sites, yielding an overall positive predictive value of 56% (95% CI, 48%-65%). The positive predictive values of Neck Imaging Reporting and Data System 3 by subsite were as follows: primary site, 56% (44/79); regional nodes, 65% (34/52); and distant sites, 79% (42/53). All 69 patients with posttreatment PET/CT interpreted as Neck Imaging Reporting and Data System 4 had true treatment failure, yielding a positive predictive value of 100% (95% CI, 96%-100%): primary site, 100% (28/28); regional nodes, 100% (32/32); and distant sites, 100% (29/29). CONCLUSIONS: The positive predictive value of Neck Imaging Reporting and Data System 3 on posttreatment PET/CT is relatively low. Thus, Neck Imaging Reporting and Data System 3 findings should be confirmed with tissue sampling before instituting new salvage treatment regimens to avoid unnecessary overtreatment and its associated toxicities. Neck Imaging Reporting and Data System 4 reliably indicates recurrent disease.

The Effects of Nitric Oxide in Oxygenator Sweep Gas During Extracorporeal Circulation in a Neonatal Ovine Model.

Extracorporeal membrane oxygenation is a life-saving intervention, but bleeding complications are frequent. Given that the combination of platelet loss and dysfunction is a major contributor to this acquired bleeding diathesis, efforts to combat these phenomena are of great clinical importance. In this study, we investigated the effects of nitric oxide (NO) added to the sweep gas of an extracorporeal circuit in a neonatal ovine model. Eight lambs (age 9.6 ± 1.9 days) were cannulated via the neck vessels and maintained on a pumpless arteriovenous extracorporeal membrane oxygenation circuit with blood flow restricted to 100 ml/min for 72 hours. All animals were heparinized, and a subset (n = 4) also received NO in the sweep gas at a concentration of 200 ppm. We observed no adverse effects from NO administration, and methemoglobin levels remained unchanged. Platelet counts significantly declined in all animals over the course of the study; however, mean counts were higher in the NO-treated group, and this difference was statistically significant at 24 hours (62 ± 3% vs. 32 ± 7% of baseline, P < 0.01). Likewise, mean plasma levels of beta-thromboglobulin, a marker of platelet activation, were lower in the NO-treated group, and this difference was also significant at the 24 hour time point (9.5 ± 2.2 vs. 19.7 ± 6.5 pg/mL/10 platelets, P < 0.05). We conclude that 200 ppm NO can be safely blended into the oxygenator sweep gas of a low-flow extracorporeal circuit and that it may transiently attenuate platelet consumption and activation.

Surgical management of pediatric thyroid disease: Complication rates after thyroidectomy at the Children's Hospital of Philadelphia high-volume Pediatric Thyroid Center.

BACKGROUND: Recent studies suggest improved outcomes for children undergoing thyroidectomy at high-volume pediatric surgery centers. We present outcomes after thyroid surgery at a single center and advocate for referral to high-volume centers for multidisciplinary management of these children. METHODS: Medical records were reviewed for all pediatric patients undergoing thyroid surgery at a single institution from 2009 through 2017. Routine recurrent laryngeal nerve and parathyroid hormone monitoring was used. Lymph node dissections were performed in appropriately selected cancer patients. Data collection focused on pathologic diagnosis, surgical technique, and surgical complications, including postoperative hematoma, neurapraxia, permanent nerve damage, hypocalcemia, and transient and permanent hypoparathyroidism. RESULTS: From 2009 through 2017, 464 patients underwent thyroid surgery. Median age of the cohort was 15 years (range 2-24). Thirty-three percent were diagnosed with benign nodules (n=151), 36% with papillary or follicular thyroid cancer (n=168), 27% with Graves' disease (n=124), 3% with medullary thyroid cancer (n=14), and 1.5% underwent prophylactic thyroidectomy for MEN2a (n=7). Six patients required return to the OR for hematoma evacuation including 5 patients after surgery for Graves' disease (RR 8.7, 95% CI 1.06-71.85). In sixteen cases, concern about neurapraxia resulted in laryngoscopy, revealing eleven patients with vocal cord paresis. Two of these patients demonstrated a persistent deficit at 6 months postoperatively (0.4%). Thirty-seven percent of patients had transient hypoparathyroidism (n=137), and two patients had persistent hypoparathyroidism 6 months after total thyroidectomy (0.6%). There was no significant difference in either hypocalcemia or hypoparathyroidism after total thyroidectomy based on age or diagnosis. CONCLUSIONS: Characterizing outcomes for pediatric patients based on diagnosis will assist in preoperative counseling for patients and their families. This high-volume center reports low complication rates after pediatric thyroid surgery, highlighting that referral to high-volume centers should be considered for children and adolescents with thyroid disease requiring surgery. LEVEL OF EVIDENCE: Level IV.

