MEDB-41. Identifying a subgroup of patients with early childhood sonic hedgehog-activated medulloblastoma with unfavorable prognosis after treatment with radiation-sparing regimens including intraventricular methotrexate [Abstract]

PURPOSE/METHODS: Clinical and molecular risk factors in 142 patients 3 years] 47% vs 85% [<1 year] vs 84% [1-3 years], p<0.001). No TP53 mutations were detected (n=47). DNA methylation classification identified three subgroups: SHH-1(v12.3) (n=39), SHH-2(v12.3) (n=19), and SHH-3(v12.3) (n=19), with distinct cytogenetic profiles (chromosome 2 gains in SHH-1(v12.3), very few alterations in SHH-2(v12.3), and chromosome 9q losses in SHH-3(v12.3)), age profiles (median age [years] SHH-1(v12.3): 1.7, SHH-2(v12.3): 0.9, SHH-3(v12.3): 3.0, p<0.001), and histological distribution (SHH-2(v12.3): 74% MBEN, SHH-1(v12.3)/SHH-3(v12.3): 77%/79% DMB, p<0.001). PFS was more unfavorable in patients with SHH-3(v12.3)-medulloblastoma (5-year PFS 53% vs 86% [SHH-1(v12.3)] vs 95% [SHH-2(v12.3)], p=0.002), which remained the only risk factor on multivariable Cox regression for PFS. OS was comparable (5-year OS 94% [SHH-3(v12.3)] vs 97% [SHH-1(v12.3)] vs 100% [SHH-2(v12.3)], p=0.6). 8/9 patients with SHH-3(v12.3)-medulloblastoma received radiotherapy at relapse (6 craniospinal, 2 local [1 Gorlin syndrome, 1 BRCA2 germline mutation], 1 no radiotherapy [Gorlin syndrome]). CONCLUSION: We identify patients with an increased risk of relapse when treated with radiation-sparing approaches among children with early childhood SHH-medulloblastoma. If these tumors differ from SHH-3-medulloblastoma typically described in older children remains to be verified. Treatment recommendations need to consider cancer predisposition syndromes

Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts

Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I-VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I-VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification

Comparing everolimus‐based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from 6 months after heart transplantation: The randomized MANDELA study

In the 12-month, open-label MANDELA study, patients were randomized at month 6 after heart transplantation to (1) convert to calcineurin inhibitor (CNI)-free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI-free, n = 71), or to (2) continue reduced-exposure CNI, with EVR and steroids (EVR/redCNI, n = 74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI-free patients at randomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 posttransplant postrandomization) with superiority of the CNI-free group vs EVR/redCNI: mean 64.1 mL/min/1.73 m(2) vs 52.9 mL/min/1.73 m(2); difference + 11.3 mL/min/1.73 m(2) (P = 10 mL/min/1.73 m(2) in 31.8% and 55.2% of EVR/redCNI and CNI-free patients, respectively, and by >= 25 mL/min/1.73 m(2) in 4.5% and 20.9%. Rates of biopsy-proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI vs the CNI-free regimen (P = .015); 6 of 15 episodes in CNI-free patients occurred with EVR concentration mL. Rates of adverse events and associated discontinuations were comparable. EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One-year renal function can be improved by early conversion to EVR-based CNI-free therapy but requires close EVR monitoring. Clinical trials registry: ClinicalTrials.gov NCT00862979

Neurological Complications in High-Risk Patients Undergoing Coronary Artery Bypass Surgery

Background: Coronary artery bypass grafting (CABG) without cardiopulmonary bypass and minimal or no aortic manipulation may be associated with a lower risk of neurological complications. We investigated this issue in patients with a high risk of perioperative stroke. Methods: Data on 7352 patients who underwent isolated CABG from January 2015 to May 2017 were included in the multicenter study E-CABG (European Coronary Artery Bypass Grafting) registry. Of these, 684 patients had an increased risk of neurological complications, ie, previous stroke or transient ischemic attack, severe carotid artery stenosis or occlusion, or previous carotid artery intervention. In this subgroup, we analyzed the rates of the combined primary endpoint comprising any postoperative stroke or transient ischemic attack. A comparative analysis between CABG with and without aortic cross-clamping was performed. Results: The primary endpoint was more often reached when aortic cross-clamping was used (propensity score matching, without vs with aortic cross-clamp: 0.9% vs 7.2%; P = .016). In comparison with all other revascularization techniques, off-pump CABG with avoidance of aortic manipulation was associated with the lowest rate of neurological complications (0.7%). Conclusions: In patients with increased risk of perioperative stroke, aortic manipulation including the use of cardiopulmonary bypass or partial clamping for central anastomoses is associated with higher rates of postoperative neurological complications. These patients may benefit from off-pump surgery without aortic manipulation if complete revascularization can be ensured

