Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance
PURPOSE/OBJECTIVE:Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS/METHODS:Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS:< .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION/CONCLUSIONS:Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
Excellent Outcome of Young Children with Nodular Desmoplastic Medulloblastoma Treated on "Head Start" III: A Multi-Institutional, Prospective Clinical Trial
BACKGROUND:"Head Start" III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma. METHODS:Following surgery, patients received five cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction. RESULTS:Between 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. 5-year event-free survival (EFS) and overall-survival (OS) rates (Â±SE) were 46Â±5% and 62Â±5% for all patients, 61Â±8% and 77Â±7% for localized medulloblastoma, and 35Â±7% and 52Â±7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (Â±SE) rates of 89Â±6% and 89Â±6% compared to 26Â±6% and 53Â±7% for classic and 38Â±13% and 46Â±14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age and sex (p<0.0001). 5-year irradiation-free EFS was 78Â±8% for ND and 21Â±5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity with two toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis.IQ and memory scores were within average range overall whereas processing speed and adaptive functioning were low-average. CONCLUSION/CONCLUSIONS:We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy with most patients surviving without irradiation.
The Role of Liquid Biopsies in Pediatric Brain Tumors
Early detection and serial therapeutic monitoring for pediatric brain tumors are essential for diagnosis and therapeutic intervention. Currently, neuropathological diagnosis relies on biopsy of tumor tissue and surgical intervention. There is a great clinical need for less invasive methods to molecularly characterize the tumor and allow for more reliable monitoring of patients during treatment and to identify patients that might potentially benefit from targeted therapies, particularly in the setting where diagnostic tissue cannot be safely obtained. In this literature review, we highlight recent studies that describe the use of circulating tumor DNA, circulating tumor cells, circulating RNA and microRNA, and extracellular vesicles as strategies to develop liquid biopsies in pediatric central nervous system tumors. Liquid biomarkers have been demonstrated using plasma, urine, and cerebrospinal fluid. The use of liquid biopsies to help guide diagnosis, determine treatment response, and analyze mechanisms of treatment resistance is foreseeable in the future. Continued efforts to improve signal detection and standardize liquid biopsy procedures are needed for clinical application.
Exploring DNA Methylation for Prognosis and Analyzing the Tumor Microenvironment in Pleomorphic Xanthoastrocytoma
Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16â€‰years (range 7-32). At median follow-up of 30â€‰months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139â€‰months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89â€‰months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (pâ€‰=â€‰0.67 and pâ€‰=â€‰0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (pâ€‰=â€‰0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (pâ€‰=â€‰0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy.
Orbital Rosai-Dorfman disease initially diagnosed as IgG4-related disease: a case report
Inflammatory orbital lesions include a broad list of diagnoses, many of them with overlapping clinical and radiographic features. They often present a diagnostic conundrum, even to the most experienced orbital specialist, thus placing considerable weight on surgical biopsy and histopathological analysis. However, histopathological diagnosis is also inherently challenging due to the rarity of these lesions and the overlaps in histologic appearance among distinct disease entities. We herein present the case of an adolescent male with a subacutely progressive orbital mass that generated a significant diagnostic dilemma. Early orbital biopsy was consistent with a benign fibro-inflammatory lesion, but corticosteroid therapy was ineffective in halting disease progression. After an initial substantial surgical debulking, histopathological analysis revealed several key features consistent with IgG4-related disease (IgG4-RD), a systemic fibro-inflammatory process typically accompanied by multifocal tumor-like lesions. Surprisingly, within months, there was clear evidence of clinical and radiographic disease progression despite second-line rituximab treatment, prompting a second surgical debulking. This final specimen displayed distinctive features of Rosai-Dorfman disease (RDD), a systemic inflammatory disease characterized by uncontrolled histiocytic proliferation. Interestingly, certain features of this re-excision specimen were still reminiscent of IgG4-RD, which not only reflects the difficulty in differentiating RDD from IgG4-RD in select cases, but also illustrates that these diagnoses may exist along a spectrum that likely reflects a common underlying pathogenetic mechanism. This case emphasizes the importance of surgical biopsy or resection and histopathological analysis in diagnosing-and, ultimately, treating-rare, systemic inflammatory diseases involving the orbit, and, furthermore, highlights the shared histopathological features between RDD and IgG4-RD.