Fetal Surgery.

Fetal surgery is an established but still rapidly evolving specialty, born from the rationale that destructive embryologic processes, recognized early in gestation, can be curtailed by prenatal correction. As more and more centers begin offering fetal interventions, quality of care must be verified through transparency about clinical capabilities and resources. Level designations should be assigned based on capability, as in trauma and neonatal ICU centers for excellence, and volume requirements must be set for fetal surgery certification. Regionalization of this specialty care may be required to optimize outcomes.

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.

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.

Laparoscopic appendectomy - Outcomes of senior trainees operating without supervision versus experienced pediatric surgeons.

AIM OF THE STUDY: Pediatric surgery trainees at our program are allowed to perform unsupervised laparoscopic appendectomies during their last year of training to promote independent operative decision-making skills. We reviewed the outcomes of laparoscopic appendectomies done by senior trainees without supervision and compared them to experienced pediatric surgeons. METHODS: We reviewed 500 laparoscopic appendectomies performed without supervision by the last 10 pediatric surgery trainees during their last year of training (first 50 cases of each trainee). We compared the outcomes of those 500 cases to the outcomes of 200 laparoscopic appendectomies performed by eight experienced pediatric surgeons (last 25 cases of each surgeon). Data are expressed as mean (SD), unless otherwise indicated. A P value of ≤0.05 was regarded as significant. MAIN RESULTS: Median age in the "trainees" and "surgeons" groups was 11 (range 2-22) and 12 (2-20) years, respectively (P = 0.35). The proportion of perforated appendicitis was similar: 98/500 (19.6%) in the trainees group and 42/200 (21%) in the surgeons group, respectively (P = 0.75). Mean operative time was 41 (SD 14.5) min in the trainees group vs. 39 (SD 16.1) min in the surgeons group (P = 0.05). Minor intraoperative complications occurred in 3/500 (0.6%) cases in the trainees group vs. 1/200 (0.5%) in the surgeons group (P = 0.69). No major complications occurred in either group. Mean hospital stay was 2 (range 0.5-26) and 2.3 (range 0.5-18) days in the trainees and surgeons groups, respectively (P = 0.25). There were 13/500 vs. 5/200 readmissions (P = 0.92), and 1/500 vs. 1/200 reoperations in the trainees and surgeons groups, respectively (P = 0.91). CONCLUSION: Allowing senior pediatric surgery trainees to perform laparoscopic appendectomies without supervision to stimulate surgical autonomy is safe and does not compromise patient outcomes. LEVEL OF EVIDENCE: III.

Negative Predictive Value of NI-RADS Category 2 in the First Posttreatment FDG-PET/CT in Head and Neck Squamous Cell Carcinoma.

BACKGROUND AND PURPOSE: FDG PET/CT has a high negative predictive value in patients with head and neck squamous cell carcinoma who responds completely to non-operative therapy. However, the treatment failure rate in patients with a partial but incomplete response is unclear. Our aim was to investigate the negative predictive value of the first posttreatment FDG-PET/CT in patients with head and neck squamous cell carcinoma with incomplete response interpreted as Neck Imaging Reporting and Data System (NI-RADS) category 2. MATERIALS AND METHODS: We retrospectively identified patients with head and neck squamous cell carcinoma treated with chemoradiation or radiation therapy with curative intent in our institution between 2008 and 2016. We included patients whose first posttreatment FDG-PET/CT was interpreted as showing marked improvement of disease but who had a mild residual mass or FDG avidity in either the primary tumor bed or lymph nodes (NI-RADS 2). The negative predictive value of FDG-PET/CT was calculated, including the 95% CI, using the Newcombe method. Two-year disease-free survival was the reference standard. RESULTS: Seventeen of 110 patients (15%) experienced locoregional treatment failure within 2 years of completing treatment, yielding a negative predictive value of 85% (95% Cl, 77%-90%). The most common location of tumor recurrence was the cervical lymph nodes (59%). The median time interval between completion of therapy and treatment failure was 10 months (range, 5-24 months). CONCLUSIONS: In patients with an incomplete response after treatment of head and neck squamous cell carcinoma, the negative predictive value of the first posttreatment FDG-PET/CT was 85%, which is lower than the 91% negative predictive value of FDG-PET/CT in patients with an initial complete response. Patients with an incomplete response (NI-RADS 2) should undergo more frequent clinical and imaging surveillance than patients with an initial complete response (NI-RADS 1).

