Central nervous system status is prognostic in T-cell acute lymphoblastic leukemia: a Children's Oncology Group report.

To determine the prognostic significance of central nervous system (CNS) leukemic involvement in newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL), outcomes on consecutive, phase 3 Children's Oncology Group clinical trials were examined. AALL0434 and AALL1231 tested efficacy of novel agents within augmented-Berlin-Frankfurt-Münster (aBFM) therapy. In addition to testing study-specific chemotherapy through randomization, the AALL0434 regimen delivered cranial radiation therapy (CRT) to most participants (90.8%), whereas AALL1231 intensified chemotherapy to eliminate CRT in 88.2% of participants. In an analysis of 2164 patients with T-ALL (AALL0434, 1550; AALL1231, 614), 1564 had CNS-1 (72.3%), 441 CNS-2 (20.4%), and 159 CNS-3 (7.3%). The 4-year event-free-survival (EFS) was similar for CNS-1 (85.1% ± 1.0%) and CNS-2 (83.2% ± 2.0%), but lower for CNS-3 (71.8% ± 4.0%; P = .0004). Patients with CNS-1 and CNS-2 had similar 4-year overall survival (OS) (90.1% ± 0.8% and 90.5% ± 1.5%, respectively), with OS for CNS-3 being 82.7% ± 3.4% (P = .005). Despite therapeutic differences, outcomes for CNS-1 and CNS-2 were similar regardless of CRT, intensified corticosteroids, or novel agents. Except for significantly superior outcomes with nelarabine on AALL0434 (4-year disease-free survival, 93.1% ± 5.2%), EFS/OS was inferior with CNS-3 status, all of whom received CRT. Combined analyses of >2000 patients with T-ALL identified that CNS-1 and CNS-2 status at diagnosis had similar outcomes. Unlike B-ALL, CNS-2 status in T-ALL does not impact outcome with aBFM therapy, without additional intrathecal therapy, with or without CRT. Although nelarabine improved outcomes for those with CNS-3 status, novel approaches are needed. These trials were registered at www.clinicaltrials.gov as #NCT00408005 (AALL0434) and #NCT02112916 (AALL1231).

Prognostic significance of ETP phenotype and minimal residual disease in T-ALL: a Children's Oncology Group study.

The early thymic precursor (ETP) immunophenotype was previously reported to confer poor outcome in T-cell acute lymphoblastic leukemia (T-ALL). Between 2009 and 2014, 1256 newly diagnosed children and young adults enrolled in Children's Oncology Group (COG) AALL0434 were assessed for ETP status and minimal residual disease (MRD) using flow cytometry at a central reference laboratory. The subject phenotypes were categorized as ETP (n = 145; 11.5%), near-ETP (n = 209; 16.7%), or non-ETP (n = 902; 71.8%). Despite higher rates of induction failure for ETP (6.2%) and near-ETP (6.2%) than non-ETP (1.2%; P < .0001), all 3 groups showed excellent 5-year event-free survival (EFS) and overall survival (OS): ETP (80.4% ± 3.9% and 86.8 ± 3.4%, respectively), near-ETP (81.1% ± 3.3% and 89.6% ± 2.6%, respectively), and non-ETP (85.3% ± 1.4% and 90.0% ± 1.2%, respectively; P = .1679 and P = .3297, respectively). There was no difference in EFS or OS for subjects with a day-29 MRD <0.01% vs 0.01% to 0.1%. However, day-29 MRD ≥0.1% was associated with inferior EFS and OS for patients with near-ETP and non-ETP, but not for those with ETP. For subjects with day-29 MRD ≥1%, end-consolidation MRD ≥0.01% was a striking predictor of inferior EFS (80.9% ± 4.1% vs 52.4% ± 8.1%, respectively; P = .0001). When considered as a single variable, subjects with all 3 T-ALL phenotypes had similar outcomes and subjects with persistent postinduction disease had inferior outcomes, regardless of their ETP phenotype. This clinical trial was registered at AALL0434 as #NCT00408005.

Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome.

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.

Is there an OAHI or O2 nadir that predicts the need for preoperative echocardiogram prior to adenotonsillectomy for children with severe obstructive sleep apnea?

