Pediatric Low-grade Glioma Patients Research Articles

Fibroblast growth factor receptor 1 gene mutation as a potential risk factor for spontaneous intracranial hemorrhage in pediatric low-grade glioma patients.

Fibroblast growth factor receptor 1 (FGFR1) mutations have been associated with poorer prognoses in pediatric central nervous system tumor patients. A recent study highlighted a link between FGFR1 mutations and spontaneous intracranial hemorrhage (ICH), demonstrating that all patients with an FGFR1 alteration experienced hemorrhage at some point during their course of treatment. The current study examined 50 out of 67 pediatric patients with low-grade gliomas (LGGs) who had genomic testing between 2011 and 2022 at our institution to determine whether a correlation exists between FGFR1 mutations and spontaneous ICH. We found that of the 50 patients with genomic data, 7 (14%) experienced ICH, and an additional spontaneous hemorrhage was recorded; however, no genomic testing was performed for this case. Five of the seven patients (71.4%) had an FGFR1 modification. In our patient population, 6 expressed a detectable FGFR1 mutation (66.7% [4/6] had N546K alteration, 16.7% [1/6] FGFR1 exons duplication, and 16.7% [1/6] had a variant of unknown significance [VUS]). The patient with the FGFR1 VUS had no reported spontaneous hemorrhage. Statistical analysis found a significant association between FGFR1 and spontaneous intracranial hemorrhage (P-value = < .0001). In the patient population, all cases of PTPN11 alterations (n = 3) co-occurred with FGFR1 mutations. Our case series highlights this link between the FGFR1 mutation and spontaneous intracranial hemorrhage in pediatric LGGs.

Chemotherapy in pediatric low-grade gliomas (PLGG).

Pediatric low-grade gliomas (PLGG) are commonly treated with a combination of surgery, radiotherapy, and chemotherapy. Recent trends prioritize reducing long-term morbidities, particularly in younger patients. While historically chemotherapy was reserved for cases progressing after radiotherapy, evolving recommendations now advocate for its early use, particularly in younger age groups. The carboplatin and vincristine (CV) combination stands as a standard systemic therapy for PLGG, varying in dosage and administration between North America and Europe. Clinical trials have shown promising response rates, albeit with varying toxicity profiles. Vinblastine has emerged as another effective regimen with minimal toxicity. TPCV, a regimen combining thioguanine, procarbazine, lomustine, and vincristine, was compared to CV in a Children's Oncology Group trial, showing comparable outcomes, but more toxicity. Vinorelbine, temozolomide, and metronomic chemotherapy have also been explored, with varied success rates and toxicity profiles. Around 40-50% of PLGG patients require subsequent chemotherapy lines. Studies have shown varied efficacy in subsequent lines, with NF1 patients generally exhibiting better outcomes. The identification of molecular drivers like BRAF mutations has led to targeted therapies' development, showing promise in specific molecular subgroups. Trials comparing targeted therapy to conventional chemotherapy aim to delineate optimal treatment strategies based on molecular profiles. The landscape of chemotherapy in PLGG is evolving, with a growing focus on molecular subtyping and targeted therapies. Understanding the role of chemotherapy in conjunction with novel treatments is crucial for optimizing outcomes in pediatric patients with low-grade gliomas.

Increased confidence of radiomics facilitating pretherapeutic differentiation of BRAF-altered pediatric low-grade glioma.

