LOW FREQUENCY OF CHROMOSOMAL ALTERATIONS IN CGH ANALYSIS IN LOW-RISK PAPILLARY BLADDER TUMORS WITH FGFR3 MUTATIONS

Purpose To determine the frequency and the prognostic value of fibroblast growth factor receptor 3 (FGFR3) mutations in patients with nonmuscle invasive bladder tumors according to tumor stage and grade. Patients and Methods Seven hundred seventy-two patients with newly diagnosed bladder tumors were recruited. Tumors were reviewed by expert pathologists. Patients were prospectively followed-up (median, 62.6 months for disease-free patients) through review of hospital records and telephone interviews. The sequence of exons 7 and 10 of FGFR3 was analyzed by polymerase chain reaction and direct sequencing. We assessed the association of mutations with stage and grade. The predictive value of mutations for recurrence, progression, and mortality were assessed using Kaplan-Meier and Cox multivariable models. Results Mutations were more common among low malignant potential neoplasms (LMPN; 77%) and TaG1/TaG2 tumors (61%/58%) than among TaG3 tumors (34%) and T1G3 tumors (17%). The S249C, Y375C, S248C, and G372C mutations accounted for 91.5% of all sequence changes. The A393E substitution was associated with LMPN (P < .001). The F386L polymorphism was more frequent among patients with low-grade tumors (odds ratio, 6.97; 95%CI, 1.40 to 47.06; P = .009). In the multivariable analysis of all superficial tumors, mutations were associated with increased risk of recurrence. However, in the stratified analyses only patients with TaG1 tumors had a significantly higher risk of recurrence (hazard ratio, 2.12; 95%CI, 1.28 to 3.53; P = .004). Conclusion The findings of this large study strongly support the notion that FGFR3 mutations characterize a subgroup of bladder cancers with good prognosis; patients with mutant TaG1 tumors have a higher risk of recurrence; and the F386L variant is selectively associated with low-grade tumors.

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“Behavioral Earthquakes:” Low Frequency, Salient Behavioral Events that Differentiate Students At-Risk for Behavioral Disorders

Behavioral Disorders ◽

10.1177/019874299602100402 ◽

1996 ◽

Vol 21 (4) ◽

pp. 277-292 ◽

Cited By ~ 29

Author(s):

Frank M. Gresham ◽

Donald L. Macmillan ◽

Kathy Bocian

Keyword(s):

High Risk ◽

Social Competence ◽

Discriminant Function ◽

Externalizing Behavior ◽

Risk Group ◽

Low Frequency ◽

Risk Groups ◽

Low Risk ◽

Risk Status ◽

School History

Children considered to be at high risk (n = 30), moderate risk (n = 55), and low risk (n = 30) for behavioral disorders were contrasted on cognitive/achievement, social competence, externalizing behavior, and school history variables. Risk status was based on a 33-item checklist known as the Critical Events Index (Walker & Severson, 1990) that is a measure of behavioral pinpoints having high salience and intensity, but relatively low frequency. Multivariate and univariate analyses showed that the three at-risk groups were differentiated primarily on social competence and externalizing behavior measures. Cross-validated stepwise discriminant function analyses contrasting the High Risk and the Low Risk groups using combinations of social competence, externalizing, internalizing, and school history variables correctly identified over 85% of the High Risk group and over 78% of the Low Risk group. Discriminant function analysis based soley on externalizing behaviors created an unacceptable false negative rate for risk status. Findings are discussed within the context of teacher judgments, critical behavioral events as being “vital signs” of childhood psychopathology, and the need for multimethod assessments of critical events.

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Combined Analysis of Smoking, TP53, and FGFR3 Mutations in Tunisian Patients with Invasive and Superficial High-Grade Bladder Tumors

Cancer Investigation ◽

10.1080/07357900902849707 ◽

2009 ◽

pp. 1-1

Author(s):

Slah Ouerhani ◽

Kamel Rouissi ◽

Nadia Kourda ◽

Raja Marrakchi ◽

Karim Bougatef ◽

...

Keyword(s):

High Grade ◽

Bladder Tumors ◽

Combined Analysis ◽

Tunisian Patients ◽

Fgfr3 Mutations

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Interim analysis of the fierce-21 phase 2 (P2) study of vofatamab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4547 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4547-4547 ◽

Cited By ~ 1

Author(s):

Begona Mellado ◽

Daniel E. Castellano ◽

S Pang ◽

Yuksul Urun ◽

Se Hoon Park ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Human Monoclonal Antibody ◽

Objective Response ◽

Low Frequency ◽

Skin Toxicity ◽

Prior Therapy ◽

Platinum Based Chemotherapy ◽

Grade 3 ◽

Reported Data ◽

Fgfr3 Mutations

4547 Background: Patients (pts) with mUC with FGFR3 mutations who have failed platinum-based chemotherapy have a poor prognosis. Their response to immune checkpoint inhibitors appears diminished 10% or less compared to WT pts. 20% of mUC pts harbor FGFR3 mutations or fusions (M/F). Vofatamab is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. FIERCE-21 is a Phase 1b/2 study designed to evaluate vofatamab monotherapy (VFM) or in combination with docetaxel (VFD). Methods: The P2 expansion enrolled mUC pts with FGFR3 M/F+ tumor (identified with FoundationONE CDx™), who failed ≥ 1 prior line of chemotherapy (including prior taxane for pts receiving VFM) or recurred ≤ 12 months of (neo)adjuvant chemotherapy. Pts had measurable disease and ECOG ≤ 1. Treatment consisted of vofatamab at 25 mg/kg alone and in combination with docetaxel at 75 mg/m2 q3w. Efficacy was assessed by investigators (RECIST 1.1). Primary objectives were safety and objective response-rate (ORR). Results: In the P2, 21 pts each received VFM and VFD. 57% of VFD pts had received at least 2, and 71% of VFM at least 3 prior lines of therapy. Best response to prior therapy was PD for 67% of VFD and 38% of VFM. The safety profile is consistent with previously reported data. TEAEs occurring in > 20% of pts were decreased appetite, diarrhea, pyrexia, asthenia, anemia, dyspnea, and fatigue. Most common vofatamab-related TEAEs in > 10% of pts were asthenia, diarrhea, decreased appetite and rash; all were Grade 1 or 2. In VFM, only 1 pt had a grade 3 TEAE and no pt discontinued treatment due to an AE. There were no cases of hyperphosphatemia, ocular or nail toxicity; 1 pt reported grade 2 skin toxicity. For pts receiving VM, median age was 70 yrs, ECOG 1 = 67%, Hgb < 10 g/dL 5%, liver metastases 19%. Responses have been seen in 7 pts to date including those receiving both VFM and VFD. Conclusions: Vofatamab both alone and combined with D in a q3w schedule are well tolerated with a low frequency of grade 3 TEAEs. Both VFM and VFD have demonstrated efficacy in terms of ORR. PFS/OS and DOR data will be presented at 7+ months for VFD and 9+ months for VFM. Clinical trial information: NCT02401542.

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Low frequency of human papillomavirus infection in initial papillary bladder tumors

Urological Research ◽

10.1007/s002400050107 ◽

1999 ◽

Vol 27 (3) ◽

pp. 180-184 ◽

Cited By ~ 17

Author(s):

Maryse Simoneau ◽

Hélène LaRue ◽

Yves Fradet

Keyword(s):

Human Papillomavirus ◽

Low Frequency ◽

Bladder Tumors ◽

Human Papillomavirus Infection ◽

Papillomavirus Infection

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Bone marrow–derived myeloid progenitors as driver mutation carriers in high- and low-risk Langerhans cell histiocytosis

Blood ◽

10.1182/blood.2020005209 ◽

2020 ◽

Vol 136 (19) ◽

pp. 2188-2199 ◽

Cited By ~ 1

Author(s):

Yanling Xiao ◽

Astrid G. S. van Halteren ◽

Xin Lei ◽

Jelske Borst ◽

Eline Steenwijk ◽

...

Keyword(s):

Bone Marrow ◽

Langerhans Cell Histiocytosis ◽

Mapk Pathway ◽

Low Frequency ◽

Langerhans Cell ◽

Low Risk ◽

Driver Mutation ◽

Myeloid Progenitor ◽

Response To Chemotherapy

Abstract Langerhans cell histiocytosis (LCH) is a myeloid neoplasia, driven by sporadic activating mutations in the MAPK pathway. The misguided myeloid dendritic cell (DC) model proposes that high-risk, multisystem, risk-organ–positive (MS-RO+) LCH results from driver mutation in a bone marrow (BM)-resident multipotent hematopoietic progenitor, while low-risk, MS-RO− and single-system LCH would result from driver mutation in a circulating or tissue-resident, DC-committed precursor. We have examined the CD34+c-Kit+Flt3+ myeloid progenitor population as potential mutation carrier in all LCH disease manifestations. This population contains oligopotent progenitors of monocytes (Mo’s)/macrophages (MΦs), osteoclasts (OCs), and DCs. CD34+c-Kit+Flt3+ cells from BM of MS-RO+ LCH patients produced Langerhans cell (LC)-like cells in vitro. Both LC-like and DC offspring from this progenitor carried the BRAF mutation, confirming their common origin. In both high- and low-risk LCH patients, CD34+c-Kit+Flt3+ progenitor frequency in blood was higher than in healthy donors. In one MS-RO+ LCH patient, CD34+c-Kit+Flt3+ cell frequency in blood and its BRAF-mutated offspring reported response to chemotherapy. CD34+c-Kit+Flt3+ progenitors from blood of both high- and low-risk LCH patients gave rise to DCs and LC-like cells in vitro, but the driver mutation was not easily detectable, likely due to low frequency of mutated progenitors. Mutant BRAF alleles were found in Mo’s /MΦs, DCs, LC-like cells, and/or OC-like cells in lesions and/or Mo and DCs in blood of multiple low-risk patients. We therefore hypothesize that in both high- and low-risk LCH, the driver mutation is present in a BM-resident myeloid progenitor that can be mobilized to the blood.

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