Molecular alterations to predict survival and response to chemotherapy of pediatric low-grade glioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10503-10503
Author(s):  
Michal Zapotocky ◽  
Scott Ryall ◽  
Anthony Arnoldo ◽  
Matthew Mistry ◽  
Alvaro Lassaletta ◽  
...  
Keyword(s):  
Large Population ◽  
Objective Response ◽  
Low Grade Glioma ◽  
Response To Therapy ◽  
Braf V600e ◽  
Low Grade ◽  
Long Term Outcome ◽  
Molecular Alterations ◽  
Response To Chemotherapy ◽  
The Impact

10503 Background: RAS/MAPK pathway mutations have been identified as the major drivers of pediatric low-grade glioma (pLGG). The impact of these alterations on outcome and response to therapy is still unknown. Methods: We performed a large population based study of all pLGG diagnosed from 1985-2015. Detailed treatment and very long term outcome data was collected on all patients. Known pLGG-related alterations were detected using NanoString and QX200™Droplet Digital™PCR. Molecular data was correlated with outcome and response to chemotherapy. Results: In our cohort of 614 patients, BRAF was found to be altered in 57% and wild-type (WT) in 43% of patients without neurofibromatosis 1 (NF1). Among BRAF-WT we identified H3.3K27M, FGFR1-TACC1, MYBL1 and other alterations. Molecular alterations stratified pLGG into several risk groups. Ten-year progression free survival (PFS) was 72.3% for NF1, 69.5% for KIAA1549-BRAF, 53.5% for BRAF-WT, 30.3% for BRAF-V600E and 0% for H3.3K27M mutations (p < 0.0001). Similarly, overall survival (OS) at 10 years delineated difference between excellent survival of KIAA1549-BRAF and NF1 compared to BRAF-V600E and BRAF-WT (p = 0.0005). Interestingly, all patients with FGFR1-TACC1 and MYBL1 were alive despite observed progressions. Strikingly, response to chemotherapy determined by changes in tumor size at 6 months of therapy correlated with pLGG alteration. Objective response to first line chemotherapy was observed in 46% of patients with KIAA1549-BRAF and 35% of NF1. In contrast, only 15% BRAF-V600E and 18% BRAF-WT responded and 41% tumors grew after six months of chemotherapy. Moreover, 5-year PFS after chemotherapy was strikingly low for BRAF-V600E and BRAF-WT (25% and 31.9% respectively) compared to KIAA1549-BRAF (50%) and NF1 (76.7%) (p = 0.001). This translated to decreased OS for BRAFV600E and BRAF-WT patients (p = 0.042). Conclusions: Our study provides evidence that molecular alterations dictate the outcome of pLGG. KIAA1549-BRAF harbors excellent prognosis and choice of therapy should be made in favor of less toxic agents to minimize deleterious late effects. In contrast, poor prognosis is associated with lack of response to chemotherapy in BRAF-V600E and BRAF-WT tumors.

scholarly journals LGG-18. MOLECULAR ALTERATIONS PREDICT RESPONSE TO CHEMOTHERAPY AND OUTCOME OF PEDIATRIC LOW-GRADE GLIOMA

2017 ◽  
Vol 19 (suppl_4) ◽  
pp. iv37-iv37
Author(s):  
Michal Zapotocky ◽  
Scott Ryall ◽  
Matthew Mistry ◽  
Anthony Arnoldo ◽  
Alvaro Lassaletta ◽  
...  
Keyword(s):  
Low Grade Glioma ◽  
Low Grade ◽  
Molecular Alterations ◽  
Response To Chemotherapy

scholarly journals Does the TT Variant of the rs966423 Polymorphism in DIRC3 Affect the Stage and Clinical Course of Papillary Thyroid Cancer?

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 423 ◽  
Author(s):  
Kinga Hińcza ◽  
Artur Kowalik ◽  
Iwona Pałyga ◽  
Agnieszka Walczyk ◽  
Danuta Gąsior-Perczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Endocrine System ◽  
Therapy Response ◽  
Initial Response ◽  
Response To Therapy ◽  
Braf V600e ◽  
Low Grade ◽  
Papillary Thyroid ◽  
The Impact

Thyroid cancer (TC) is the most common cancer of the endocrine system. Most new diagnoses are of low-grade papillary thyroid cancer (PTC), suggesting that PTC may be over-diagnosed. However, the incidence of advanced-stage PTC has increased in recent years. It is therefore very important to identify prognostic factors for advanced PTC. Somatic mutation of the BRAF gene at V600E, or the coexistence of the BRAF V600E mutation and mutations in the TERT promoter are associated with more aggressive disease. It would also be valuable to identify genetic risk factors affecting PTC prognosis. We therefore evaluated the impact of the rs966423 polymorphism in the DIRC3 gene, including its relationship with unfavorable histopathological and clinical features and mortality, in differentiated thyroid cancer (DTC). The study included 1466 patients diagnosed with DTC from one center. There was no significant association between the DIRC3 genotype at rs966423 (CC, CT, or TT) and any histopathological or clinic factor examined, including initial response to therapy, response at follow-up, or overall mortality, in DTC patients.