Pineoblastoma in children less than six years of age: The Head Start I, II, and III experience
BACKGROUND:We report the outcomes of patients with pineoblastoma and trilateral retinoblastoma syndrome enrolled on the Head Start (HS) I-III trials. METHODS:Twenty-three children were enrolled prospectively between 1991 and 2009. Treatment included maximal surgical resection followed by five cycles of intensive chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction. RESULTS:Median age was 3.12 years (range, 0.44-5.72). Three patients withdrew from the study treatment and two patients experienced chemotherapy-related death. Eight patients experienced progressive disease (PD) during induction chemotherapy and did not proceed to HDCx/AuHCR. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7Â Gy (range, 18-36Â Gy) with boost(s) (median dose 27Â Gy; range, 18-36Â Gy); three received CSI as adjuvant therapy (two post-HDCx/AuHCR) and four upon progression/recurrence. The five-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95% confidence intervals [CI]: 2.6%-36.0%) and 13% (95% CI: 4.5%-37.5%), respectively. Only three patients survived beyond five years. Favorable OS prognostic factors were CSI (hazard ratio [HR]Â =Â 0.30 [0.11-0.86], PÂ =Â 0.025) and HDCx/AuHCR (HRÂ =Â 0.40 [0.16-0.99], PÂ =Â 0.047). CONCLUSIONS:Within the HS I-III trials, CSI and HDCx/AuHCR were statistically associated with improved survival. The high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles prior to consolidation and the potential intensification of consolidation with multiple cycles of marrow-ablative chemotherapy and irradiation.
Subgroup-specific outcomes of children with malignant childhood brain tumors treated with an irradiation-sparing protocol
PURPOSE/OBJECTIVE:Molecular subgroups of pediatric brain tumors associated with divergent biological, clinical, and prognostic features have been identified. However, data regarding the impact of subgroup affiliation on the outcome of children with malignant brain tumors treated with radiation-sparing protocol is limited. We report long-term clinical outcomes and the molecular subgroups of malignant brain tumors in young children whose first-line treatment was high-dose chemotherapy without irradiation. METHODS:Tumor subclassification was performed using the Illumina HumanMethylation450 BeadChip (450k) genome-wide methylation array profiling platform.Â Clinical information was obtained from chart review. RESULTS:Methylation array profiling yielded information on molecular subgroups in 22 children. Median age at surgery was 26Â months (range 1-119Â months). Among medulloblastomas (MB), all 6 children in the infant sonic hedgehog (SHH) subgroup were long-term survivors, whereas all 4 children in subgroup 3 MB died. There was one long-term survivor in subgroup 4 MB. One out of five children with ependymoma was a long-term survivor (RELPOS). Both children with primitive neuroectodermal tumors died. One child with ATRT TYR and one child with choroid plexus carcinoma were long-term survivors. CONCLUSIONS:The efficacy of high-dose chemotherapy radiation-sparing treatment appears to be confined to favorable molecular subgroups of pediatric brain tumors, such as infant SHH MB. Identification of molecular subgroups that benefit from radiation-sparing therapy will aid in the design of prospective, "precision medicine"-driven clinical trials.
CLINICAL EFFICACY OF ONC201 IN NEWLY DIAGNOSED DIPG AND IN PREVIOUSLY IRRADIATED PEDIATRIC H3 K27M-MUTANT GLIOMAS [Meeting Abstract]
CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA [Meeting Abstract]
PHASE II STUDY OF EVEROLIMUS (AFINITOR (R)) FOR CHILDREN WITH RECURRENT OR PROGRESSIVE EPENDYMOMA [Meeting Abstract]