Currently, the BRAF status of pediatric low-grade glioma (pLGG) patients is determined through a biopsy. We established a nomogram to predict BRAF status non-invasively using clinical and radiomic factors. Additionally, we assessed an advanced thresholding method to provide only high-confidence predictions for the molecular subtype. Finally, we tested whether radiomic features provide additional predictive information for this classification task, beyond that which is embedded in the location of the tumor. Random forest (RF) models were trained on radiomic and clinical features both separately and together, to evaluate the utility of each feature set. Instead of using the traditional single threshold technique to convert the model outputs to class predictions, we implemented a double threshold mechanism that accounted for uncertainty. Additionally, a linear model was trained and depicted graphically as a nomogram. The combined RF (AUC: 0.925) outperformed the RFs trained on radiomic (AUC: 0.863) or clinical (AUC: 0.889) features alone. The linear model had a comparable AUC (0.916), despite its lower complexity. Traditional thresholding produced an accuracy of 84.5%, while the double threshold approach yielded 92.2% accuracy on the 80.7% of patients with the highest confidence predictions. Models that included radiomic features outperformed, underscoring their importance for the prediction of BRAF status. A linear model performed similarly to RF but with the added benefit that it can be visualized as a nomogram, improving the explainability of the model. The double threshold technique was able to identify uncertain predictions, enhancing the clinical utility of the model. Radiomic features and tumor location are both predictive of BRAF status in pLGG patients. We show that they contain complementary information and depict the optimal model as a nomogram, which can be used as a non-invasive alternative to biopsy. • Radiomic features provide additional predictive information for the determination of the molecular subtype of pediatric low-grade gliomas patients, beyond what is embedded in the location of the tumor, which has an established relationship with genetic status. • An advanced thresholding method can help to distinguish cases where machine learning models have a high chance of being (in)correct, improving the utility of these models. • A simple linear model performs similarly to a more powerful random forest model at classifying the molecular subtype of pediatric low-grade gliomas but has the added benefit that it can be converted into a nomogram, which may facilitate clinical implementation by improving the explainability of the model.

Clinical features and outcomes of pediatric intracranial gliomas: results from single center's 226 cases and corroborated with SEER database.

Pediatric gliomas are the most common central nervous system (CNS) tumors in children and adolescents and show different clinical and histopathological characteristics from the adult. The prognostic factors were poorly defined in pediatric intracranial gliomas. We collected pediatric intracranial glioma cases in our institution between February 2011 and June 2022. The patient clinical data, tumor growth characteristics, treatments, and follow-up data were analyzed by Cox regression analysis to identify impact factors on the prognosis of pediatric intracranial glioma patients. To corroborate our data, an independent cohort of pediatric intracranial glioma from the Surveillance, Epidemiology, and End Results Program (SEER) database was analyzed. A total of 181 cases of pediatric low-grade glioma (PLGG) and 45 cases of pediatric high-grade glioma (PHGG) were included. In multivariate Cox regression analysis, tumor size > 59.5mm (p = 0.006) and non-gross total resection (non-GTR; subtotal resection, STR, p = 0.042; biopsy, p = 0.012) were associated with decreased overall survival (OS) in PLGG patients. In PHGG patients, only chemotherapy (p = 0.023) was associated with OS while tumor size was marginally prognostic for OS (p = 0.051). Additional independent analysis of 2734 PLGG and 741 PHGG from the SEER database corroborated that larger tumor size was associated with decreased OS in LGG (p = 0.001) and HGG (p < 0.001) patients, separately. In this study, we found that tumor size was a significant prognostic factor for the OS of PLGG patients in our series. Besides the tumor size, the extent of resection also independently impacted the prognosis of PLGG patients. While in PHGG patients, only chemotherapy was associated with improved OS and tumor size was marginally prognostic.

MiR-1248: a new prognostic biomarker able to identify supratentorial hemispheric pediatric low-grade gliomas patients associated with progression

BackgroundPediatric low-grade gliomas (pLGGs), particularly incompletely resected supratentorial tumours, can undergo progression after surgery. However to date, there are no predictive biomarkers for progression. Here, we aimed to identify pLGG-specific microRNA signatures and evaluate their value as a prognostic tool.MethodsWe identified and validated supratentorial incompletey resected pLGG-specific microRNAs in independent cohorts from four European Pediatric Neuro-Oncology Centres.ResultsThese microRNAs demonstrated high accuracy in differentiating patients with or without progression. Specifically, incompletely resected supratentorial pLGGs with disease progression showed significantly higher miR-1248 combined with lower miR-376a-3p and miR-888-5p levels than tumours without progression. A significant (p < 0.001) prognostic performance for miR-1248 was reported with an area under the curve (AUC) of 1.00. We also highlighted a critical oncogenic role for miR-1248 in gliomas tumours. Indeed, high miR-1248 levels maintain low its validated target genes (CDKN1A (p21)/FRK/SPOP/VHL/MTAP) and consequently sustain the activation of oncogenic pathways.ConclusionsAltogether, we provide a novel molecular biomarker able to successfully identify pLGG patients associated with disease progression that could support the clinicians in the decision-making strategy, advancing personalized medicine.