scholarly journals LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii370-iii371
Author(s):  
Stacy Chapman ◽  
Demitre Serletis ◽  
Colin Kazina ◽  
Mubeen Rafay ◽  
Sherry Krawitz ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Pilocytic Astrocytoma ◽  
Clinical Symptoms ◽  
Obstructive Hydrocephalus ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Low Grade ◽  
Dramatic Improvement ◽  
Chemotherapeutic Regimen ◽  
Response To Chemotherapy

Abstract In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.

scholarly journals A Retrospective Experience of Helicobacter pylori Histology in a Large Sample of Subjects in Northern Italy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 650
Author(s):  
Davide Giuseppe Ribaldone ◽  
Carlo Zurlo ◽  
Sharmila Fagoonee ◽  
Chiara Rosso ◽  
Angelo Armandi ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Large Population ◽  
Population Data ◽  
Signet Ring Cell ◽  
Current Data ◽  
Low Grade ◽  
Gastric Cardia Adenocarcinoma ◽  
Significant Difference ◽  
H Pylori ◽  
The Impact

Updated data about the prevalence of Helicobacter pylori (H. pylori) and its correlation with histological results are scarce. The aim of our study was to provide current data on the impact of H. pylori in a third-level endoscopy service. We performed a large, retrospective study analyzing the results of all histological samples of gastroscopy from the year 2019. In total, 1512 subjects were included. The prevalence of H. pylori was 16.8%. A significant difference between the prevalence in subjects born in Italy and those from eastern Europe, south America, or Africa was found (p < 0.0001, p = 0.006, and p = 0.0006, respectively). An association was found between H. pylori and active superficial gastritis (p < 0.0001). Current H. pylori and/or a previous finding of H. pylori was related to antral atrophy (p < 0.0001). Fifteen patients had low-grade dysplasia. There were no statistically significant associations with current or past H. pylori infection. One patient presented gastric cardia adenocarcinoma with regular gastric mucosa. One patient, H. pylori positive, was diagnosed with gastric signet ring cell adenocarcinoma in a setting of diffuse atrophy, without metaplasia.. Our study provides updated, solid (biopsy diagnosis and large population) data on the prevalence of H. pylori infection in a representative region of southern Europe.

scholarly journals LGG-06. LONG-TERM OUTCOME OF NEWLY DIAGNOSED LOW GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii367-iii367
Author(s):  
Nongnuch Sirachainan ◽  
Attaporn Boongerd ◽  
Samart Pakakasama ◽  
Usanarat Anurathapan ◽  
Ake Hansasuta ◽  
...  
Keyword(s):  
Surgical Management ◽  
Progression Free Survival ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Common Location ◽  
Suprasellar Region

Abstract INTRODUCTION Low grade glioma (LGG) is the most common central nervous system (CNS) tumor in children accounted for 30–50%. Regarding benign characteristic of disease, surgical management remains the mainstay of treatment. However, surgical approach is limited in some conditions such as location at brainstem or infiltrative tumor. Chemotherapy and radiation treatments have been included in order to control tumor progression. The 5-years survival rate is approach 90% especially in patients who receive complete resection. However, the outcome of children with LGG in low to middle income is limited. Therefore, the aim of the study was to determine long-term outcome of children with newly diagnosed LGG. METHODS A retrospective study enrolled children aged &lt;18 years who were newly diagnosed LGG during January 2006- December 2019. Diagnosis of LGG was confirmed by histological findings of grade I and II according to WHO criteria. RESULTS A total of 40 patients, female to male ratio was 1:1.35 and mean (SD) for age was 6.7 (4.0) years. The most common location was optic chiasmatic pathway (42.5%), followed by suprasellar region (25.0%). Sixty percent of patients received at least partial tumor removal. Chemotherapy and radiation had been used in 70% and 10.0% respectively. The 10-year progression free survival was 74.1±11.4% and overall survival was 96.2±3.8%. SUMMARY: Treatment of Pediatric LGG mainly required surgical management, however, chemotherapy and radiation had been used in progressive disease. The outcome was excellent.

