Clinical Risk Factors Associated with Late-Onset Invasive Group B Streptococcal Disease: Systematic Review and Meta-analyses.

BACKGROUND: Group B streptococcal (GBS) infection remains one of the most significant causes of late-onset sepsis and meningitis (LOGBS) among young infants. However, transmission routes and risk factors for LOGBS are not yet fully understood. METHODS: We conducted systematic reviews on clinical risk factors previously reported in the literature (prematurity, low birth weight [<2500 g], antenatal colonization, multiple-gestation pregnancy, maternal age <20 years, male infant sex, intrapartum fever, prolonged rupture of membranes) and meta-analyses to determine pooled estimates of risk. RESULTS: We included 27 articles, reporting 5315 cases. Prematurity (odds ratio 5.66; 95% confidence interval [4.43-7.22]), low birth weight (6.73; [4.68-9.67]), maternal colonization (2.67; [2.07-3.45]), and multiple-gestation pregnancies (8.01; [5.19-12.38]) were associated with an increased risk of LOGBS. CONCLUSIONS: Prematurity/low birth weight and maternal colonization are major risk factors for LOGBS. Future GBS vaccine studies should try to establish the optimal time for vaccination during pregnancy to protect preterm infants

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

Local and systemic therapy of recurrent medulloblastomas in children and adolescents: results of the P-HIT-REZ 2005 study

SIMPLE SUMMARY: A medulloblastoma recurrence is usually associated with an unfavorable prognosis. The German P-HIT-REZ 2005 Study gathered data from patients with relapsed medulloblastomas treated in different, non-randomized therapy arms dependent on preconditions of the patients (previous treatment, comorbidities, relapse pattern), the decision of treating physicians, and the patients’/parents’ choice. A total of 93 evaluable patients with refractory or relapsed medulloblastoma were enrolled. The main aim of this study was to analyze the impact of patient and disease characteristics as well as local and systemic therapies on post-relapse progression-free (PFS) and overall survival (OS). In multivariate analysis, a short time until the first recurrence (<18 months) was the strongest predictor for a worse PFS and OS, which was mainly associated with molecular subgroup 3. Metastatic disease, at relapse, only had a significant impact on OS. Re-biopsy, at relapse, is highly recommended to investigate the histopathological and molecular genetic tumor characteristics and to exclude a secondary malignancy. ABSTRACT: Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients’ survival

Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes

In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I–VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families

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

Clinical and molecular characterization of isolated M1 disease in pediatric medulloblastoma: experience from the German HIT-MED studies

PURPOSE: To evaluate the clinical impact of isolated spread of medulloblastoma cells into cerebrospinal fluid without additional macroscopic metastases (M1-only). METHODS: The HIT-MED database was searched for pediatric patients with M1-only medulloblastoma diagnosed from 2000 to 2019. Corresponding clinical and molecular data was evaluated. Treatment was stratified by age and changed over time for older patients. RESULTS: 70 patients with centrally reviewed M1-only disease were identified. Clinical data was available for all and molecular data for 45/70 cases. 91% were non-WNT/non-SHH medulloblastoma (Grp3/4). 5-year PFS for 52 patients ≥ 4 years was 59.4 (± 7.1) %, receiving either upfront craniospinal irradiation (CSI) or SKK-sandwich chemotherapy (CT). Outcomes did not differ between these strategies (5-year PFS: CSI 61.7 ± 9.9%, SKK-CT 56.7 ± 6.1%). For patients < 4 years (n = 18), 5-year PFS was 50.0 (± 13.2) %. M1-persistence occurred exclusively using postoperative CT and was a strong negative predictive factor (p$_{PFS/OS}$ < 0.01). Patients with additional clinical or molecular high-risk (HR) characteristics had worse outcomes (5-year PFS 42.7 ± 10.6% vs. 64.0 ± 7.0%, p = 0.03). In n = 22 patients ≥ 4 years with full molecular information and without additional HR characteristics, risk classification by molecular subtyping had an effect on 5-year PFS (HR 16.7 ± 15.2%, SR 77.8 ± 13.9%; p = 0.01). CONCLUSIONS: Our results confirm that M1-only is a high-risk condition, and further underline the importance of CSF staging. Specific risk stratification of affected patients needs attention in future discussions for trials and treatment recommendations. Future patients without contraindications may benefit from upfront CSI by sparing risks related to higher cumulative CT applied in sandwich regimen

Clinical and molecular characterization of isolated M1 disease in pediatric medulloblastoma: experience from the German HIT-MED studies

PURPOSE: To evaluate the clinical impact of isolated spread of medulloblastoma cells into cerebrospinal fluid without additional macroscopic metastases (M1-only). METHODS: The HIT-MED database was searched for pediatric patients with M1-only medulloblastoma diagnosed from 2000 to 2019. Corresponding clinical and molecular data was evaluated. Treatment was stratified by age and changed over time for older patients. RESULTS: 70 patients with centrally reviewed M1-only disease were identified. Clinical data was available for all and molecular data for 45/70 cases. 91% were non-WNT/non-SHH medulloblastoma (Grp3/4). 5-year PFS for 52 patients ≥ 4 years was 59.4 (± 7.1) %, receiving either upfront craniospinal irradiation (CSI) or SKK-sandwich chemotherapy (CT). Outcomes did not differ between these strategies (5-year PFS: CSI 61.7 ± 9.9%, SKK-CT 56.7 ± 6.1%). For patients < 4 years (n = 18), 5-year PFS was 50.0 (± 13.2) %. M1-persistence occurred exclusively using postoperative CT and was a strong negative predictive factor (p(PFS/OS) < 0.01). Patients with additional clinical or molecular high-risk (HR) characteristics had worse outcomes (5-year PFS 42.7 ± 10.6% vs. 64.0 ± 7.0%, p = 0.03). In n = 22 patients ≥ 4 years with full molecular information and without additional HR characteristics, risk classification by molecular subtyping had an effect on 5-year PFS (HR 16.7 ± 15.2%, SR 77.8 ± 13.9%; p = 0.01). CONCLUSIONS: Our results confirm that M1-only is a high-risk condition, and further underline the importance of CSF staging. Specific risk stratification of affected patients needs attention in future discussions for trials and treatment recommendations. Future patients without contraindications may benefit from upfront CSI by sparing risks related to higher cumulative CT applied in sandwich regimen. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-021-03913-5

A multi-institutional retrospective pooled outcome analysis of molecularly annotated pediatric supratentorial ZFTA-fused ependymoma

BACKGROUND ZFTA-RELA (formerly known as c11orf-RELA) fused supratentorial ependymoma (ZFTAfus ST-EPN) has been recognized as a novel entity in the 2016 WHO classification of CNS tumors and further defined in the recent 2021 edition. ZFTAfus ST-EPN was reported to portend poorer prognosis when compared to its counterpart, YAP1 ST-EPN in some previously published series. The aim of this study was to determine the treatment outcome of molecularly confirmed and conventionally treated ZFTAfus ST-EPN patients treated in multiple institutions. METHODS We conducted a retrospective analysis of all pediatric patients with molecularly confirmed ZFTAfus ST-EPN patients treated in multiple institutions in 5 different countries (Australia, Canada, Germany, Switzerland, and Czechia). Survival outcomes were analyzed and correlated with clinical characteristics and treatment approaches. RESULTS A total of 108 patients were collated from multiple institutions in 5 different countries across three continents. We found across the entire cohort that the 5- and 10-year PFS were 65% and 63%, respectively. The 5- and 10-year OS of this cohort of patients were 87% and 73%. The rates of gross total resection (GTR) were high with 84 out of 108 (77.8%) patients achieving GTR. The vast majority of patients also received post-operative radiotherapy, 98 out of 108 (90.7%). Chemotherapy did not appear to provide any survival benefit in our patient cohort. CONCLUSION This is the largest study to date of contemporaneously treated molecularly confirmed ZFTAfus ST-EPN patients which identified markedly improved survival outcomes compared to previously published series. This study also re-emphasizes the importance of maximal surgical resection in achieving optimal outcomes in pediatric patients with supratentorial ependymoma

Therapeutic implications of improved molecular diagnostics for rare CNS-embryonal tumor entities: results of an international, retrospective study

BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS-embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumor with multi-layered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n=307). Additional cases (n=66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n=292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58(19%) cases as ETMR, 57(19%) as HGG, 36(12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63%±7%, OS: 85%±5%, n=63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18%±6% and 22%±7%, and 5-year OS of 24%±6% and 25%±7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk-CSI based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments