Taste and Smell Functions in Long-term Survivors after Childhood Medulloblastoma/CNS-PNET

Purpose Our aim was to investigate taste and smell functions in survivors, with a minimum of 2 years follow-up time, after treatment of childhood medulloblastoma/CNS-PNET. Methods This cross-sectional study included 40 survivors treated ≤ 20 years of age. Taste strips with four concentrations of sweet, sour, salt, and bitter were used to assess taste function in all participants. Score from 0-16; ≥ 9 normogeusia, < 9 hypogeusia, and complete ageusia which equals no sensation. No sensation of a specific taste quality equals ageusia of that quality. Thirty-two participants conducted smell testing using three subtests of Sniffin’ sticks; threshold, discrimination, and identification. Together they yield a TDI-score from 1-48; functional anosmia ≤ 16.00, hyposmia >16.00 - < 30.75, normosmia ≥ 30.75 - < 41.50, and ≥ 41.50 super smeller. Results were compared with normative data. Survivors subjectively rated their taste and smell functions using a numerical rating scale (NRS) score 0-10. Results Forty survivors with a mean follow-up of 20.5 years, 13 (32.5 %) were diagnosed with hypogeusia, nine (22.5 %) of these being ageusic of one or more taste qualities. Seventeen (53 %) of 32 participants were diagnosed with hyposmia. Comparing survivors with hyposmia to those with normosmia, a significant difference (p<0.05) was found in TDI-score and in all the subtests. The mean NRS score of subjective ratings of functions were high.Conclusion Our study showed impaired taste and smell functions in long-term survivors of childhood MB/CNS-PNET using objective measurements. However, subjective ratings did not reflect objective findings.

PPM1D Is a Therapeutic Target in Childhood Neural Tumors

Childhood medulloblastoma and high-risk neuroblastoma frequently present with segmental gain of chromosome 17q corresponding to aggressive tumors and poor patient prognosis. Located within the 17q-gained chromosomal segments is PPM1D at chromosome 17q23.2. PPM1D encodes a serine/threonine phosphatase, WIP1, that is a negative regulator of p53 activity as well as key proteins involved in cell cycle control, DNA repair and apoptosis. Here, we show that the level of PPM1D expression correlates with chromosome 17q gain in medulloblastoma and neuroblastoma cells, and both medulloblastoma and neuroblastoma cells are highly dependent on PPM1D expression for survival. Comparison of different inhibitors of WIP1 showed that SL-176 was the most potent compound inhibiting medulloblastoma and neuroblastoma growth and had similar or more potent effects on cell survival than the MDM2 inhibitor Nutlin-3 or the p53 activator RITA. SL-176 monotherapy significantly suppressed the growth of established medulloblastoma and neuroblastoma xenografts in nude mice. These results suggest that the development of clinically applicable compounds inhibiting the activity of WIP1 is of importance since PPM1D activating mutations, genetic gain or amplifications and/or overexpression of WIP1 are frequently detected in several different cancers.

Medulloblastoma in Adulthood

Defined as a tumour with increased malignancy potential in childhood, medulloblastoma was first reported in the literature by Percival Bailey and Harvey Cushing in 1925. Scientific studies over the years have shown that this type of tumour represents about 20% of all intracranial tumours encountered in childhood, their percentage decreasing with advancing age. The genetic factor plays an important part in the appearance of medulloblastoma; there are certain diseases, in the patient’s history, that can be associated with this type of tumour. Here, we can specify Turcot syndrome (an autosomal recessive disease, rarely encountered) or basal cell carcinoma syndrome. This article presents the case of a young patient (41-year-old) suffering from a cerebellar tumour formation that turned out to be, after histopathological examination, a medulloblastoma. In practice we can find several types of medulloblastoma (desmoplastic or nodular, anaplastic, classical or undifferentiated). In what follows I will try to highlight a few aspects of a classic medulloblastoma.

CoMB-Deep: Composite Deep Learning-Based Pipeline for Classifying Childhood Medulloblastoma and Its Classes