PURPOSE: To investigate threshold values for obstructive apnea-hypopnea index (OAHI) and nadir oxygen saturation (NspO2) in children with severe obstructive sleep apnea (OSA) to identify children most appropriate for preoperative echocardiography. METHODS: A multi-institutional retrospective chart review was performed on children who underwent echocardiography and polysomnogram within a year. Children with severe OSA as defined by OAHI > 10 or NspO2 < 80% were included. Receiver operator curves and Youden's J index were used to assess the discriminatory ability and threshold values of OAHI and NspO2 for right heart strain (RHS) on echocardiography. RESULTS: A total of 173 prepubertal (< 10 years) children and 71 postpubertal (≥ 10 years) children of age were included. RHS was seen in 9 (5%) prepubertal children and 4 (6%) postpubertal children. In prepubertal children, OAHI and NspO2 were poor predictors of RHS (area under the curve [AUC] 0.53 [95%CI 0.45-0.61], p = 0.748; AUC 0.56 [95%CI 0.48-0.64], p = 0.609). In postpubertal children, threshold values of 55 events/hour and 69% were strong predictors for RHS (AUC 0.88 [95%CI 0.78-0.95], p < 0.001; AUC 0.92 [95%CI 0.83-0.97], p < 0.001). CONCLUSION: In children with severe OSA, evidence of RHS is low. Postpubertal children with OAHI > 55 and NspO2 < 69% appear most appropriate for echocardiography. Clinicians should weigh the risks and benefits of preoperative echocardiography for each child with these threshold values in mind.

Surgical outcomes and revision rates for velopharyngeal insufficiency (VPI) in syndromic and non-syndromic children: A systematic review and meta-analysis.

PURPOSE: To evaluate pre- and post-operative resonance, surgical technique, revision rate, and revision indication among syndromic and non-syndromic children with velopharyngeal insufficiency (VPI). MATERIALS AND METHODS: A systematic review was conducted through July 2022. Children surgically treated for VPI were included. A meta-analysis of single means, proportions, comparison of proportions, and mean differences with 95 % confidence interval [CI] was conducted. RESULTS: Twenty-three articles (n = 1437) were included in the analysis. The most common surgery was Sphincter Pharyngoplasty (SP), 62.6 % [31.3-88.9] for syndromic and 76.3 % [37.5-98.9] for non-syndromic children. Among all surgical techniques, for syndromic and non-syndromic children, 54.8 % [30.9-77.5] and 73.9 % [61.3-84.6] obtained normal resonance post-operatively, respectively. Syndromic patients obtained normal resonance post-operatively in 83.3 % [57.7-96.6] of Combined Furlow Palatoplasty and Sphincter Pharyngoplasty (CPSP), 72.6 % [54.5-87.5] of Pharyngeal Flap (PF), and 45.1 % [13.2-79.8] of Sphincter Pharyngoplasty (SP) surgeries. Non-syndromic patients obtained normal resonance post-operatively in 79.2 % [66.4-88.8] of PF and 75.2 % [61.8-86.5] of SP surgeries. The revision rate for syndromic and non-syndromic patients was 19.9 % [15.0-25.6] and 11.3 % [5.8-18.3], respectively. The difference was statistically significant, 8.6 % [2.9-15.0, p = 0.003]. Syndromic patients who underwent PF were least likely to undergo revision surgery as compared to SP and CPSP, 7.7 % [2.3-17.9] vs. 23.7 % [15.5-33.1] and 15.3 % [2.8-40.7], respectively. CONCLUSIONS: Syndromic children had higher revision rates and were significantly less likely to obtain normal resonance following primary surgery than non-syndromic patients. Among syndromic children, PF and CPSP have been shown to improve resonance and reduce revision rates more so than SP alone.

Cleft Lip and/or Palate Repair in Children With Hypopituitarism: Analysis of the Kids' Inpatient Database.

