High Intra-Tumor Transforming Growth Factor Beta 2 Level as a Predictor of Poor Treatment Outcomes in Pediatric Diffuse Intrinsic Pontine Glioma

2023-03-2910:00

Fatih M UckunSanjive QaziVuong Trieu

Here, we report that tumor samples from newly diagnosed pediatric diffuse intrinsic pontine glioma (DIPG) patients express significantly higher levels of transforming growth factor beta 2 (TGFB2) messenger ribonucleic acid (mRNA) than control pons samples, which correlated with augmented expression of transcription factors that upregulate TGFB2 gene expression. Our study also demonstrated that RNA sequencing (RNAseq)-based high TGFB2 mRNA level is an indicator of poor prognosis for DIPG...

Here, we report that tumor samples from newly diagnosed pediatric diffuse intrinsic pontine glioma (DIPG) patients express significantly higher levels of transforming growth factor beta 2 (TGFB2) messenger ribonucleic acid (mRNA) than control pons samples, which correlated with augmented expression of transcription factors that upregulate TGFB2 gene expression. Our study also demonstrated that RNA sequencing (RNAseq)-based high TGFB2 mRNA level is an indicator of poor prognosis for DIPG...

Cancers (Basel). 2023 Mar 9;15(6):1676. doi: 10.3390/cancers15061676.

ABSTRACT

Here, we report that tumor samples from newly diagnosed pediatric diffuse intrinsic pontine glioma (DIPG) patients express significantly higher levels of transforming growth factor beta 2 (TGFB2) messenger ribonucleic acid (mRNA) than control pons samples, which correlated with augmented expression of transcription factors that upregulate TGFB2 gene expression. Our study also demonstrated that RNA sequencing (RNAseq)-based high TGFB2 mRNA level is an indicator of poor prognosis for DIPG patients, but not for pediatric glioblastoma (GBM) patients or pediatric diffuse midline glioma (DMG) patients with tumor locations outside of the pons/brainstem. Notably, DIPG patients with high levels of TGFB2 mRNA expression in their tumor samples had significantly worse overall survival (OS) and progression-free survival (PFS). By comparison, high levels of transforming growth factor beta 3 (TGFB3) mRNA expression in tumor samples was associated with significantly better survival outcomes of DIPG patients, whereas high levels of transforming growth factor beta 1 (TGFB1) expression was not prognostic. Our study fills a significant gap in our understanding of the clinical significance of high TGFB2 expression in pediatric high-grade gliomas.

PMID:36980562 | PMC:PMC10046593 | DOI:10.3390/cancers15061676

Positioning Transclival Tumor-Treating Fields for the Treatment of Diffuse Intrinsic Pontine Gliomas

2023-03-2910:00

Walid Ibn EssayedCasey A JarvisJoshua D BernstockAnna SlingerlandJohn AlbaneseGregory K FriedmanOmar ArnaoutLissa Baird

Diffuse intrinsic pontine glioma (DIPG) carries an extremely poor prognosis, with 2-year survival rates of

Diffuse intrinsic pontine glioma (DIPG) carries an extremely poor prognosis, with 2-year survival rates of

Life (Basel). 2023 Feb 21;13(3):601. doi: 10.3390/life13030601.

ABSTRACT

Diffuse intrinsic pontine glioma (DIPG) carries an extremely poor prognosis, with 2-year survival rates of <10% despite the maximal radiation therapy. DIPG cells have previously been shown to be sensitive to low-intensity electric fields in vitro. Accordingly, we sought to determine if the endoscopic endonasal (EE) implantation of an electrode array in the clivus would be feasible for the application of tumor-treating fields (TTF) in DIPG. Anatomic constraints are the main limitation in pediatric EE approaches. In our Boston Children's Hospital's DIPG cohort, we measured the average intercarotid distance (1.68 ± 0.36 cm), clival width (1.62 ± 0.19 cm), and clival length from the base of the sella (1.43 ± 0.69 cm). Using a linear regression model, we found that only clival length and sphenoid pneumatization were significantly associated with age (R2 = 0.568, p = 0.005 *; R2 = 0.605, p = 0.0002 *). Critically, neither of these parameters represent limitations to the implantation of a device within the dimensions of those currently available. Our findings confirm that the anatomy present within this age group is amenable to the placement of a 2 × 1 cm electrode array in 94% of patients examined. Our work serves to demonstrate the feasibility of implantable transclival devices for the provision of TTFs as a novel adjunctive therapy for DIPG.

PMID:36983757 | PMC:PMC10059731 | DOI:10.3390/life13030601

Multimodal MRI radiomic models to predict genomic mutations in diffuse intrinsic pontine glioma with missing imaging modalities

2023-03-1310:00

Fahad KhalidJessica Goya-OutiThibault EscobarVolodia Dangouloff-RosAntoine GrigisCathy PhilippeNathalie BoddaertJacques GrillVincent FrouinFrédérique Frouin

CONCLUSION: Compared with a single modality approach, the multi-modal model combining multiple MRI modalities and clinical features was the most powerful to predict H3.1, ACVR1, and TP53 mutations and provided prediction, even in the case of missing modality. It could be proposed in the absence of a conclusive biopsy.

CONCLUSION: Compared with a single modality approach, the multi-modal model combining multiple MRI modalities and clinical features was the most powerful to predict H3.1, ACVR1, and TP53 mutations and provided prediction, even in the case of missing modality. It could be proposed in the absence of a conclusive biopsy.

Front Med (Lausanne). 2023 Feb 23;10:1071447. doi: 10.3389/fmed.2023.1071447. eCollection 2023.

ABSTRACT

PURPOSE: Predicting H3.1, TP53, and ACVR1 mutations in DIPG could aid in the selection of therapeutic options. The contribution of clinical data and multi-modal MRI were studied for these three predictive tasks. To keep the maximum number of subjects, which is essential for a rare disease, missing data were considered. A multi-modal model was proposed, collecting all available data for each patient, without performing any imputation.

METHODS: A retrospective cohort of 80 patients with confirmed DIPG and at least one of the four MR modalities (T1w, T1c, T2w, and FLAIR), acquired with two different MR scanners was built. A pipeline including standardization of MR data and extraction of radiomic features within the tumor was applied. The values of radiomic features between the two MR scanners were realigned using the ComBat method. For each prediction task, the most robust features were selected based on a recursive feature elimination with cross-validation. Five different models, one based on clinical data and one per MR modality, were developed using logistic regression classifiers. The prediction of the multi-modal model was defined as the average of all possible prediction results among five for each patient. The performances of the models were compared using a leave-one-out approach.

RESULTS: The percentage of missing modalities ranged from 6 to 11% across modalities and tasks. The performance of each individual model was dependent on each specific task, with an AUC of the ROC curve ranging from 0.63 to 0.80. The multi-modal model outperformed the clinical model for each prediction tasks, thus demonstrating the added value of MRI. Furthermore, regardless of performance criteria, the multi-modal model came in the first place or second place (very close to first). In the leave-one-out approach, the prediction of H3.1 (resp. ACVR1 and TP53) mutations achieved a balanced accuracy of 87.8% (resp. 82.1 and 78.3%).

CONCLUSION: Compared with a single modality approach, the multi-modal model combining multiple MRI modalities and clinical features was the most powerful to predict H3.1, ACVR1, and TP53 mutations and provided prediction, even in the case of missing modality. It could be proposed in the absence of a conclusive biopsy.

PMID:36910474 | PMC:PMC9995801 | DOI:10.3389/fmed.2023.1071447

Institutional Patterns of Care of Diffuse Intrinsic Pontine Glioma

2023-03-0211:00

Rahul KrishnatryShakthivel ManiJifmi J ManjaliPallavi P RaneAbhishek ChatterjeeJayant S GodaAmit JanuArpita SahuTejpal GuptaRakesh Jalali

CONCLUSION: Many patient families still do not choose radiotherapy treatment, although it has a consistent and significant positive association with survival and steroid usage. reRT further improves outcomes in the selective cohorts. Involvement of cranial nerves IX and X needs improved care.

CONCLUSION: Many patient families still do not choose radiotherapy treatment, although it has a consistent and significant positive association with survival and steroid usage. reRT further improves outcomes in the selective cohorts. Involvement of cranial nerves IX and X needs improved care.

Neurol India. 2023 Jan-Feb;71(1):72-78. doi: 10.4103/0028-3886.370459.

ABSTRACT

BACKGROUND AND AIM: Despite recent advances, the outcomes of diffuse intrinsic pontine glioma (DIPG) remain dismal. This is a retrospective study to understand the pattern of care and its impact on DIPG patients diagnosed over 5 years in a single institute.

SUBJECTS AND METHODS: DIPGs diagnosed between 2015 and 2019 were retrospectively reviewed to understand the demographics, clinical features, patterns of care, and outcomes. The usage of steroids and response to treatment were analyzed as per the available records and criteria. The re-irradiation cohort was propensity matched with patients with a progression-free survival (PFS) >6 months treated with supportive care alone based on PFS and age as a continuous variable. Survival analysis was performed using the Kaplan-Meier method, and Cox regression model was used to identify any potential prognostic factors.

RESULTS: One hundred and eighty-four patients were identified with demographic profiles similar to western population-based data in the literature. Of them, 42.4% were residents from outside the state of the institution. About 75.2% of patients completed their first radiotherapy treatment, of which only 5% and 6% had worsening clinical symptoms and persistent need for steroids 1 month posttreatment. On multivariate analysis, Lansky performance status <60 (P = 0.028) and cranial nerve IX and X (P = 0.026) involvement were associated with poor survival outcomes while receiving radiotherapy with better survival (P < 0.001). In the cohort of patients receiving radiotherapy, only re-irradiation (reRT) was associated with improved survival (P = 0.002).