Abstract CT025: Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG)

2021 ◽  
Author(s):  
Vivek Subbiah ◽  
Alexander Stein ◽  
Martin van den Bent ◽  
Antje Wick ◽  
Filip Y. de Vos ◽  
...  
Keyword(s):  
Low Grade Glioma ◽  
Braf V600e ◽  
Low Grade ◽  
High Grade

Molecular Alterations in Pediatric Low-Grade Gliomas That Led to Death

2021 ◽  
Author(s):  
Jared T Ahrendsen ◽  
Claire Sinai ◽  
David M Meredith ◽  
Seth W Malinowski ◽  
Tabitha M Cooney ◽  
...  
Keyword(s):  
Braf V600e ◽  
Molecular Characteristics ◽  
Low Grade ◽  
Diffuse Astrocytoma ◽  
Term Survival ◽  
Pten Loss ◽  
Low Grade Gliomas ◽  
Molecular Alterations ◽  
Idh1 R132h ◽  
Poor Outcomes

Abstract Pediatric low-grade gliomas (PLGGs) have excellent long-term survival, but death can occasionally occur. We reviewed all PLGG-related deaths between 1975 and 2019 at our institution: 48 patients were identified; clinical data and histology were reviewed; targeted exome sequencing was performed on available material. The median age at diagnosis was 5.2 years (0.4–23.4 years), at death was 13.0 years (1.9–43.2 years), and the overall survival was 7.2 years (0.0–33.3 years). Tumors were located throughout CNS, but predominantly in the diencephalon. Diagnoses included low-grade glioma, not otherwise specified (n = 25), pilocytic astrocytoma (n = 15), diffuse astrocytoma (n = 3), ganglioglioma (n = 3), and pilomyxoid astrocytoma (n = 2). Recurrence occurred in 42/48 cases, whereas progression occurred in 10. The cause of death was direct tumor involvement in 31/48 cases. Recurrent drivers included KIAA1549-BRAF (n = 13), BRAF(V600E) (n = 3), NF1 mutation (n = 3), EGFR mutation (n = 3), and FGFR1-TACC1 fusion (n = 2). Single cases were identified with IDH1(R132H), FGFR1(K656E), FGFR1 ITD, FGFR3 gain, PDGFRA amplification, and mismatch repair alteration. CDKN2A/B, CDKN2C, and PTEN loss was recurrent. Patients who received only chemotherapy had worse survival compared with patients who received radiation and chemotherapy. This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes.

scholarly journals Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas

1997 ◽  
Vol 2 (3) ◽  
pp. E1
Author(s):  
Roger J. Packer ◽  
Joanne Ater ◽  
Jeffrey Allen ◽  
Peter Phillips ◽  
Russell Geyer ◽  
...  
Keyword(s):  
Objective Response ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Low Grade ◽  
Significant Prognostic Factor ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Low Grade Gliomas ◽  
Response To Chemotherapy

The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided. There has been increased interest in the use of chemotherapy for young children, but little information concerning the long-term efficacy of such treatment. Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed, progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy. The patients were followed for a median of 30 months from diagnosis, with 31 patients followed for more than 3 years. Fifty-eight children had diencephalic tumors, 12 had brainstem gliomas, and three had diffuse leptomeningeal gliomas. Forty-four (56%) of 78 patients showed an objective response to treatment. Progression-free survival rates were 75 ± 6% at 2 years and 68 ± 7% at 3 years. There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year, progression-free survival 79 ± 11% vs. 75 ± 6%, respectively). The histological subtype of the tumor, its location, and its maximum response to chemotherapy did not have an impact on the duration of disease control. The only significant prognostic factor was age: children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 ± 7% compared with a rate of 39 ± 21% in older children (p < 0.01). Treatment with carboplatin and vincristine is effective, especially in younger children, in controlling newly diagnosed progressive low-grade gliomas.

A multicenter open-label phase 1 study evaluating the safety and tolerability of HMPL-306 in patients with locally advanced or metastatic solid tumors with IDH mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3159-TPS3159
Author(s):  
Filip Janku ◽  
John S. Kauh ◽  
Christopher Tucci ◽  
Zhao Yang ◽  
Marek K. Kania ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tricarboxylic Acid Cycle ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Low Grade Glioma ◽  
Statistical Hypothesis ◽  
Low Grade ◽  
Open Label ◽  
Idh Mutations