OBJECTIVE: Children with hypopituitarism (CwHP) can present with orofacial clefting, frequently in the setting of multiple midline anomalies. Hypopituitarism (HP) can complicate medical and surgical care; the perioperative risk in CwHP during the traditionally lower risk cleft lip and/or palate (CL/P) repair is not well described. The objective of this study is to examine the differences in complications and mortality of CL/P repair in CwHP compared to children without hypopituitarism (CwoHP). DESIGN: A retrospective cross-sectional analysis. SETTING: The 1997 to 2019 Kids' Inpatient Databases (KID). PATIENTS: Children 3 years old and younger who underwent CL/P repair. MAIN OUTCOME MEASURE(S): Complications and mortality. RESULTS: A total of 34 106 weighted cases were analyzed, with 86 having HP. CwHP had a longer length of stay (3.0 days [IQR 2.0-10.0] vs 1.0 day [IQR 1.0-2.0], P < .001) and higher rates of complications and mortality (12.8% vs 2.9%, P < .001) compared to CwoHP. Controlling for demographic factors, CwHP had 6.61 higher odds of complications and mortality than CwoHP (95% CI 3.38-12.94, P < .001). CONCLUSIONS: CwHP can present with a CL/P and other midline defects that can increase the complexity of their care. These data show a significant increase in length of stay, complications, and mortality in CwHP undergoing CL/P repair. Increased multidisciplinary attention and monitoring may be needed for these children peri- and postoperatively, especially if additional comorbidities are present. Further studies on perioperative management in this population are warranted to reduce morbidity and mortality.

Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1).

BACKGROUND: Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. PROCEDURE: The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug re-induction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1-3) and subsequently combined with re-induction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. RESULTS: Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. CONCLUSIONS: Palbociclib in combination with re-induction chemotherapy was well tolerated with a RP2D of 50 mg/m2 /day for 21 days. Complete responses were observed among heavily pretreated patients.

Minimal residual disease predicts outcomes in KMT2A-rearranged but not KMT2A-germline infant acute lymphoblastic leukemia: Report from Children's Oncology Group study AALL0631.

We measured minimal residual disease (MRD) by multiparameter flow cytometry at three time points (TP) in 117 infants with KMT2A (lysine [K]-specific methyltransferase 2A)-rearranged and 58 with KMT2A-germline acute lymphoblastic leukemia (ALL) on Children's Oncology Group AALL0631 study. For KMT2A-rearranged patients, 3-year event-free survival (EFS) by MRD-positive (≥0.01%) versus MRD-negative (<0.01%) was: TP1: 25% (±6%) versus 49% (±7%; p = .0009); TP2: 21% (±8%) versus 47% (±7%; p < .0001); and TP3: 22% (±14%) versus 51% (±6%; p = .0178). For KMT2A-germline patients, 3-year EFS was: TP1: 88% (±12%) versus 87% (±5%; p = .73); TP2: 100% versus 88% (±5%; p = .24); and TP3: 100% versus 87% (±5%; p = .53). MRD was a strong independent outcome predictor in KMT2A-rearranged, but not KMT2A-germline infant ALL.

Delayed Sublingual Edema Following Neonatal Mandibular Distraction Osteogenesis.

The authors aim to report a rare sequela following neonatal mandibular distraction osteogenesis (MDO) involving delayed onset sublingual swelling. They performed a retrospective chart review of 3 patients who presented with delayed onset sublingual edema following neonatal MDO. The 3 patients presented at 2, 4, and 12 months following MDO for micrognathia secondary to Robin sequence with intermittent sublingual swelling associated with sialorrhea and feeding difficulties. There was no associated recent illness, fevers, or purulent drainage. All 3 children underwent magnetic resonance imaging which demonstrated asymmetric sublingual gland edema. The edema was located on the left sublingual gland in 2 children and was bilateral in the third. The symptoms continue to recur 25.5±3.3 months (range, 22.3-28.9) postoperatively and all are being managed conservatively. Chronic delayed onset intermittent sublingual edema is a possible long-term complication following neonatal MDO and further studies should explore the incidence and management of this finding.

Inhibition of Topoisomerases by Metal Thiosemicarbazone Complexes.

Topoisomerases, common targets for anti-cancer therapeutics, are crucial enzymes for DNA replication, transcription, and many other aspects of DNA metabolism. The potential anti-cancer effects of thiosemicarbazones (TSC) and metal-TSC complexes have been demonstrated to target several biological processes, including DNA metabolism. Human topoisomerases were discovered among the molecular targets for TSCs, and metal-chelated TSCs specifically displayed significant inhibition of topoisomerase II. The processes by which metal-TSCs or TSCs inhibit topoisomerases are still being studied. In this brief review, we summarize the TSCs and metal-TSCs that inhibit various types of human topoisomerases, and we note some of the key unanswered questions regarding this interesting class of diverse compounds.

Impact of Syndromes on Sleep-Disordered Breathing in Children After Cleft Palate Repair.