CONCLUSION: Many patient families still do not choose radiotherapy treatment, although it has a consistent and significant positive association with survival and steroid usage. reRT further improves outcomes in the selective cohorts. Involvement of cranial nerves IX and X needs improved care.

PMID:36861577 | DOI:10.4103/0028-3886.370459

Second course of re-irradiation in pediatric diffuse intrinsic pontine glioma : A case study

2023-03-0211:00

Paula Maria BergengruenPablo Hernaíz DrieverVolker BudachDaniel ZipsArne Grün

CONCLUSION: A second course of re-irradiation can be an additional tool in patients with progressive disease after first- and second-line irradiation. It is unclear whether and to what extent it contributes to progression-free survival prolongation and if-since our patient was asymptomatic-progression-associated neurological deficits can be alleviated.

CONCLUSION: A second course of re-irradiation can be an additional tool in patients with progressive disease after first- and second-line irradiation. It is unclear whether and to what extent it contributes to progression-free survival prolongation and if-since our patient was asymptomatic-progression-associated neurological deficits can be alleviated.

Strahlenther Onkol. 2023 Mar 2. doi: 10.1007/s00066-023-02057-x. Online ahead of print.

ABSTRACT

PURPOSE: Concomitant chemoradiation followed by repeat (dose-deescalated) irradiation has become standard of care in treating childhood diffuse intrinsic pontine glioma (DIPG) during first line treatment and at first progression. Progression after re-irradiation (re-RT) is in most cases symptomatic and either treated systemically with chemotherapy or new innovative approaches including targeted therapy. Alternatively, the patient receives best supportive care. Data on second re-irradiation in DIPG patients with second progression and good performance status are sparse. This is a case report of second short-term re-irradiation to shed further light on this option.

METHODS: Retrospective case report of a 6-year-old boy with DIPG receiving a second course of re-irradiation (with 21.6 Gy) as part of an individual multimodal approach in a patient with very low symptom burden.

RESULTS: The second course of re-irradiation was feasible and well tolerated. No acute neurological symptoms or radiation-induced toxicity occurred. Overall survival was 24 months after initial diagnosis.

CONCLUSION: A second course of re-irradiation can be an additional tool in patients with progressive disease after first- and second-line irradiation. It is unclear whether and to what extent it contributes to progression-free survival prolongation and if-since our patient was asymptomatic-progression-associated neurological deficits can be alleviated.

PMID:36862153 | DOI:10.1007/s00066-023-02057-x

Towards Standardisation of a Diffuse Midline Glioma Patient-Derived Xenograft Mouse Model Based on Suspension Matrices for Preclinical Research

2023-02-2511:00

Elvin 't HartJohn BiancoHelena C BesseLois A Chin Joe KieLesley CornetKimberly L EikelenboomThijs J M van den BroekMarc DerieppeYan SuEelco W HovingMario G RiesDannis G van Vuurden

Diffuse midline glioma (DMG) is an aggressive brain tumour with high mortality and limited clinical therapeutic options. Although in vitro research has shown the effectiveness of medication, successful translation to the clinic remains elusive. A literature search highlighted the high variability and lack of standardisation in protocols applied for establishing the commonly used HSJD-DIPG-007 patient-derived xenograft (PDX) model, based on animal host, injection location, number of cells...

Diffuse midline glioma (DMG) is an aggressive brain tumour with high mortality and limited clinical therapeutic options. Although in vitro research has shown the effectiveness of medication, successful translation to the clinic remains elusive. A literature search highlighted the high variability and lack of standardisation in protocols applied for establishing the commonly used HSJD-DIPG-007 patient-derived xenograft (PDX) model, based on animal host, injection location, number of cells...

Biomedicines. 2023 Feb 11;11(2):527. doi: 10.3390/biomedicines11020527.

ABSTRACT

Diffuse midline glioma (DMG) is an aggressive brain tumour with high mortality and limited clinical therapeutic options. Although in vitro research has shown the effectiveness of medication, successful translation to the clinic remains elusive. A literature search highlighted the high variability and lack of standardisation in protocols applied for establishing the commonly used HSJD-DIPG-007 patient-derived xenograft (PDX) model, based on animal host, injection location, number of cells inoculated, volume, and suspension matrices. This study evaluated the HSJD-DIPG-007 PDX model with respect to its ability to mimic human disease progression for therapeutic testing in vivo. The mice received intracranial injections of HSJD-DIPG-007 cells suspended in either PBS or Matrigel. Survival, tumour growth, and metastases were assessed to evaluate differences in the suspension matrix used. After cell implantation, no severe side effects were observed. Additionally, no differences were detected in terms of survival or tumour growth between the two suspension groups. We observed delayed metastases in the Matrigel group, with a significant difference compared to mice with PBS-suspended cells. In conclusion, using Matrigel as a suspension matrix is a reliable method for establishing a DMG PDX mouse model, with delayed metastases formation and is a step forward to obtaining a standardised in vivo PDX model.

PMID:36831063 | PMC:PMC9952880 | DOI:10.3390/biomedicines11020527

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