Childhood medulloblastoma (MB) is a threatening malignant tumor affecting children all over the globe. It is believed to be the foremost common pediatric brain tumor causing death. Early and accurate classification of childhood MB and its classes are of great importance to help doctors choose the suitable treatment and observation plan, avoid tumor progression, and lower death rates. The current gold standard for diagnosing MB is the histopathology of biopsy samples. However, manual analysis of such images is complicated, costly, time-consuming, and highly dependent on the expertise and skills of pathologists, which might cause inaccurate results. This study aims to introduce a reliable computer-assisted pipeline called CoMB-Deep to automatically classify MB and its classes with high accuracy from histopathological images. This key challenge of the study is the lack of childhood MB datasets, especially its four categories (defined by the WHO) and the inadequate related studies. All relevant works were based on either deep learning (DL) or textural analysis feature extractions. Also, such studies employed distinct features to accomplish the classification procedure. Besides, most of them only extracted spatial features. Nevertheless, CoMB-Deep blends the advantages of textural analysis feature extraction techniques and DL approaches. The CoMB-Deep consists of a composite of DL techniques. Initially, it extracts deep spatial features from 10 convolutional neural networks (CNNs). It then performs a feature fusion step using discrete wavelet transform (DWT), a texture analysis method capable of reducing the dimension of fused features. Next, the CoMB-Deep explores the best combination of fused features, enhancing the performance of the classification process using two search strategies. Afterward, it employs two feature selection techniques on the fused feature sets selected in the previous step. A bi-directional long-short term memory (Bi-LSTM) network; a DL-based approach that is utilized for the classification phase. CoMB-Deep maintains two classification categories: binary category for distinguishing between the abnormal and normal cases and multi-class category to identify the subclasses of MB. The results of the CoMB-Deep for both classification categories prove that it is reliable. The results also indicate that the feature sets selected using both search strategies have enhanced the performance of Bi-LSTM compared to individual spatial deep features. CoMB-Deep is compared to related studies to verify its competitiveness, and this comparison confirmed its robustness and outperformance. Hence, CoMB-Deep can help pathologists perform accurate diagnoses, reduce misdiagnosis risks that could occur with manual diagnosis, accelerate the classification procedure, and decrease diagnosis costs.

Novel PHOX2B germline mutation in childhood medulloblastoma: a case report

Background Medulloblastoma is an aggressive brain tumor mostly found in children, few studies on pathogenic germline mutations predisposing this disease was reported. Case presentation We present an 11-year-old male with medulloblastoma, who harbors a de novo PHOX2B germline mutation as detected by whole exome sequencing (WES). Family history was negative. Sanger sequencing confirmed this mutation in peripheral blood, hair bulbs, urine and saliva. Identification of novel germline mutations is beneficial for childhood cancer screening. Conclusions This case revealed a de novo PHOX2B germline mutation as a potential cause of medulloblastoma in a child and suggests familial germline variant screening is useful when an affected family is considering having a second child.

Prognostic Clinical and Biologic Features for Overall Survival after Relapse in Childhood Medulloblastoma

Given the very poor prognosis for children with recurrent medulloblastoma, we aimed to identify prognostic factors for survival post-relapse in children with childhood medulloblastoma. We retrospectively collected clinico-biological data at diagnosis and main clinical characteristics at relapse of children newly diagnosed with a medulloblastoma between 2007 and 2017 at Gustave Roussy and Necker Hospital. At a median follow-up of 6.6 years (range, 0.4–12.3 years), relapse occurred in 48 out 155 patients (31%). The median time from diagnosis to relapse was 14.3 months (range, 1.2–87.2 months). Relapse was local in 9, metastatic in 22 and combined (local and metastatic) in 17 patients. Second-line treatment consisted of chemotherapy in 31 cases, radiotherapy in 9, SHH-inhibitor in four and no treatment in the remaining four. The 1-year overall survival rate post-relapse was 44.8% (CI 95%, 31.5% to 59.0%). While molecular subgrouping at diagnosis was significantly associated with survival post-relapse, the use of radiotherapy at relapse and time to first relapse (>12 months) might also have a potential impact on post-relapse survival.

MBCL-20. DETECTION OF SOMATIC MUTATIONS BY USING RNA-SEQ DATA IN CHILDHOOD MEDULLOBLASTOMA AND ITS POTENTIAL CLINICAL APPLICATION: A COHORT SERIES OF 52 CASES STUDY IN TAIWAN

BACKGROUND In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). Part of our aim was to explore the clinical application for drug target identification and finding clues to genetic predisposition. METHODS In total, 52 frozen tumor tissues of childhood MBs were collected. RNA-Seq and DNA methylation array data were generated. Molecular subgrouping was performed. We selected 51 clinically relevant genes for somatic variant calling using RNA-Seq data. Correlated clinical findings to genetic predisposition were defined. Potential drug targets and genetic predispositions were explored. RESULTS Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Potential drug targets were detected in the pathways of DNA damage response. Five patients with relevant clinical findings to genetic predisposition clustered in SHH MBs. The corresponding somatic driver mutations involved TP53, MSH6, PTEN, PTCH1, and TERT promoter (suspicious). For validation, whole exome sequencing (WES) of blood and tumor tissue was used in 10 patients with SHH MBs in the cohort series. This study included the five patients with potential genetic predispositions. Four patients exhibited relevant germline mutations named as TP53, MSH6, PTEN, and SUFU. CONCLUSION The findings of this study provide valuable information for personalized care of childhood MB in our cohort series and in Taiwan.