OBJECTIVE: Prior research suggests that children with cleft palate (CP) are at increased risk of obstructive sleep-disordered breathing (SDB). However, few studies differentiate the effects of CP repair on SDB based on syndrome status. The goal of this study was to evaluate differences in SDB after palatoplasty among children with nonsyndromic CP, syndromic CP, and isolated Robin sequence (RS). DESIGN: Retrospective chart review. SETTING: Tertiary academic children's hospital. PATIENTS/PARTICIPANTS: A total of 145 children who underwent primary CP repair from 2014 to 2021. MAIN OUTCOME MEASURE: Post-palatoplasty SDB is defined as parent-reported symptoms and/or evidence of obstructive sleep apnea (OSA). RESULTS: Median age at palatoplasty was 11.1 [IQR 10.2-13.6] months. Most patients (61.4%) had nonsyndromic CP, 26.9% had a syndrome, and 11.7% had RS. Children with syndromic CP and RS had more post-palatoplasty SDB symptoms (56.4% vs 58.8% vs 30.3%, P = .006) and higher rates of OSA (25.6% vs 29.4% vs 5.6%, P = .001) compared to children with nonsyndromic CP after palatoplasty. Children with syndromic CP and RS had nearly 3 to 4 higher odds of post-palatoplasty SDB than children with nonsyndromic CP (adjusted odds ratio [aOR] 2.88, 95% CI 1.29-6.47, P = .010; aOR 3.73, 95% CI 1.19-11.70, P = .024). CONCLUSION: This study showed that children with CP experience higher rates of SDB after palatoplasty than the general pediatric population. Within the cohort, children with syndromic CP and isolated RS were more likely to have obstructive sleep disorders than nonsyndromic children after palatoplasty. Clinicians should counsel caregivers accordingly and closely monitor these groups for SDB after palate repair.

Evaluating Prenatal Diagnostic Imaging for Micrognathia: A Systematic Review and Meta-Analysis.

OBJECTIVE: Studies evaluating the ability to diagnose and accurately predict the severity of micrognathia prenatally have yielded inconsistent results. This review aimed to evaluate reliability of prenatal diagnostic imaging in the diagnosis and characterization of micrognathia. DESIGN: Systematic review and meta-analysis. SETTING: Studies with a prenatal diagnosis of micrognathia via ultrasound with a confirmatory postnatal examination were included. Prenatal severity was defined with and without mandibular measurements. Extent of airway obstruction at birth was defined by level of intervention required. Meta-analyses of proportions and relative risk were performed. PATIENTS: A total of 16 studies with 2753 neonates were included. MAIN OUTCOME MEASURES: Primary outcome was the efficacy of characterizing the degree of micrognathia on prenatal imaging as it relates to respiratory obstruction at birth. Secondary outcome was the accuracy of prenatal diagnosis with the utilization of mandibular measurements versus without. RESULTS: Performing meta-analysis of proportions, the proportion of missed prenatal diagnoses of micrognathia made without mandibular measurements was 11.62% (95%CI 2.58-25.94). Utilizing mandibular measurements, the proportion of cases missed were statistically lower (0.20% [95%CI 0.00-0.70]). Patients determined to have severe micrognathia by prenatal imaging did not have a statistically significant increase in risk for more severe respiratory obstruction at birth (RR 3.13 [95%CI 0.59-16.55], P = .180). CONCLUSION: The proportion micrognathia cases missed when prenatal diagnosis was made without mandibular measurements was over 1 in 10, with mandibular measures improving accuracy. This study highlights the need for a uniform objective criterion to improve prenatal diagnosis and planning for postnatal care.

Sex-based disparities in outcome in pediatric acute lymphoblastic leukemia: a Children's Oncology Group report.

BACKGROUND: Boys with acute lymphoblastic leukemia (ALL) have historically experienced inferior survival compared to girls. This study determined whether sex-based disparities persist with contemporary therapy and whether patterns of treatment failure vary by sex. METHODS: Patients 1 to 30.99 years old were enrolled on frontline Children's Oncology Group trials between 2004 and 2014. Boys received an additional year of maintenance therapy. Sex-based differences in the distribution of various prognosticators, event-free survival (EFS) and overall survival (OS), and subcategories of relapse by site were explored. RESULTS: A total of 8202 (54.4% male) B-cell ALL (B-ALL) and 1562 (74.3% male) T-cell ALL (T-ALL) patients were included. There was no sex-based difference in central nervous system (CNS) status. Boys experienced inferior 5-year EFS and OS (EFS, 84.6% ± 0.5% vs 86.0% ± 0.6%, P = .009; OS, 91.3% ± 0.4% vs 92.5% ± 0.4%, P = .02). This was attributable to boys with B-ALL, who experienced inferior EFS (hazard ratio [HR], 1.2; 95% confidence interval [95% CI], 1.1-1.3; P = .004) and OS (HR, 1.2; 95% CI, 1.0-1.4; P = .046) after adjustment for prognosticators. Inferior B-ALL outcomes in boys were attributable to more relapses (5-year cumulative incidence 11.2% ± 0.5% vs 9.6% ± 0.5%; P = .001), particularly involving the CNS (4.2% ± 0.3% vs 2.5% ± 0.3%; P < .0001). There was no difference in isolated bone marrow relapses (5.4% ± 0.4% vs 6.2% ± 0.4%; P = .49). There were no sex-based differences in EFS or OS in T-ALL. CONCLUSIONS: Sex-based disparities in ALL persist, attributable to increased CNS relapses in boys with B-ALL. Studies of potential mechanisms are warranted. Improved strategies to identify and modify treatment for patients at highest risk of CNS relapse may have particular benefit for boys.

Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia.

Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic leukemia.

Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient cell death in animal models. Studies in leukemia and other malignancies, suggest that schedule is important when combining CDK4/6 inhibitors (CDKi) with cytotoxic agents. Based on these observations, we broadened evaluation of two CDKi, palbociclib (PD-0332991, Pfizer) and ribociclib (LEE011, Novartis) in B- and T-ALL as single agent and in combination with conventional cytotoxic chemotherapy, using different schedules in preclinical models. As monotherapy, CDKi caused cell cycle arrest with a significant decrease in S phase entry and were active in vivo across a broad number of patient-derived xenograft samples. Prolonged monotherapy induces resistance, for which we identified a potential novel mechanism using transcriptome profiling. Importantly, simultaneous but not sequential treatment of CDKi with conventional chemotherapy (dexamethasone, L-asparaginase and vincristine) led to improved efficacy compared to monotherapy in vivo. We provide novel evidence that combining CDKi and conventional chemotherapy can be safe and effective. These results led to the rational design of a clinical trial.

The effect of national disease-modifying therapy subsidy policy on long-term disability outcomes in people with multiple sclerosis.

BACKGROUND: Disease-modifying therapies (DMTs) are used to treat people with relapsing-onset multiple sclerosis (ROMS), but our knowledge is largely limited to their short-term effects. OBJECTIVE: To determine (1) the impact of national-level DMT subsidy policy on DMT use and health outcomes in people with MS (PwMS) and (2) the long-term effects of DMT on disability and quality of life (QoL; 5-level EQ-5D version (EQ-5D-5L) utility value). METHODS: This observational cohort study compared Australian and New Zealand populations with different levels of DMT availability 10-20 years post-ROMS diagnosis. Between-country differences were assessed using standardised differences. Associations were assessed with multivariable linear regression models. RESULTS: We recruited 328 Australians and 256 New Zealanders. The Australian cohort had longer DMT treatment duration, greater proportion of disease course treated and shorter duration between diagnosis and starting DMT. The Australian cohort had lower median Expanded Disability Status Scale (EDSS) (3.5 vs 4.0) and Multiple Sclerosis Severity Score (MSSS) (3.05 vs 3.71) and higher QoL (0.71 vs 0.65). In multivariable models, between-country differences in disability and QoL were largely attributed to differential use of DMT. CONCLUSIONS: This study provides evidence for the impact of national-level DMT policy on disability outcomes in PwMS. Where DMTs are more accessible, PwMS experienced less disability progression and improved QoL 10-20 years post-diagnosis.

Charting a global research strategy for progressive MS-An international progressive MS Alliance proposal.

BACKGROUND: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progressive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have been mixed. The recent introduction of the term 'active' secondary progressive MS into the therapeutic lexicon has introduced potential confusion to disease description and thereby clinical management. OBJECTIVE: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf of the International Progressive MS Alliance, a global research strategy for progressive MS. METHODS: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search terms "progressive multiple sclerosis", "primary progressive multiple sclerosis", "secondary progressive MS". Proposed strategies were developed through a series of in-person and virtual meetings of the International Progressive MS Alliance Scientific Steering Committee. RESULTS: Sustaining and accelerating progress will require greater understanding of underlying mechanisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative interventions are starting to address ongoing challenges experienced by people with progressive MS. CONCLUSION: We need to manage these challenges and realise the opportunities in the context of a global research strategy, which will improve quality of life for people with progressive MS.

