Abstract
INTRODUCTION
The prognostic impact of tumour marker (TM) decline rate has been demonstrated for extracranial poor prognostic non-seminomatous/germinomatous germ cell tumours (NGGCT). The ...current series aimed to assess if this finding can be applied to intracranial primaries.
METHODS
Patients were retrieved from the SIOP-CNS-GCT-96 database. They were selected if they had i/assessable values of serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (HCG) before and 18 to 28 days after the first course of chemotherapy and ii/ available data for outcome. Decline rate was calculated using a logarithmic transformation and expressed as time to normalization (TTN) as published by Fizazi (JCO 2004). TTN≤ 9 weeks for AFP and ≤ 6 weeks for HCG were considered as favourable decline rate. Prognostic impact of TTN on outcomes was assessed using the log-rank test.
RESULTS
Out of 149 patients with NGGCT, 59 were evaluable for both HCG and AFP TTN of whom 44 (74%) had a favourable decline rate. After a median follow-up of 88 months (2–251), 20 relapses and 15 deaths occurred. The 5-year PFS rates were 72% and 60% in patients who had a favourable and an unfavourable TTN, respectively (p=0.15). The 5-year OS rates were 77 % and 69%, respectively (p=0.66). Separate analysis of TTN based only on AFP or only on HCG gave similar results.
CONCLUSION
Despite the use of a methodology similar to that used in extracranial NGGCT, no significant impact of serum TM decline on prognosis was observed, but insufficient statistical power cannot be ruled out.
Abstract
Background
The prognosis for Li–Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development ...of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients.
Methods
In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated.
Results
The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup “SHH_3” (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively).
Conclusions
LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.
Graphical Abstract
Graphical Abstract
Abstract
Patients with Li-Fraumeni syndrome (LFS) who develop medulloblastoma (MB) have a very poor prognosis. The development of novel therapeutic strategies is challenged by the lack of clinical ...data for this patient group. We here present clinical and molecular data on a retrospective cohort of pediatric patients with LFS-associated MB.
This is an international, retrospective, multicenter cohort study. Patients with LFS-associated MB under 21 years and class 5 (pathogenic) or class 4 (likely pathogenic) constitutional TP53 variants were included. We evaluated TP53 mutation status (constitutional and somatic), DNA methylation subgroup, treatment modalities, event-free (EFS) and overall survival (OS), patterns of recurrence, as well as occurrence of secondary neoplasms.
Forty-seven individuals with LFS-associated MB were included. MBs were classified mainly as Sonic Hedgehog (SHH) group (87%). TP53 variants were classified as class 5 (70%) and class 4 (30%). The majority (74%) of TP53 variants represented missense variants. The 2-year (y-) EFS and -OS were 33% and 53%, respectively. A significantly better outcome was seen in patients who received post-operative radiotherapy (RT) (2y-EFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-EFS: 24%, 2y-OS: 48%) compared with patients who received no RT (2y-EFS: n.a., 2y-OS: 25%). No significantly different outcomes were seen between patients treated either according to protocols including high-intensity chemotherapy or receiving only maintenance-type chemotherapy (2y-EFS: 42% and 31%, 2y-OS: 68% and 53%, respectively).
Patients with LFS-associated MB have a dismal prognosis. Use of RT in LFS-associated MB significantly increased survival rates in the presented cohort, but choice of chemotherapy regimen did not influence their clinical outcome. To improve the outcome of patients with LFS-associated MB, prospective collection of clinical data and development of novel treatments are required.
The purpose of this study was to evaluate the long-term cognitive sequelae and to describe the neuropsychological profile of patients with intracranial germ cell tumors according to tumor location ...(pineal or suprasellar site).
Forty-five children treated at Gustave Roussy between 1991 and 2010 were assessed with neuropsychological tests to measure IQ, memory, visuospatial, motor, and executive skills at a mean delay of 4.2 years after diagnosis. All patients have received chemotherapy associated with surgery in 17 cases. Thirty-nine patients received, radiotherapy (focal 27, focal plus ventricles 8, craniospinal 4). Twenty-three patients had 2 IQ assessments with a mean delay of 4.1 years between the first and second.
