High-grade trichoblastic carcinoma with sarcomatoid differentiation harboring TP53 and PIK3CA mutations

2021 ◽  
Author(s):  
A. Mouchard ◽  
C. Monegier-Dusorbier ◽  
P. Berthon ◽  
B. Cribier ◽  
N. Basset Seguin ◽  
...  
Keyword(s):  
High Grade ◽  
Pik3ca Mutations ◽  
Sarcomatoid Differentiation

CTNI-22. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi64-vi64
Author(s):  
Nader Sanai ◽  
An-Chi Tien ◽  
Jun Jiang ◽  
Yu-Wei Chang ◽  
Chelsea Pennington-Krygier ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
High Grade ◽  
Mtor Inhibition ◽  
Who Grade ◽  
Expansion Phase ◽  
Pik3ca Mutations ◽  
Pten Loss ◽  
Drug Concentrations ◽  
Phase 0 ◽  
Unbound Concentration

Abstract BACKGROUND mTOR activation is a mechanism of resistance in CDK4/6 targeting. We evaluated tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent high-grade glioma (HGG) patients. METHODS Recurrent HGG patients with (1) intact RB, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations receive five days of presurgical ribociclib plus everolimus prior to resection at 2, 8 or 24 hours after the final dose. Beginning at 400mg QD ribociclib plus 2.5mg QD everolimus, six dose-escalations summit at 600mg QD plus 60mg QW. Gadolinium [Gd]-enhancing and nonenhancing tumor regions, CSF, and plasma are collected. Total and unbound drug concentrations are determined using validated LC-MS/MS methods. RB and S6 phosphorylation are compared to matched archival tissue. To select patients for a therapeutic expansion phase of combined drug therapy, the protocol includes a PK ‘trigger’ (i.e., for each drug, unbound concentration in Gd-nonenhancing tumor > 5-fold biochemical IC50) and a PD ‘trigger’ (i.e., for each tumor, > 30% decrease in pRB and pS6). RESULTS 21 patients with WHO Grade III (n=2) and IV (n=19) gliomas were enrolled into the Phase 0 component of the study. No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 719 nM, whereas unbound everolimus tumor concentrations were undetectable. Across all dose-levels, 62% (13/21) and 22% (5/21) of tumors demonstrated decreased tumor RB and S6 phosphorylation, respectively. Tumor proliferation (MIB-1) was decreased in 67% (14/21) of all patients. No patients qualified for the therapeutic expansion phase. CONCLUSION In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor whereas everolimus exhibits no meaningful tumor penetration. These findings support further clinical development of ribociclib, but not everolimus, for the treatment of high-grade glioma patients.

OS05.8.A A Phase 0/1 ‘Trigger’ Trial of Ribociclib Plus Everolimus in Recurrent High-Grade Glioma

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
N Sanai ◽  
A Tien ◽  
J Jiang ◽  
Y Chang ◽  
C Pennington-Krygier ◽  
...  
Keyword(s):  
Tumor Resection ◽  
High Grade Glioma ◽  
High Grade ◽  
Mtor Inhibition ◽  
Who Grade ◽  
Pik3ca Mutations ◽  
Drug Concentrations ◽  
Limit Of Quantitation ◽  
Unbound Concentration ◽  
Dose Levels

Abstract BACKGROUND The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients. MATERIAL AND METHODS Eligible patients had recurrent HGG with (1) intact RB expression, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of presurgical ribociclib (400mg QD) plus everolimus (2.5mg QD) and then underwent tumor resection at 2, 8 or 24 hours following the last dose. Five subsequent dose-escalation cohorts each enrolled three additional patients, reaching a maximum dose-level of ribociclib (600mg QD) plus everolimus (60mg QW). Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects, including RB and S6 phosphorylation, were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration > 5-fold biochemical IC50) and a PD ‘trigger’ (>30% decrease in both pRB and pS6) were set for each drug. Gd-nonenhancing tissue exhibiting both PK and PD effects in excess of these thresholds qualified patients for postoperative combination therapy. RESULTS 21 patients with WHO Grade III (n=2) and WHO Grade IV (n=19) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 719 nM (i.e., > 5-fold biochemical IC50 for CDK4/6 inhibition), whereas the unbound everolimus tumor concentrations in all patients were below the lower limit of quantitation (i.e., < 0.2 nM). The median total concentrations of everolimus in tumors at dose-levels 0 to 5 were 2.9, 8.8, 10.3, 5.0, 15.7, and 13.7 nM, respectively. Across all dose-levels, 62% (13/21) and 22% (5/21) of tumors demonstrated decreased tumor RB and S6 phosphorylation, respectively. Tumor proliferation (MIB-1) was decreased in 67% (14/21) of all patients. CONCLUSION In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor, consistent with the observed tumor PD effects. Everolimus exhibits very limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.

