Earworms-A Narrative Review of Infectious Music.

This Arts and Medicine feature reviews the clinical and neurophysiologic features of earworms, music fragments heard in the mind that repeat over and over as if jammed in playback mode.

HLA-haploidentical stem cell transplantation in children with inherited bone marrow failure syndromes: A retrospective analysis on behalf of EBMT severe aplastic Anemia and pediatric diseases working parties.

Haploidentical stem cell transplantation (haplo-SCT) represents the main alternative for children with inherited bone marrow failure syndrome (I-BMF) lacking a matched donor. This retrospective study, conducted on behalf of the EBMT SAAWP and PDWP, aims to report the current outcomes of haplo-SCT in I-BMFs, comparing the different in vivo and ex vivo T-cell depletion approaches. One hundred and sixty-two I-BMF patients who underwent haplo-SCT (median age 7.4 years) have been registered. Fanconi Anemia was the most represented diagnosis (70.1%). Based on different T-cell depletion (TCD) approaches, four categories were identified: (1) TCRαß+/CD19+-depletion (43.8%); (2) T-repleted with post-transplant Cyclophosphamide (PTCy, 34.0%); (3) In-vivo T-depletion with ATG/alemtuzumab (14.8%); (4) CD34+ positive selection (7.4%). The cumulative incidences (CI) of neutrophil and platelet engraftment were 84% and 76% respectively, while that of primary and secondary graft failure was 10% and 8% respectively. The 100-day CI of acute GvHD grade III-IV(95% CI) was 13%, while the 24-month CI of extensive chronic GvHD was 4%. After a median follow-up of 43.4 months, the 2-year overall survival(OS) and GvHD/Rejection-free Survival (GRFS) probabilities are 67% and 53%, respectively. The TCR CD3+αß+/CD19+ depletion group showed a significantly lower incidence of both acute and chronic GvHD and higher OS (79%; p0.013) and GRFS (71%; p < .001), while no significant differences in outcomes have been observed by different diagnosis and conditioning regimens. This large retrospective study supports the safety and feasibility of haplo-SCT in I-BMF patients. TCRαß+/CD19+ depletion offers higher chances of patients' survival, with a significantly lower risk of severe a- and c-GvHD in I-BMFs compared to other platforms.

Home Insulin Pump Use in Hospitalized Children With Type 1 Diabetes.

Importance: Pediatric data on inpatient home insulin pumps are absent in the literature. Understanding safety of home insulin pumps, managed by patients or caregivers, during times of illness will help diabetes technology securely move into pediatric hospitals. Objective: To examine whether insulin can be safely and accurately delivered to hospitalized children through home insulin pumps when managed by patients or caregivers. Design, Setting, and Participants: This single-center, retrospective, observational cohort study included children with insulin-dependent diabetes admitted to a tertiary children's hospital from January 1, 2016, to December 31, 2021. In all these patients, diabetes was the primary or secondary diagnosis on admission. Exposure: Insulin delivery via home insulin pump, hospital insulin pump, or subcutaneous injection. Main Outcomes and Measures: Hyperglycemia (glucose, >250 mg/dL) and hypoglycemia (glucose, <45 mg/dL) rates (quantified as the proportion of total insulin-days), glucose variability, and diabetic ketoacidosis (DKA) recurrences were compared for hospital pumps (manual mode), home pumps (manual mode), and subcutaneous injections using bivariate tests. Results: There were 18 096 insulin-days among 2738 patients aged 0.5 to 25 years (median age, 15.8 years [IQR, 12.3-18.3 years]). Overall, 990 (5.5%) of insulin-days involved hospital insulin pumps, and 775 (4.3%) involved home pumps. A total of 155 insulin-days (15.7%) involving hospital pumps were hyperglycemic, compared with 209 (27.0%) involving home pumps and 7374 (45.2%) involving injections (P < .001). Moderate hypoglycemia days comprised 31 insulin-days (3.1%) involving hospital pumps compared with 35 (4.5%) involving home pumps and 830 (5.1%) involving injections (P = .02). Severe hypoglycemia did not differ significantly according to insulin delivery method. Two patients using injections (0.01%) developed DKA; no patients using hospital or home pumps developed DKA. Conclusions and Relevance: In this cohort study, home insulin pump use was found to be safe in a children's hospital regarding hyperglycemia and hypoglycemia. These data support use of home insulin pumps during pediatric admissions in patients who do not require intensive care and without active DKA.