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.

Erythematous, friable nipple with loss of protrusion · history of breastfeeding · Dx?

A 34-year-old healthy woman presented to the breast surgical oncology clinic with skin changes to her left nipple after being referred by her primary care provider. She attributed the skin changes to shearing from breastfeeding her third child 5 years earlier. Physical examination revealed an erythematous and friable nipple with loss of protrusion. The patient reported routine bleeding from her nipple, but said the skin changes had remained stable and denied any breast masses. The patient's last mammogram was 2.5 years earlier and had only been remarkable for bilateral benign calcifications.

Oncologic outcomes and patient-reported quality of life in patients with oropharyngeal squamous cell carcinoma treated with definitive transoral robotic surgery versus definitive chemoradiation.

OBJECTIVE: It has been postulated that treatment outcomes are similar between transoral robotic surgery (TORS) and definitive chemoradiation (CRT) for oropharyngeal squamous cell carcinomas (OPSCC). We compared oncologic and quality of life (QOL) outcomes between definitive CRT and definitive TORS. MATERIALS AND METHODS: An observational comparison study was performed on 92 patients treated with TORS±adjuvant therapy and 46 patients treated with definitive CRT between July 2005 and January 2016. The Kaplan Meier method was used for survival analyses, and the Mann-Whitney test was used to compare QOL scores between groups. RESULTS: All patients had T0-T2 and N0-N2 disease, although CRT patients had higher clinical staging (p<0.001). HPV+ disease was present in 79% (n=73) of TORS patients and 91% (n=19) of tested CRT patients. Median follow-up was 22.1months (range: 0.33-83.4). There were no significant differences in locoregional control or overall survival between CRT and TORS groups. Definitive TORS resulted in better saliva-related QOL than definitive CRT at 1, 6, 12, and 24months (p<0.001, p=0.025, p=0.017, p=0.011). Among TORS patients, adjuvant therapy was associated with worse QOL in the saliva domain at 6, 12, and 24months (p<0.001, p<0.001, p=0.007), and taste domain at 6 and 12months (p=0.067, p=0.008). CONCLUSION: Definitive CRT and definitive TORS offer similar rates of locoregional control, overall survival, and disease-free survival in patients with early stage OPSCC. TORS resulted in significantly better short and long-term saliva-related QOL, whereas adjuvant therapy was associated with worse saliva and taste-related QOL compared to TORS alone.

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.

A case of fatal Type I congenital disorders of glycosylation (CDG I) associated with low dehydrodolichol diphosphate synthase (DHDDS) activity.

BACKGROUND: Type I congenital disorders of glycosylation (CDG-I) are mostly complex multisystemic diseases associated with hypoglycosylated serum glycoproteins. A subgroup harbour mutations in genes necessary for the biosynthesis of the dolichol-linked oligosaccharide (DLO) precursor that is essential for protein N-glycosylation. Here, our objective was to identify the molecular origins of disease in such a CDG-Ix patient presenting with axial hypotonia, peripheral hypertonia, enlarged liver, micropenis, cryptorchidism and sensorineural deafness associated with hypo glycosylated serum glycoproteins. RESULTS: Targeted sequencing of DNA revealed a splice site mutation in intron 5 and a non-sense mutation in exon 4 of the dehydrodolichol diphosphate synthase gene (DHDDS). Skin biopsy fibroblasts derived from the patient revealed ~20 % residual DHDDS mRNA, ~35 % residual DHDDS activity, reduced dolichol-phosphate, truncated DLO and N-glycans, and an increased ratio of [2-(3)H]mannose labeled glycoprotein to [2-(3)H]mannose labeled DLO. Predicted truncated DHDDS transcripts did not complement rer2-deficient yeast. SiRNA-mediated down-regulation of DHDDS in human hepatocellular carcinoma HepG2 cells largely mirrored the biochemical phenotype of cells from the patient. The patient also harboured the homozygous ALG6(F304S) variant, which does not cause CDG but has been reported to be more frequent in PMM2-CDG patients with severe/fatal disease than in those with moderate presentations. WES did not reveal other strong candidate causal genes. CONCLUSIONS: We describe a patient presenting with severe multisystem disease associated with DHDDS deficiency. As retinitis pigmentosa is the only clinical sign in previously reported cases, this report broadens the spectrum of phenotypes associated with this condition.

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.