Comprehensive genomic characterization of upper tract urothelial carcinoma (UTUC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 375-375
Author(s):  
Tyler J. Moss ◽  
Yuan Qi ◽  
Liu Xi ◽  
Bo Peng ◽  
Maribel E Mosqueda ◽  
...  
Keyword(s):  
Tobacco Use ◽  
Molecular Subtypes ◽  
Integrated Analysis ◽  
Marker Genes ◽  
Low Grade ◽  
High Grade ◽  
Pik3ca Mutations ◽  
Tgfβ Receptors ◽  
Muscle Invasive ◽  
Fgfr3 Mutations

375 Background: Integrated analysis of UTUC was performed to characterize the genomic landscape of UTUC and provide insights into biology. Methods: 31 untreated samples underwent WES, RNAseq, and RPPA. Consensus mutation calls from independent pipelines of 2 centers identified gene expression clusters using unsupervised consensus hierarchical clustering (UCHC). Results: Clinical data are shown in the Table. WES identified mutations in FGFR3 (74.1%; 92% low grade, 60% high grade), KMT2D (44.4%), PIK3CA (25.9%), TP53 (22.2%). APOBEC and CpG signatures were identified. Expressed marker genes from bladder TCGA were not associated with molecular subtypes in this study. UCHC of RNAseq segregated samples into 4 molecular subtypes. Cluster 1: no PIK3CA mutations; enriched for nonsmokers, high grade non-muscle invasive tumors, high recurrence rates and favorable survival. Cluster 2: 100% FGFR3 mutations; enriched for low grade, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations; high tobacco use and bladder recurrence (62.5%); tumors all non-muscle invasive. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations; enriched for high grade, muscle-invasive disease, tobacco use, CIS, reduced survival; novel fusion of SH3KBP1-CNTNAP5 was identified, with high expression levels in the sample. Conclusions: We show mutations in UTUC occurring at differing frequencies and subtypes than bladder cancer. Novel fusion SH3KBP1 regulates RTK signaling and acts to recycle TGFβ receptors. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation. [Table: see text]

1278: The Role of Diagnostic Criteria of Obstruction in Patients with High Grade Cystocele: Correlation to Subjective Symptoms

2007 ◽  
Vol 177 (4S) ◽  
pp. 421-421
Author(s):  
Veronica Triaca ◽  
Christian O. Twiss ◽  
Ramdev Konijeti ◽  
Larissa V. Rodriguez ◽  
Shlomo Raz
Keyword(s):  
Diagnostic Criteria ◽  
High Grade ◽  
Subjective Symptoms

474: Prostate Specific Antigen (PSA) vs. Cancer Volume and High-Grade Cancer (PCA) Volume at Radical Prostatectomy (RP) in a Large European Cohort: Is the PSA Era Over in Europe as Well?

2005 ◽  
Vol 173 (4S) ◽  
pp. 130-130
Author(s):  
Pierre I. Karakiewicz ◽  
Paul Perrotte ◽  
Thomas Steuber ◽  
Alexander Haese ◽  
Markus Graefen ◽  
...  
Keyword(s):  
Radical Prostatectomy ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
High Grade

1632: High Grade Varicocele and Low Sperm Density are Associated with High Degree of Sperm Chromatin Damage in Infertile Men

2006 ◽  
Vol 175 (4S) ◽  
pp. 526-526
Author(s):  
Mara A. Monoski ◽  
Darius A. Paduch ◽  
Marc Goldstein
Keyword(s):  
Sperm Chromatin ◽  
High Grade ◽  
Sperm Density ◽  
Infertile Men ◽  
High Degree

High-Grade Anogenital IN Requires Long-Term Surveillance for Progression

2007 ◽  
Vol 38 (2) ◽  
pp. 48
Author(s):  
Sharon Worcester
Keyword(s):  
High Grade
Sign in / Sign up

Export Citation Format

Share Document