Impact of Surgeon Experience and Centre Volume on Outcome After Off-Pump Coronary Artery Bypass Surgery: Results from the European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG) Registry

Aim: The aim of this study was to assess the impact of surgeon experience and centre volume on early operative outcomes in patients undergoing off-pump coronary artery bypass (OPCAB) surgery. Method: Of 7,352 patients in the European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG) registry, 1,549 underwent OPCAB and were included in the present analysis. Using adjusted regression analysis, we compared major early adverse events after procedures performed by experienced OPCAB surgeons (i.e., ≥20 cases per year; n=1,201) to those performed by non-OPCAB surgeons (n=348). Furthermore, the same end points were compared between procedures performed by OPCAB surgeons in high OPCAB volume centres (off-pump technique used in &gt;50% of cases; n=894) and low OPCAB volume centres (n=307). Results: In the experienced OPCAB surgeon group, we observed shorter procedure times (β -43.858, 95% confidence interval [CI] -53.322 to -34.393; p&lt;0.001), a lower rate of conversion to cardiopulmonary bypass (odds ratio [OR] 0.284, 95% CI 0.147-0.551; p&lt;0.001), a lower rate of prolonged inotrope or vasoconstrictor use (OR 0.492, 95% CI 0.371-0.653; p&lt;0.001), a lower rate of early postprocedural percutaneous coronary interventions (OR 0.335, 95% CI 0.169-0.663; p=0.002), and lower 30-day mortality (OR 0.423, 95% CI 0.194-0.924; p=0.031). In high OPCAB volume centres, we found a lower rate of prolonged inotrope use (OR 0.584, 95% CI 0.419-0.814; p=0.002), a lower rate of postprocedural acute kidney injury (OR 0.382, 95% CI 0.198-0.738; p=0.004), shorter duration of intensive care unit (β -1.752, 95% CI -2.240 to -1.264; p&lt;0.001) and hospital (β -1.967; 95% CI -2.717 to -1.216; p&lt;0.001) stays, and lower 30-day mortality (OR 0.316, 95% CI 0.114-0.881; p=0.028). Conclusions: Surgeon experience and centre volume may play an important role on the early outcomes after OPCAB surgery

Risk prediction in early childhood sonic hedgehog medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than 2 subgroups

BACKGROUND The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse. METHODS One hundred and forty-four patients with DMB (n = 99) or MBEN (n = 45) aged <5 years and treated with radiation-sparing approaches, including intraventricular methotrexate in 132 patients were evaluated. RESULTS Patients with DMB had less favorable 5-year progression-free survival than MBEN (5y-PFS, 71% [DMB] vs. 93% [MBEN]). Patients aged >3 years were associated with more unfavorable 5y-PFS (47% [>3 years] vs. 85% [<1 year] vs. 84% [1-3 years]). DNA methylation profiles available (n = 78) were reclassified according to the 2021 WHO classification into SHH-1 (n = 39), SHH-2 (n = 38), and SHH-3 (n = 1). Hierarchical clustering delineated 2 subgroups among SHH-2: SHH-2a (n = 19) and SHH-2b (n = 19). Patients with SHH-2b medulloblastoma were older, predominantly displayed DMB histology, and were more often located in the cerebellar hemispheres. Chromosome 9q losses were more frequent in SHH-2b, while few chromosomal alterations were observed in SHH-2a. SHH-2b medulloblastoma carried a significantly increased relapse risk (5y-PFS: 58% [SHH-2b] vs. 83% [SHH-1] vs. 95% [SHH-2a]). Subclassification of SHH-2 with key clinical and cytogenetic characteristics was confirmed using 2 independent cohorts (total n = 188). Gene mutation analysis revealed a correlation of SHH-2a with SMO mutations. CONCLUSIONS These data suggest further heterogeneity within early childhood SHH-DMB/MBEN: SHH-2 splits into a very low-risk group SHH-2a enriched for MBEN histology and SMO mutations, and SHH-2b comprising older DMB patients with a higher risk of relapse

Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort

PURPOSE The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma