Background
To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single‐agent everolimus in pediatric patients with radiographically progressive low‐grade glioma (LGG).
Methods
...Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48‐week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients.
Results
Twenty‐three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2‐6.7 years), the 2‐, 3‐, and 5‐year progression‐free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2‐, 3‐, and 5‐year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5‐15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho‐S6, 4E‐BP1, and modulation of c‐Myc expression.
Conclusion
Daily oral everolimus provides a well‐tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Identifying modifiers of glioma risk in patients with type I neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis, and potentially ...identify novel therapeutic targets. Here, we report genetic polymorphisms in the human adenylate cyclase gene adenylate cyclase 8 (ADCY8) that correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth-promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.
Management of CNS germinoma Osorio, Diana S; Allen, Jeffrey C
CNS oncology,
2015, Volume:
4, Issue:
4
Journal Article
Peer reviewed
Open access
The following is a general overview of the management of CNS germinomas. Over the last 35 years, CNS germinomas have become one of the pediatric brain tumors with the best outcomes with a greater ...than 85% overall survival over 5 years. This is in part due to the fact that germinomas are very responsive to chemotherapy and radiation. Some of the major challenges going forward will be to find ways to minimize the adverse effects of our treatments particularly with regard to radiation and to improve the quality of life of patients who develop neurologic, neurocognitive and/or endocrine deficiencies.
Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based ...on its lack of reproducibility in predicting patients’ outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
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•DNA methylation profiling of ependymomas identifies nine molecular subgroups•YAP1 and RELA fusions characterize two distinct groups of supratentorial ependymoma•Patients with PFA or supratentorial RELA-positive ependymoma show dismal prognosis•Risk stratification by molecular subgrouping is superior to histological grading
Pajtler et al. classify 500 ependymal tumors using DNA methylation profiling into nine molecular subgroups. This molecular classification outperforms the current histopathological grading in the risk stratification of patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
On the tax efficiency of startup firms Allen, Eric J.; Allen, Jeffrey C.; Raghavan, Sharat ...
Review of accounting studies,
12/2023, Volume:
28, Issue:
4
Journal Article
Peer reviewed
Open access
We examine the choice of organizational structure for VC-backed startup firms. These firms overwhelmingly organize as C-corporations rather than as tax advantaged limited liability companies (LLCs). ...This results in foregone tax savings of $43.9 billion, or 4.9% of the total equity invested in the sample firms. The decision is puzzling, given plausible estimates of the direct costs involved, but appears related to “hassle” and other transition costs generated by participants implementing a new form. Firms with more employees and investors are likely to choose the C-corporation. VCs appear to prefer the C-corporation form, as receiving VC money is associated with most LLC firms switching to a C-corporation within 30 days. Greater VC preferences for C-corporations are linked to a preference for familiarity, and less attention to taxes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This phase II trial evaluated the effect of neoadjuvant chemotherapy with or without second-look surgery before craniospinal irradiation on response rates and survival outcomes in children with newly ...diagnosed non-germinomatous germ cell tumors.
Induction chemotherapy consisted of six cycles of carboplatin/etoposide alternating with ifosfamide/etoposide. Patients demonstrating less than complete response after induction chemotherapy were encouraged to undergo second-look surgery. Patients who did not achieve complete response or partial response after chemotherapy with or without second-look surgery proceeded to high-dose chemotherapy with thiotepa and etoposide and autologous peripheral blood stem-cell rescue before craniospinal irradiation.
The study included 102 patients treated between January 2004 and July 2008. Median age was 12 years, and 76% were male; 53.9% had pineal region masses, and 23.5% had suprasellar lesions. Sixty-nine percent of patients achieved complete response or partial response with neoadjuvant chemotherapy. At 5 years, event-free survival was 84% ± 4% (SE) and overall survival was 93% ± 3%. During the median follow-up of 5.1 years, 16 patients recurred or progressed, with seven deaths after relapse. No deaths were attributed to therapy-related toxicity. Relapse occurred at the site of primary disease in 10 patients, at a distant site in three patients, or both in one patient. In two patients, progression was detected by marker increase alone. Increased serum α-fetoprotein was a negative prognostic variable. Histologic subtype and increase of beta-human chorionic gonadotropin were not significantly correlated with worse outcomes.
Neoadjuvant chemotherapy with or without second-look surgery achieved high response rates contributing to excellent survival outcomes in children with newly diagnosed non-germinomatous germ cell tumors. This regimen should be included as a backbone for further studies.
Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we ...identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.
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IJS, NUK, SBMB, UL, UM, UPUK
Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, ...mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis.
Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m
/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses.
Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings.
To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m
/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.
The majority of intramedullary spinal cord tumors (IMSCT) in children and young adults are low-grade gliomas. Radical resection of similar tumors in the cerebral hemisphere or cerebellum is usually ...curative; however, the conventional management for IMSCTs remains partial resection followed by radiotherapy because of the concern for surgical morbidity. Nevertheless, radical resection of IMSCTs without routine adjuvant treatment has been the rule at our institution since 1980. In an attempt to resolve this controversy, the long-term morbidity and survival in a large series of children have been retrospectively reviewed.
The database records and current status of 164 patients 21 years of age and younger in whom an IMSCT was resected were reviewed. A gross-total resection (>95%) was achieved in 76.8% of the surgical procedures. Subtotal resections (80-95%) were performed in 20. 1%. The majority of patients (79.3%) had histologically low-grade lesions. There were no deaths due to surgery. When comparing the preoperative and 3-month postoperative functional grades, 60.4% stayed the same, 15.8% improved, and 23.8% deteriorated. Only 13 patients deteriorated by more than one functional grade. Patients with either no deficits or only mild deficits before surgery were rarely injured by the procedure, reinforcing the importance of early diagnosis and treatment. The major determinant of long-term patient survival was histological composition of the tumor. The 5-year progression-free survival rate was 78% for patients with low-grade gliomas and 30% for those with high-grade gliomas. Patients in whom an IMSCT was only partially resected (<80%) fared significantly worse.
The long-term survival and quality of life for patients with low-grade gliomas treated by radical resection alone is comparable or superior to minimal resection and radiotherapy. The optimum therapy for patients with high-grade gliomas is yet to be determined.
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