Busulfan-fludarabine- or treosulfan-fludarabine-based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties.

How important is choice of conditioning regimen in allogeneic haematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD)? We compared HSCT outcomes by conditioning regimen in paediatric patients with SCD from the EBMT registry. In 2010-2020, 251 patients aged <18 years underwent a first matched sibling donor (MSD) HSCT with conditioning based on busulfan-fludarabine (bu-flu; n = 89) or treosulfan-fludarabine (treo-flu; n = 162). In the bu-flu and treo-flu groups, 51.7% and 99.4% of patients, respectively, received thiotepa. Median follow-up was 2.7 years. Two-year overall survival (OS) was 98.7% (95% confidence interval [CI]: 90.9-99.8) with bu-flu and 99.3% (95% CI: 95.2-99.9) with treo-flu (p = 0.63). Grade III-IV acute graft-versus-host disease (GVHD) at 100 days was 2.4% (95% CI: 0.4-7.5) and 0.6% (0.1%-3.2%) for bu-flu and treo-flu respectively (p = 0.25). The 2-year incidence of extensive chronic GVHD was 1.5% (95% CI: 0.1-7.3) with bu-flu and 8.0% (95% CI: 4.1-13.3) with treo-flu (p = 0.057). These multinational data confirm the excellent curative capacity of MSD HSCT with myeloablative conditioning. Both conditioning regimens yielded excellent OS, low rates of acute and chronic GVHD, and low rates of graft failure.

Endocrine Management and Clinical Outcomes in a Cohort of Pediatric Patients Undergoing Total Pancreatectomy with Islet Autotransplantation.

Objective: To describe management strategies that contributed to optimal outcomes in pediatric recipients of a total pancreatectomy with islet autotransplantation (TPIAT). Research Design and Methods: We provide a comprehensive report of the approach to endocrine management of the pediatric TPIAT recipient from initial evaluation through the first 4 years postsurgery. We performed a retrospective review of the endocrine outcomes of TPIAT recipients to describe the impact of this approach on post-TPIAT glycemic management. Results: Outcome data from 86 TPIAT recipients were reviewed. At 12 months post-TPIAT (n = 82), the median HbA1C was 6.0% (25-75th percentile 5.6-6.7), at 18 months (n = 56) HbA1C was 6.4% (5.6-7.5), at 2 years (n = 46) HbA1C was 6.4% (5.6-7.4), at 3 years (n = 31) HbA1C was 6.5% (5.5-8.1), and at 4 years (n = 16) HbA1C was 7.2% (6.2-8.3). Conclusions: Pediatric patients at our institution have favorable endocrine outcomes as evidenced by median HbA1C under the goal of 6.5% through the initial 3 years by following our modified management protocols.

Risk factors for a severe disease course in children with SARS-COV-2 infection following hematopoietic cell transplantation in the pre-Omicron period: a prospective multinational Infectious Disease Working Party from the European Society for Blood and Marrow Transplantation group (EBMT) and the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH) study.

Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1-18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0-181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course.

T-cell replete cord transplants give superior outcomes in high-risk and relapsed/refractory pediatric myeloid malignancy.

Stem cell transplant (SCT) outcomes in high-risk and relapsed/refractory (R/R) pediatric acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been historically poor. Cord blood (CB) allows T-cell replete CB transplant (TRCB), enabling enhanced graft-versus-leukemia. We consecutively collected data from 367 patients undergoing TRCB (112 patients) or other cell source (255 patients) SCT for pediatric AML/MDS in the United Kingdom and Ireland between January 2014 and December 2021. Data were collected about the patient's demographics, disease, and its treatment; including previous transplant, measurable residual disease (MRD) status at transplant, human leukocyte antigen-match, relapse, death, graft versus host disease (GvHD), and transplant-related mortality (TRM). Univariable and multivariable analyses were undertaken. There was a higher incidence of poor prognosis features in the TRCB cohort: 51.4% patients were MRD positive at transplant, 46.4% had refractory disease, and 21.4% had relapsed after a previous SCT, compared with 26.1%, 8.6%, and 5.1%, respectively, in the comparator group. Event free survival was 64.1% within the TRCB cohort, 50% in MRD-positive patients, and 79% in MRD-negative patients. To allow for the imbalance in baseline characteristics, a multivariable analysis was performed where the TRCB cohort had significantly improved event free survival, time to relapse, and reduced chronic GvHD, with some evidence of improved overall survival. The effect appeared similar regardless of the MRD status. CB transplant without serotherapy may be the optimal transplant option for children with myeloid malignancy.