TPS3159 Background: Isocitrate dehydrogenase (IDH) is a rate-limiting tricarboxylic acid cycle enzyme with 3 isoforms. Mutations in IDH1 and IDH2 result in gain-of-function activity that can cause tumor formation and/or progression and have been associated with various tumor types. Therefore, selective, single mutant IDH (mIDH) isotype inhibitors (mIDH1 or mIDH2) can lead to insufficient efficacy and the potential for tumor resistance. HMPL-306 is an innovative, small-molecule, orally available, highly selective, potent inhibitor of both mIDH1 and mIDH2. Clinical development of a compound that concurrently targets, inhibits, and suppresses multiple mIDHs could lead to significant and durable clinical benefit for patients (pts) with solid tumors harboring IDH mutations. Methods: This is a phase 1, open-label, dose escalation (Part 1) and dose expansion (Part 2) study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HMPL-306 in pts ≥18 years with locally advanced or metastatic solid tumors with any IDH mutations. HMPL-306 will be administered orally, once daily in a 28-day continuous dosing treatment cycle. The HMPL-306 dose will be escalated in Part 1 according to the modified toxicity probability interval-2 (mTPI-2) design in 4 cohorts in approximately 15-20 pts: 50, 100, 150, and 200 mg. Eligible pts must have locally advanced or metastatic solid tumors with IDH1 or IDH2 mutations. The primary objectives are to evaluate safety, dose limiting toxicities (DLTs), tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and PK. Approximately 95 pts will be enrolled at the RP2D in Part 2 to further characterize the safety, tolerability, PK, PD, and preliminary anti-tumor activities of HMPL-306. Part 2 will include 5 dose expansion cohorts: cholangiocarcinoma (n = 20), skeletal chondrosarcoma (n = 20), low-grade glioma (n = 20), perioperative low-grade glioma (n = 15), any other solid tumor harboring an IDH1/2 mutation (n = 20). All pts will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or at the investigator’s discretion. Safety will be assessed based on reports of adverse events including clinical laboratory testing, vital signs, physical examinations, and electrocardiograms. All pts who receive any study treatment will be included in safety and efficacy analyses. Antitumor activity based on investigator-assessed overall response will be evaluated using descriptive analyses. Objective response rate will be calculated with 95% confidence interval using the Clopper-Pearson method. The Kaplan-Meier method will be used to summarize the time-to-event data such as progression-free survival and duration of response. No statistical hypothesis testing is planned. Enrollment started February 2021.

Selumetinib in patients with tumors with MAPK pathway alterations: Results from Arm E of the NCI-COG pediatric MATCH trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10008-10008
Author(s):  
Carl E. Allen ◽  
Olive Eckstein ◽  
Paul M. Williams ◽  
Sinchita Roy-Chowdhuri ◽  
David R Patton ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stable Disease ◽  
Thromboembolic Event ◽  
Mapk Pathway ◽  
Low Grade Glioma ◽  
Braf V600e ◽  
Low Grade ◽  
Match Trial ◽  
Hotspot Mutations ◽  
Clinical Trial Information

10008 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Arm E evaluated the MEK inhibitor selumetinib (ARRY-142886) in patients whose tumors harbored activating alterations in the MAPK pathway ( ARAF, BRAF, HRAS, KRAS, NRAS, MAP2K1, GNA11, GNAQ hotspot mutations; NF1 inactivating mutations; BRAF fusions). Methods: Patients received selumetinib 25 mg/m2/dose (max 75 mg/dose) PO BID for 28-day cycles until disease progression or intolerable toxicity with response assessments obtained every 2-3 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS). Patients with low grade glioma were excluded. Results: A total of 21 patients (median age 14 years; range 5-21) were enrolled between 10/2017 and 8/2019, with 20 patients evaluable for response. Diagnoses were high grade glioma (HGG; n = 8), rhabdomyosarcoma (n = 7), adenocarcinoma (n = 2), and one each of MPNST, endodermal sinus/yolk sac tumor, plexiform neurofibroma (PN), and neuroblastoma. MAPK pathway alterations detected consisted of inactivating NF1 mutations (n = 8), hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease (HGG with NF1 mutation, 6 cycles; HGG with KRAS mutation, 12 cycles; PN with NF1 mutation, 13 cycles prior to removal for dose-limiting toxicity). Six-month PFS was 15% (95% CI: 4%, 34%). Adverse events that were deemed possibly, probably, or definitely attributable to study drug included one case each of grade 3 uveitis, lymphopenia, and thromboembolic event; one grade 4 CPK elevation; and one grade 5 thromboembolic event. Conclusions: Selumetinib did not result in tumor regression in this cohort of children and young adults with treatment-refractory tumors with activating MAPK pathway alterations. Of note, two patients with HGG initially had stable disease, but ultimately progressed after 6 and 12 cycles, respectively. Selumetinib has previously demonstrated activity in low grade glioma and PN and is now FDA-approved for PN. The results of our study indicate that MAPK pathway mutation status alone is insufficient to predict response to selumetinib monotherapy. It is likely that selumetinib and other MEK inhibitors will require combination with targeted or cytotoxic agents for optimal efficacy in children with persistent or progressive cancers after front-line chemotherapy. Clinical trial information: NCT03213691. Clinical trial information: NCT03155620.

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