Full scale IQ was preserved, with higher verbal IQ than other IQ indexes. Visuospatial, fine-motor, and executive difficulties were present in a significant proportion of patients. Visuospatial and fine-motor deficits were significantly associated with oculomotor difficulties, more present in the pineal than in the suprasellar group. No cognitive decline was observed between the first and the second IQ assessment.
Overall cognitive abilities were preserved in children treated for central nervous system germ cell tumor.
Abstract
Glioma are frequently seen in the second decade of life in children with constitutional mismatch repair deficiency (CMMRD) syndrome. They are often associated with a high mutation load but ...their characteristics have not been extensively described. Your study describes 15 cases including 2 siblings from the radiological, histological et molecular (Whole Exome Sequencing) points of view. Tumors were frequently associated with lesions of different ages (multicentric) or vascular malformations. Different histologies were observed with a majority of glioblastomas (n=9) and giant tumor cells were almost always present. Immunohistochemistry was positive for p53 in 14/15 (concordant with mutations detected with sequencing) and was negative for ATRX in 11/15 (concordant with mutations detected with sequencing in all but one patient). PDL1 expression was only seen in 6/15. Mutation load was above 100/Mb in all but four; all hypermutated tumors had secondary mutations in POLE or POLD1. PMS2 and MSH2 were the two most frequently MMR genes mutated. The distribution of the variant allele frequency was most frequently bi- or tri-modal suggesting different waves of mutations gains. SomaticSignatures and DeconstructSig identified various combinations of signatures in the different exomes. Qualitatively mutations observed in the CMMRD samples were different from those observed in common pediatric high-grade gliomas (pHGG): absence of K27M and G34R/V mutations in H3F3A, absence of BRAF V600E mutation, absence of IDH1 R132H mutation, TP53 mutations were present in all but one. In conclusion, CMMRD-associated gliomas represent a distinct entity of pHGG with a specific oncogenesis.
Abstract
PURPOSE: The prognosis for SHH-medulloblastoma (MB) patients with Li-Fraumeni syndrome (LFS) is poor. Due to lack of comprehensive data for these patients, it is challenging to establish ...effective therapeutic recommendations. We here describe the largest retrospective cohort of pediatric LFS SHH-MB patients to date and their clinical outcomes. PATIENTS AND METHODS: N=31 patients with LFS SHH-MB were included in this retrospective multicenter study. TP53 variant type, clinical parameters including treatment modalities, event-free survival (EFS) and overall survival (OS), as well as recurrence patterns and incidence of secondary neoplasms, were evaluated. RESULTS: All LFS-MBs were classified as SHH subgroup, in 30/31 cases based on DNA methylation analysis. The majority of constitutional TP53 variants (72%) represented missense variants, and all except two truncating variants were located within the DNA-binding domain. 54% were large cell anaplastic, 69% gross totally resected and 81% had M0 status. The 2-(y)ear and 5-(y)ear EFS were 26% and 8,8%, respectively, and 2y- and 5y-OS 40% and 12%. Patients who received post-operative radiotherapy (RT) followed by chemotherapy (CT) showed significantly better outcomes (2y-EFS:43%) compared to patients who received CT before RT (30%) (p<0.05). The 2y-EFS and 2y-OS were similar when treated with protocols including high-dose chemotherapy (EFS:22%, OS:44%) compared to patients treated with maintenance-type chemotherapy (EFS:31%, OS:45%). Recurrence occurred in 73.3% of cases independent of resection or M-status, typically within the radiation field (75% of RT-treated patients). Secondary malignancies developed in 12.5% and were cause of death in all affected patients. CONCLUSIONS: Patients with LFS-MBs have a dismal prognosis. This retrospective study suggests that upfront RT may increase EFS, while intensive therapeutic approaches including high-dose chemotherapy did not translate into increased survival of this patient group. To improve outcomes of LFS-MB patients, prospective collection of clinical data and development of treatment guidelines are required.
Abstract Background Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to biallelic mutations in one of the mismatch repair (MMR) genes associated with early onset of ...cancers, especially high-grade gliomas. Our aim was to decipher the molecular specificities of these gliomas. Methods Clinical, histopathological and whole exome sequencing data were analyzed in 12 children with genetically proven CMMRD and a high-grade glioma. Results PDL1 expression was present on immunohistochemistry in 50% of the samples. In 9 patients, the glioma harbored an ultra-hypermutated phenotype (104-635 coding single nucleotide variants (SNV) per Mb, median 204). Driver mutations in POLE and POLD1 exonuclease domains were described for 8 and 1 patients respectively and were always present in the mutation burst with the highest variant allele frequency (VAF). The mutational signatures were dominated by MMR-related ones and similar in the different mutation bursts of a same patient without subsequent enrichment of the mutation signatures with POL-driven ones. Median number of coding SNV with VAF above the one of the driving polymerase mutation per Mb was 57 (17-191). Our findings suggest that somatic polymerase alterations does not entirely explain the ultra-hypermutant phenotype. SETD2, TP53, NF1, EPHB2, PRKDC and DICER1 genes were frequently mutated with higher VAF than the deleterious somatic polymerase mutation. Conclusions CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors.
The Lynch syndrome (LS)-glioma association is poorly documented. As for mismatch repair deficiency (MMRd) in glioma, a hallmark of LS-associated tumors, there are only limited data available. We ...determined MMRd and LS prevalence in a large series of unselected gliomas, and explored the associated characteristics. Both have major implications in terms of treatment, screening, and prevention.
Somatic next-generation sequencing was performed on 1,225 treatment-naive adult gliomas referred between 2017 and June 2022. For gliomas with ≥1 MMR pathogenic variant (PV), MMR immunohistochemistry (IHC) was done. Gliomas with ≥1 PV and protein expression loss were considered MMRd. Eligible patients had germline testing. To further explore MMRd specifically in glioblastomas, isocitrate dehydrogenase (IDH)-wild type (wt), we performed IHC, and complementary sequencing when indicated, in a series of tumors diagnosed over the 2007-2021 period.
Nine gliomas were MMRd (9/1,225; 0.73%). Age at glioma diagnosis was <50 years for all but one case. Eight were glioblastomas, IDH-wt, and one was an astrocytoma, IDH-mutant.
(n = 5) and
(n = 8) PV were common. There was no
promoter PV or
amplification. LS prevalence was 5/1,225 (0.41%). One 77-year-old patient was a known LS case. Four cases had a novel LS diagnosis, with germline PV in
(n = 3) and
(n = 1). One additional patient had
-associated constitutional mismatch repair deficiency. Germline testing was negative in three MSH6-deficient tumors. In the second series of glioblastomas, IDH-wt, MMRd prevalence was 12.5% in the <40-year age group, 2.6% in the 40-49 year age group, and 1.6% the ≥50 year age group.
Screening for MMRd and LS should be systematic in glioblastomas, IDH-wt, diagnosed under age 50 years.
Abstract
PURPOSE
To assess radiological response to first-line chemotherapy in pediatric low-grade gliomas (pLGG) according to histopathology and BRAF alterations.
METHODS
We performed a ...population-based study of all patients diagnosed with a pLGG between 2006 and 2015 at Gustave Roussy and treated with vincristine-carboplatin, as first-line chemotherapy. Pathology samples were reviewed according to 2016 WHO classification. BRAF alterations were detected using immunohistochemistry, fluorescence in situ hybridization and/or sequencing. Tumor response was assessed by an independent central review.
RESULTS
Sixty-one patients were included in our cohort: 46 pilocytic astrocytomas (75.4%) and 15 gangliogliomas (24.6%). BRAF was found with an alteration in 44 samples (72%) and wild-type (WT) in 11 (18%) cases (molecular data incomplete = 6). Eleven pLGGs harbored the BRAF V600E mutation and 33 BRAF rearrangements. At the end of the first-line of chemotherapy, the objective response rate (complete or partial response) of pilocytic astrocytomas and gangliogliomas were 69% and 38%, respectively. The objective response rate of BRAF rearrangement, BRAF V600E and WT pLGGs were 72%, 22% and 60%, respectively. The 3-year event-free survival of patients with BRAF duplication pLGGs was 70% versus 45% for those with BRAF V600E pLGGs.
CONCLUSION
BRAF V600E pLGG constitutes a distinct entity with poor prognosis when treated with standard treatments.
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