Efficacy of Cytomegalovirus Specific Immunoglobulins to Reduce CMV Reactivation in Pediatric Hematopoietic Stem Cell Transplant Recipients.

Cytomegalovirus (CMV) infection is a serious complication of pediatric hematopoietic stem cell transplant (HSCT). To date, antiviral therapy has been the mainstay of prophylaxis, with conflicting results regarding the benefits of CMV-specific immunoglobulins (CMV-Ig). After introducing prophylactic CMV-Ig to HSCT recipients at risk (seropositive recipient and/or donor), we conducted a single-center retrospective study comparing the incidence and severity of CMV infection with and without CMV-Ig. We identified 49 'at risk' recipients from 76 consecutive HSCTs over 3.5 years, in addition to standard antiviral prophylaxis, 10 patients received CMV-Ig and 39 did not. There was no significant difference in donor type, cell source, conditioning, or CMV status between the groups. We observed a potential trend toward reduction of incidence of CMV reactivation in patients exposed to CMV-Ig (30%) compared with those who weren't (38.4%). Besides, no symptomatic or lethal infection was observed in the CMV-Ig group, and time to recovery seemed shorter (21 [±7] vs 51.4 [±55] days) and peak titers lower (4578 [±4788] vs 24131 [±49257]) with CMV-Ig. No adverse events were noted. The statistical significance of the results was limited by the small sample size. These data raise interest in prophylactic CMV-Ig as a safe way of potentially reducing the severity and duration of CMV reactivation in HSCT.

Efficacy of early haematopoietic stem cell transplantation versus enzyme replacement therapy on neurological progression in severe Hunter syndrome: Case report of siblings and literature review.

Hunter syndrome is a neurodegenerative lysosomal storage disorder with limited treatment options to halt the progressive neurocognitive decline. Whilst Intravenous enzyme replacement therapy (ERT) does not cross the blood brain barrier; Intrathecal ERT, in clinical studies, did not demonstrate significant effect on cognition, despite having better CNS delivery. Hematopoietic stem cell transplantation (HSCT) has the potential to treat CNS disease. We reviewed the literature and outline our experience of treating two siblings with severe Hunter syndrome: 'Sibling A' with intravenous and intrathecal ERT and 'Sibling B' with Early HSCT. A literature review identified 8 articles reporting on the comparative efficacy of both treatments. Our clinical outcomes indicate that Sibling B performed better than Sibling A in relation to early developmental milestones as well as neurocognition, activities of daily living, quality of life and neurophysiological outcomes in mid childhood. Sibling A's developmental trajectory fell within the extremely low range and Sibling B's development trajectory fell within the low-average to average range. This suggests HSCT had a disease modifying effect and highlights the efficacy of early HSCT in moderating the CNS progression in Hunter syndrome. Long term follow up is needed to elucidate the efficacy of HSCT on neurological progression.

An Initiative to Reduce Insulin-Related Adverse Drug Events in a Children's Hospital.

OBJECTIVES: Adverse drug events (ADEs) during hospitalization are common. Insulin-related events, specifically, are frequent and preventable. At a tertiary children's hospital, we sought to reduce insulin-related ADEs by decreasing the median event rate of hyper- and hypoglycemia over a 12-month period. METHODS: Using Lean 6 σ methodology, we instituted a house-wide process change from a single-order ordering process to a pro re nata (PRN) standing order process. The standardized process included parameters for administration and intervention, enabling physician and nursing providers to practice at top of licensure. Automated technology during dose calculation promoted patient safety during dual verification processes. Control charts tracked rates of insulin-related ADEs, defined as hyperglycemia (glucose level >250 mg/dL) or hypoglycemia (glucose level <65 mg/dL). Events were standardized according to use rates of insulin on each nursing unit. The rates of appropriately timed insulin doses (within 30 minutes of a blood sugar check) were assessed. RESULTS: Baseline median house-wide frequencies of hyperglycemic and hypoglycemic episodes were 55 and 6.9 events (per 100 rapid-acting insulin days), respectively. The median time to insulin administration was 32 minutes. The implementation of the PRN process reduced the median frequencies of hyperglycemic and hypoglycemic episodes to 45 and 3.8 events, respectively. The median time to insulin administration decreased to 18 minutes. CONCLUSIONS: A PRN ordering process and education decreased insulin-associated ADEs and the time to insulin dosing compared with single-entry processes. Engaging bedside providers was instrumental in reducing insulin-related ADEs. Strategies that decrease the time from patient assessment to drug administration should be studied for other high-risk drugs.

Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial.

BACKGROUND: Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. METHODS: The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. DISCUSSION: Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020.

Improved Glycemic Outcomes with Early Initiation of Insulin Pump Therapy in Pediatric Postoperative Total Pancreatectomy with Islet Autotransplantation.

Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical procedure for patients with chronic pancreatitis and poor quality of life. Euglycemia is critical for islet cell survival and engraftment. We reviewed clinical care practice and hypothesized that early in-hospital transition from intravenous insulin to insulin pump therapy, managed by an endocrine unit trained on post-surgical care, would improve glucose control and impact the length of hospital stay. We completed a retrospective analysis of 40 pediatric patients who underwent TPIAT. Comparative hospitalized postoperative groups included those who received insulin intravenously, followed by multiple daily injections, subsequently managed by pump therapy (n = 14), versus those who received insulin intravenously followed by early pump therapy provided on the endocrine unit trained to manage post-surgical patients (n = 26). The outcomes analyzed included percentage of blood glucoses in target (4.44-6.66 mmol/L (80-120 mg/dL)), hypoglycemia (<3.33 mmol/L (<60 mg/dL)) and hyperglycemia (>7.77 mmol/L (>140 mg/dL)), blood glucose variability, and length of hospital unit stay post-ICU. Hospitalized patients with early transition to pump therapy on a specialized endocrine unit had a higher proportion of glucose values in the target range (61% vs. 51%, p = 0.0003), a lower proportion of hyperglycemia (15% vs. 19%, p = 0.04), and a lower proportion of hypoglycemia, though not statistically significant (3.4% vs. 4.4%, p = 0.33). Early pump users also had lower variability in glucose values over 10 days post-intravenous insulin (p = 0.001), and the post-transition median length of stay was shorter by 5 days (median: 11.5 vs. 16.5 days, p = 0.005). Early in-hospital pump therapy managed by the specialized endocrine unit improved glucose outcomes and reduced the duration of in-unit stay.

A multicentre, multinational, prospective, observational registry study of defibrotide in patients diagnosed with veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation: an EBMT study.

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan-Meier-estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.

Continuous Glucose Monitoring in the Intensive Care Unit Following Total Pancreatectomy with Islet Autotransplantation in Children: Establishing Accuracy of the Dexcom G6 Model.

Hyperglycemia is detrimental to postoperative islet cell survival in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT). This makes continuous glucose monitoring (CGM) a useful management tool. We evaluated the accuracy of the Dexcom G6 CGM in pediatric intensive care unit patients following TPIAT. Twenty-five patients who underwent TPIAT had Dexcom G6 glucose values compared to paired serum glucose values. All paired glucose samples were obtained within 5 minutes of each other during the first seven days post TPIAT. Data were evaluated using mean absolute difference (MAD), mean absolute relative difference (MARD), %20/20, %15/15 accuracy, and Clarke Error Grid analysis. Exclusions included analysis during the CGM "warm-up" period and hydroxyurea administration (known drug interference). A total of 183 time-matched samples were reviewed during postoperative days 2-7. MAD was 14.7 mg/dL and MARD was 13.4%, with values of 15.2%, 14.0%, 12.1%, 11.4%, 13.2% and 14.1% at days 2, 3, 4, 5, 6 and 7, respectively. Dexcom G6 had a %20/20 accuracy of 78%, and a %15/15 accuracy of 64%. Clarke Error Grid analysis showed that 77% of time-matched values were clinically accurate, and 100% were clinically acceptable. The Dexcom G6 CGM may be an accurate tool producing clinically acceptable values to make reliable clinical decisions in the immediate post-TPIAT period.

Inaccurate Glucose Sensor Values After Hydroxyurea Administration.