LGG-14. LOGGIC (Low Grade Glioma in Children) Core BioClinical Data Bank: Establishment and added clinical value of an international molecular diagnostic registry for pediatric low-grade glioma patients

BACKGROUND: The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data. In addition to routine histopathological and molecular analyses, LOGGIC Core determines the driver alteration as precisely as possible to support treatment decisions and participation in interventional trials. Hence, the question arises whether comprehensive implementation of RNA sequencing using Fresh Frozen (FF) tumor tissue to identify underlying gene fusions improves diagnostic accuracy and provides a clinical benefit. METHODS: Establishment of an international molecular and clinical registry including the logistical and analytical pipeline. First analysis of all patients age 0 to 18, which were included in Germany as part of the German HIT-LOGGIC-program between April 2019 and February 2021, and for whom FF tissue was available. This included histopathological evaluation, immunohistochemistry, 850k methylation analysis, gene panel sequencing, RNA sequencing using FF tissue. RESULTS: FF tissue was available in 178/379 included cases. RNA sequencing was performed on 125 samples. In this prospective, population based cohort, we confirmed KIAA1549:BRAF-fusion (57%), BRAFV600E-mutation (9%) and FGFR1-changes (10%) as most frequent alterations. 12% of cases presented rare gene fusions (e.g. TPM3:NTRK1, EWSR1:VGLL1, GOPC:ROS1, SH3PXD2A:HTRA1, PDGFB:LRP1). In 19% of cases, RNA sequencing detected an actionable target not identified by conventional methods. CONCLUSION: The addition of RNA sequencing reveals clinically relevant alterations including rare gene fusions. By demonstrating improvement of diagnostic accuracy and making precision oncology studies (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible, the added value for pLGG patients becomes apparent. LOGGIC Core is currently being rolled out internationally and aims to define the new state of the art standard molecular diagnostics. We propose to include RNA sequencing as part of routine diagnostic procedures for all pLGG patients, especially in tumors where no common MAPK alteration was identified.

Response to trametinib treatment in progressive pediatric low-grade glioma patients

IntroductionA hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy.MethodsIn this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity.ResultsWe observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2–4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%).ConclusionsTrametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.

Predictors of neuropsychological late effects and white matter correlates in children treated for a brain tumor without radiation therapy.

Little is known about cognition and predictors of neuropsychological outcomes in pediatric low-grade glioma (PLGG) survivors treated without radiation therapy. This research expands upon our previous work by further identifying the cognitive profile of PLGG patients treated without radiation therapy, investigating the specific medical and demographic variables that predict functioning, and examining white matter structure and its relationship to neuropsychological performance. Nineteen PLGG patients (11-19 years) were administered the Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale, and subtests from the Woodcock-Johnson Tests of Cognition (visual matching, rapid picture naming, and pair cancellation) and Cambridge Neuropsychological Test Automated Battery (pattern recognition memory, delayed matching to sample, intra-extra dimensional set shift, motor screening task, rapid visual information processing, and spatial span). The sample had normative weaknesses in verbal working memory, brief attention/vigilance, psychomotor speeded output, visual perception and matching, overall cognition, working memory, and processing speed. Increased surgeries or subtotal resections, hydrocephalus, shunting procedures, chemotherapy, NF1, and supratentorial location were predictive of cognitive deficits. Broad white matter involvement of the frontal, temporal, parietal, and occipital lobes as well as the cerebellum, as inferred from diffusion tensor imaging indices of decreased fiber orientation and increased water diffusion, was related to many cognitive difficulties. This study comprehensively examines cognitive functioning in PLGG patients treated without radiation therapy, predictors of cognition, and its relation to white matter structure. Our findings indicate that medical and demographic variables other than radiation therapy can lead to cognitive late effects with diffuse white matter involvement.

OA41 - Higher Rates of Pseudoprogression Among Pediatric Low-Grade Glioma Patients Treated with Proton versus Photon Radiotherapy

OA41 - Higher Rates of Pseudoprogression Among Pediatric Low-Grade Glioma Patients Treated with Proton versus Photon Radiotherapy

Molecular genetics and therapeutic targets of pediatric low-grade gliomas.