Activation of the mitogen-activated protein kinase-extracellular signal-regulated kinase pathway in childhood B-cell acute lymphoblastic leukemia.

RAS mutations are frequently observed in childhood B-cell acute lymphoblastic leukemia (B-ALL) and previous studies have yielded conflicting results as to whether they are associated with a poor outcome. We and others have demonstrated that the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK) pathway can be activated through epigenetic mechanisms in the absence of RAS pathway mutations. Herein, we examined whether MAPK activation, as determined by measuring phosphorylated extracellular signal-regulated kinase (pERK) levels in 80 diagnostic patient samples using phosphoflow cytometry, could be used as a prognostic biomarker for pediatric B-ALL. The mean fluorescence intensity of pERK (MFI) was measured at baseline and after exogenous stimulation with or without pretreatment with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Activation levels (MFI stimulated/MFI baseline) ranged from 0.76 to 4.40 (median = 1.26), and inhibition indexes (MFI stimulated/MFI trametinib stimulated) ranged from 0.439 to 5.640 (median = 1.30), with no significant difference between patients with wildtype versus mutant RAS for either. Logistic regression demonstrated that neither MAPK activation levels nor RAS mutation status at diagnosis alone or in combination was prognostic of outcome. However, 35% of RAS wildtype samples showed MAPK inhibition indexes greater than the median, thus raising the possibility that therapeutic strategies to inhibit MAPK activation may not be restricted to patients whose blasts display Ras pathway defects.

Management of the parotid for high-risk cutaneous squamous cell carcinoma: A review from the salivary section of the American Head and Neck Society.

BACKGROUND: Metastases to the parotid nodal basin in patients with high-risk cutaneous squamous cell carcinoma (HRcSCC) impact disease specific survival (DSS) and overall survival (OS). METHODS: A writing group convened by the Salivary Section of the American Head and Neck Society (AHNS) developed contemporary, evidence-based recommendations regarding management of the parotid nodal basin in HRcSCC based on available literature, expert consultation, and collective experience. The statements and recommendations were then submitted and approved by the AHNS Salivary Committee. RESULTS: These recommendations were developed given the wide variation of practitioners who treat HRcSCC in order to streamline management of the parotid nodal basin including indications for imaging, surgery, radiation, and systemic treatment options as well. CONCLUSIONS: This clinical update represents contemporary optimal management of the parotid nodal basin in HRcSCC and is endorsed by the Salivary Section of the AHNS.

Moving to a more restrictive transfusion protocol: Outcomes in head and neck free flap surgery.

PURPOSE: To determine if a more restrictive transfusion protocol results in increased rates of adverse flap outcomes in patients undergoing free tissue transfer. MATERIALS AND METHODS: Mixed retrospective and prospective cohort study. Patients who underwent surgery before the protocol change were collected retrospectively. Patients who underwent surgery after the protocol change were collected prospectively. RESULTS: Of the 460 patients who underwent free tissue transfer, 116 patients in the pre-change cohort (N = 211) underwent transfusion (54.98%) and 78 in the post-change cohort(N = 249) (31.33%) (p < 0.001). The mean number of units transfused was 1.55 + 2.00 in the pre-change cohort, and 0.78 + 1.51 in the post-change cohort (p < 0.001). When separated temporally, the pre-change cohort received significantly more blood transfusions than the post-change cohort in the operating room (33.65% vs 18.07%) (p < 0.01), within 72 h of surgery (35.55% vs 15.66%) (p < 0.001), and after 72 h after surgery to discharge (16.59% vs 8.03%) (p = 0.018017). The rate of flap failure was 6.70% in the pre-change cohort, and 5.31% in the post-change cohort (p = 0.67). In a logistic regression model controlling for potential confounders, transfusion protocol was not significantly associated with flap failure (OR = 1.1080, 95% CI: 0.48-2.54). There were no significant differences between cohorts for medical morbidity, ICU transfer, or death. CONCLUSION: Our data support the conclusion that patients undergoing free tissue transfer to the head and neck can be transfused following the same protocols as other patients, without increasing the rate of flap failure or other morbidities. LEVEL OF EVIDENCE: 3 (mixed retrospective, prospective cohort study).