Objective: To assess the degree, duration, mean absolute relative difference (MARD), and error analysis of discrepant values per continuous glucose monitoring (CGM) systems after hydroxyurea (HU) administration. Research Design and Methods: Inpatient glucometer and CGM data from 16 total pancreatectomy/islet autotransplantation patients using Dexcom Professional G4 and 12 patients using Dexcom G6 were analyzed after daily dosing with HU. Timing of HU dosing and median of 9.5 days of sensor and glucometer values were assessed per patient. Results: A large positive elevation of sensor readings was identified after HU dosing. The greatest discrepancy between glucometer and sensor readings occurred 0.5-2 h after HU administration [G4 (mean 3.0 mmol/L, median 2.4 mmol/L, MARD 55%), G6 (mean 4.2 mmol/L, median 4.6 mmol/L, MARD 91%)]. The discrepancy was <1.1 mmol/L, mean (-0.5 mmol/L) and median (-0.5 mmol/L), MARD 14% (G4) and <1.1 mmol/L, mean (0.3 mmol/L) and median (0.3 mmol/L), MARD 17% (G6), by 6 h after administration. Error analysis with the G6 system found 94% of pairs in clinically acceptable range by 6-9 h after HU administration. Aspirin, also given once daily, did not result in glucose value discrepancy with the G6 system but variability was observed with the G4 system. Conclusions: There was marked elevation of sensor glucose readings compared with glucometer values [up to 13.9 mmol/L (G4), 13 mmol/L (G6)] from 0.5 to 6 h after HU administration. It is important to counsel a patient using a Dexcom CGM system and HU therapy on this finding and to advise reliance on glucometer testing for accurate glucose assessment up to 6-9 h after HU administration.

Trametinib-associated Hyponatremia in a Child With Low-grade Glioma is Not Seen Following Treatment With Alternative MEK Inhibitor.

Molecularly targeted therapy with MEK inhibitors has been increasingly incorporated into the treatment of pediatric low-grade gliomas, but this promising therapy is associated with distinctive and specific toxicities. Understanding life-threatening MEK inhibitor toxicities and their management is critical to MEK inhibitor safety, especially among young children. This report describes severe hyponatremia associated with trametinib in an infant with progressive low-grade glioma without underlying endocrine dysfunction, which recurred despite significant dose reduction. Therapy with an alternative MEK inhibitor, binimetinib, provided excellent tumor response without hyponatremia, suggesting that some toxicities may be avoided by changing MEK inhibitor agents within the same class.

Progression of Vasculopathy in Young Individuals with Turner Syndrome.

Vasculopathy has been identified in young individuals with Turner syndrome (TS). No studies in young individuals with TS have investigated whether this vasculopathy progresses over time. The objective of this study is to describe the changes in vasculopathy over time in a cohort of young individuals with TS. Repeat ultrasound and SphygmoCor CPV® (AtCor Medical) measurements of carotid thickness and peripheral arterial stiffness were performed. Vascular measurements were compared at baseline and follow-up. Follow-up measurements were also compared to historical lean (L) and obese (O) age-, race-, and sex-matched non-TS controls. Thirty-five individuals with TS were studied at a mean age of 19.4 years (range, 13.9-27.5). Mean time to follow-up was 7.2 years (range, 7.1-7.8). Carotid intima media thickness increased by 0.03 ± 0.07 mm (p < 0.01) over time, but was less than L and O controls at follow-up. Pulse wave velocity carotid-femoral increased by 0.51 ± 0.86 m/s (p < 0.01) over time, but was similar to L and less than O controls at follow-up. Augmentation index (AIx) remained unchanged (p = 0.09) over time, but was significantly higher at follow-up than both control groups (p < 0.01 for both). There were no identified differences between 45,X and other TS genotypes. We demonstrate evidence of vascular thickening and stiffening over 7 years in a cohort of young individuals with TS, as well as a persistently increased augmentation index compared to L and O non-TS controls. It is unclear whether the increase in vascular structure and function are related to normal aging or if TS is a risk factor. Higher body mass index seems to be a risk factor. Early estrogen replacement and longer exposure to growth hormone therapy need to be further explored as potential protective factors.

A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

PURPOSE: Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients. METHODS: Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m2; 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively. RESULTS: The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)-all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3-14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10-30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ . CONCLUSIONS: Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies. TRIAL REGISTRATION: NCT02607124.