Pediatric low-grade gliomas (PLGGs) have relatively favorable prognosis and some resectable PLGGs, such as cerebellar pilocytic astrocytoma, can be cured by surgery alone. However, many PLGG cases are unresectable and some of them undergo tumor progression. Therefore, a multidisciplinary approach is necessary to treat PLGG patients. Recent genomic analysis revealed a broad genomic landscape underlying PLGG. Notably, the majority of PLGGs present MAPK pathway-associated genomic alterations and MAPK signaling-dependent tumor progression. Following preclinical evidence, many clinical trials based on molecular target therapy have been conducted on PLGG patients, some of whom exhibited durable response to target therapy. Here, we provide an overview of PLGG genetics and the evidence supporting the application of molecular target therapy in these patients.

Increased Risk of Pseudoprogression Among Pediatric Low-Grade Glioma Patients Treated with Proton Versus Photon Radiation Therapy

Increased Risk of Pseudoprogression Among Pediatric Low-Grade Glioma Patients Treated with Proton Versus Photon Radiation Therapy

CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles

Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with ‘paradox breaker’ RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein–protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.

Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study.

The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown. This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database. At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes. The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients.

Hypersensitivity reactions to carboplatin in children with low-grade gliomas

The prognosis of pediatric low-grade gliomas is relatively favorable, but unresectable progressive tumors remain a challenge. Chemotherapy including carboplatin-containing regimens can delay the need for radiation therapy in young children. However, hypersensitivity reactions to carboplatin can at times be a severe complication. We have retrospectively evaluated and characterized the hypersensitivity reactions associated with carboplatin administration in pediatric low-grade glioma patients treated on an outpatient basis according to the SIOP/GPOH (International Society of Pediatric Oncology/ Gesellschaft fur Padiatrische Onkologie und Hamatologie) low-grade glioma 1996 protocol, and also reviewed the literature. Of nine patients consecutively treated with carboplatin, seven (78%) developed carboplatin hypersensitivity reactions. The first hypersensitivity reactions (always grade 2) occurred after a median of nine courses (range, 7-12). Although desensitization has been used successfully, there have been reports of severe cases of allergic reaction to carboplatin despite desensitization, including anaphylaxis and death. Since carboplatin hypersensitivity reactions are common and desensitization has not been proven to be safe, efforts should be made to design future therapy protocols for low-grade gliomas with clear guidelines on how to substitute carboplatin when hypersensitivity reactions occur. (J Pediatr Neurol 2004; 2(3): 151-155).

Outcomes of Pediatric Low-grade Gliomas Treated With Radiation Therapy

Radiation therapy is often considered the treatment of choice for low-grade gliomas. However, given the long-term effects of radiation on the developing brain, the appropriate use of radiation therapy in pediatric patients remains controversial. The purpose of this study was to evaluate progression-free survival (PFS) of pediatric low-grade glioma patients treated with radiation therapy. Data were obtained through a retrospective chart review of patients treated between 1991 and 2008 from a single tertiary care center in the midwest. The study population consisted of 17 patients, of whom 8 (47%) had tumor recurrence after radiation therapy. The median follow-up time was 8.2 years, with a range of 2.3 to 17.2 years. The median age at diagnosis was 5.4 years, and the median age at radiation therapy was 9.4 years. The 3- and the 10-year PFS were 69%± 11.7% and 46%± 13.3%, respectively. A significant difference in PFS was seen when comparing brainstem tumors with hypothalamic/optic pathway tumors (P=0.019). Differences in PFS based on the age at diagnosis, the extent of initial surgery, and indication for radiation therapy were not significant. A larger multicenter study is needed to better assess PFS in these patients.

Prognostic Factors and Survival Patterns in Pediatric Low-grade Gliomas Over 4 Decades

This study reports changes in long-term survival after the introduction of modern imaging in pediatric patients with low-grade gliomas (LGGs). Records from 351 consecutive pediatric patients diagnosed with LGG between 1970 and 2009 at Mayo Clinic Rochester were reviewed and divided into diagnosis before (group I: 1970 to 1989) and after (group II: 1990 to 2009) postoperative magnetic resonance imaging became regularly used in pediatric LGG. Median progression-free survival (PFS) and overall survival (OS) were not reached. Overall, 10-year PFS was 62% and OS was 90%. On multivariate analysis, improved PFS was associated with gross total resection (GTR; P<0.0001) and postoperative radiation therapy (RT; P<0.0001). In those undergoing less than GTR, PFS was improved with RT, nearing rates of patients receiving GTR (P=0.12). On multivariate analysis, higher OS was associated with GTR (P<0.0001) and pilocytic histology (P=0.03). Group II had fewer headaches, fewer sensory/motor symptoms, less postoperative RT, and more GTRs. OS and PFS were not different between the groups. This large series of pediatric LGG patients with long-term follow-up found no significant changes in OS or PFS over time. Overall, GTR was associated with improved OS and PFS. RT was associated with an improvement in PFS, with the greatest benefit seen in patients undergoing less than GTR.

Analysis of risk factors for pediatric low-grade glioma patients after long term follow-up of the HIT-LGG 1996 trial

Analysis of risk factors for pediatric low-grade glioma patients after long term follow-up of the HIT-LGG 1996 trial

Effectiveness of novel combination chemotherapy, consisting of 5-fluorouracil, vincristine, cyclophosphamide and etoposide, in the treatment of low-grade gliomas in children

Low-grade gliomas (LGG), which account for about 30% of brain tumors in children, are usually treated with surgical excision and/or radiotherapy. For patients who have significant residual tumor after resection or relapse after radiation, the proper chemotherapy regimen has not yet been identified. Thirteen children diagnosed with LGG outside the cerebellum between January 1999 and December 2004, all of whom had significant residual tumor after surgical resection, relapsed after radiation or showed visual deterioration, were treated for 18 months with a multi-drug regimen of vincristine, etoposide, cyclophosphamide and 5-fluorouracil. Of the 7 patients who completed chemotherapy, 1 showed complete response (CR), 5 showed partial response (PR), and 1 had stable disease (SD). In 5 patients, chemotherapy was prematurely discontinued; 4 of these patients showed tumor progression and 1 had SD. One patient is still undergoing treatment. The side effects of chemotherapy were manageable. The median time to tumor response was 34 months (range, 2-82 months). The progression free survival was 67.3%. Pediatric LGG patients with residual tumor after surgery or who undergo relapse(s) may be successfully treated using our combination chemotherapy regimen.

The Role of Telomere Maintenance in the Spontaneous Growth Arrest of Pediatric Low-Grade Gliomas

Spontaneous tumor regression is a unique feature of pediatric low-grade gliomas (PLGG). We speculated that lack of telomere maintenance is responsible for this behavior. We first looked for evidence of telomerase activity and alternative-lengthening telomeres (ALT) in 56 PLGG. Telomerase activity was observed in 0 of 11 PLGG in contrast to 10 of 13 high-grade pediatric brain tumors. There was no ALT in 45 of 45 samples. We applied Q-FISH to eight patients whose indolent PLGG underwent two metachronous biopsies over a lag of several years. Telomere shortening was observed in the second biopsy in all tumors but not in a normal brain control (P < .0001), indicating that lack of telomere maintenance is associated with continuous telomere erosion. Based on these observations, we observed that younger PLGG patients who exhibit more aggressive and frequently recurrent tumors had significantly longer telomeres than older ones (P = .00014). Tumors with a terminal restriction fragment length of <7.5 did not recur, whereas the presence of longer telomeres (>8.0) conferred a high likelihood of late recurrences in PLGG. Our findings provide a plausible biological mechanism to explain the tendency of PLGG to exhibit growth arrest and spontaneous regression. Telomere maintenance may therefore represent the first known biologic prognostic marker in PLGG.

Weekly vinblastine in pediatric low‐grade glioma patients with carboplatin allergic reaction

Carboplatin-based regimens have demonstrated activity in unresectable low-grade glioma (LGG) in children. Despite an interesting toxicity profile, the use of these regimens has been limited by the development of carboplatin hypersensitivity reaction (HSR) in up to 30% of patients. Desensitization has been the recommended approach for HSR. However, no guidelines have existed to aid physicians when carboplatin desensitization techniques fail. A pilot study of monotherapy with weekly vinblastine for LGG in 9 children who developed carboplatin HSR on a carboplatin and vincristine regimen was performed. Vinblastine toxicity was moderate and readily manageable. None of the 9 patients had disease progression on therapy. Magnetic resonance imaging evaluation of tumor size from diagnosis to the end of vinblastine treatment showed 1 complete response (CR), 1 partial response (PR), 5 objective effects (OE), and 2 stable diseases (SD). This experience suggested that weekly vinblastine has a good efficacy to toxicity ratio in the treatment of LGG and can be a valuable option for children who develop severe HSR.