Recent studies have reported mutations in the telomerase reverse transcriptase promoter (
p) in meningiomas. We sought to determine the frequency, clonality and clinical significance of telomere gene ...alterations in a cohort of patients with progressive/higher-grade meningiomas.
We characterized 64 temporally- and regionally-distinct specimens from 26 WHO grade III meningioma patients. On initial diagnoses, the meningiomas spanned all WHO grades (3 grade I, 13 grade II and 10 grade III). The tumor samples were screened for
p and
mutations, and
rearrangements. Additionally,
p was sequenced in a separate cohort of 19 patients with radiation-associated meningiomas. We examined the impact of mutational status on patients' progression and overall survival.
Somatic
p mutations were detected in six patients (6/26 = 23%). Regional intratumoral heterogeneity in
p mutation status was noted. In 4 patients,
p mutations were detected in recurrent specimens but not in the available specimens of the first surgery. Additionally, a
gene fusion (
) was found in one sample. In contrary, none of the investigated samples harbored an
or
mutation. In the cohort of radiation-induced meningiomas,
p mutation was detected in two patients (10.5%). Importantly, we found that patients with emergence of
p mutations had a substantially shorter OS than their
p wild-type counterparts (2.7 years, 95% CI 0.9 - 4.5 years versus 10.8 years, 95% CI 7.8 -12.8 years, p=0.003).
In progressive/higher-grade meningiomas,
p mutations are associated with poor survival, supporting a model in which selection of this alteration is a harbinger of aggressive tumor development. In addition, we observe spatial intratumoral heterogeneity of
p mutation status, consistent with this model of late emergence in tumor evolution. Thus, early detection of
p mutations may define patients with more aggressive meningiomas. Stratification for
alterations should be adopted in future clinical trials of progressive/higher-grade meningiomas.
Evaluate the impact of BAALC (brain and acute leukemia, cytoplasmic), a gene whose expression has been associated with adverse outcome in acute myeloid leukemia (AML) with normal cytogenetics, and ...FLT3 internal tandem duplication (ITD) mutations as independent prognostic factors in a larger study.
BAALC expression was determined by real-time reverse transcriptase polymerase chain reaction in pretreatment blood samples of 307 adults <or= 60 years of age with AML with normal cytogenetics. Patients were dichotomized at BAALC's median expression into low and high expressers. The FLT3 ITD mutant:wild-type ratio was determined by fragment analysis.
Compared with low-BAALC patients, high-BAALC patients had a higher rate of primary resistant leukemia (16% v 6%; P = .006). High BAALC expression was associated with a higher cumulative incidence of relapse (CIR; P = .018) and an inferior overall survival (OS; 3-year OS, 36% v 54%; P = .001). On multivariable analysis, high BAALC was independently predictive of resistant disease (P = .019), and high BAALC as well as a high FLT3 mutant:wild-type ratio were confirmed as the only factors predicting a high CIR (BAALC, P = .03; FLT3, P = .01) and inferior OS (BAALC, P = .001; FLT3, P = .012).
This study strengthens BAALC expression as one of the most important prognostic factors in AML patients with normal cytogenetics. BAALC expression and FLT3 mutation status should assist in tailoring induction and postremission therapies.
We investigated cup-like nuclear morphology of acute myeloid leukemia blasts in 266 randomly selected patients and its association with hematologic findings, disease markers and outcome data. ...Cup-like acute myeloid leukemia was diagnosed in 55 patients (21%). It was associated with female sex, high white blood cell and blast cell counts, normal karyotype, and low CD34 and HLA-DR expression. Mutations of FLT3, NPM1 or both were detected in 84.9% compared with 58.1% in cases without this morphology (p=0.001). There was no influence on response to treatment or survival. Therefore, cup-like nuclear morphology is an indicator of normal karyotype and should guide more specific molecular analyses.
BACKGROUND: Recombinant human G–CSF is widely used to mobilize PBPCs in healthy donors for allogeneic transplantation. There have been concerns about donor safety because of splenic ruptures during ...G–CSF application. To address this problem, changes in splenic size in 91 healthy donors during G–CSF mobilization of allogeneic PBPCs were investigated.
STUDY DESIGN AND METHODS: For mobilization, G–CSF in a dosage of 7.5 μg per kg per day was administered for 5 days and PBPC collection started Day 5. Splenic size was determined by ultrasound before G–CSF application was started and on the day of the first apheresis.
RESULTS: The mean increase in splenic length was 11 mm (range, 0‐28 mm; p<0.0001), whereas a mean increase of 5 mm in width (range, 0‐14 mm; p<0.0001) was measured. No major side effects could be observed. There was no significant correlation between the increase in splenic size and the hematologic values, or the age and body‐mass index. In a multivariant analysis, no independent risk factor for the development of a spleen enlargement over 19 mm in length and 9 mm in thickness was found in 20 percent of investigated donors.
CONCLUSION: In this prospective trial, a significant spleen enlargement was observed in healthy donors during G–CSF mobilization of allogeneic PBPCs. Further investigations are needed to define the degree of spleen enlargement with higher G–CSF dosages to improve donor safety.
To assess the optimal cumulative dose of cytarabine for treatment of young adults with acute myeloid leukemia (AML) within a prospective multicenter treatment trial.
Between 1996 and 2003, 933 ...patients (median age, 47 years; range 15 to 60 years) with untreated AML were randomly assigned at diagnosis to receive cytarabine within the first consolidation therapy at either a intermediate-dose of 12 g/m² (I-MAC) or a high-dose of 36 g/m² (H-MAC) combined with mitoxantrone. Autologous hematopoietic stem-cell transplantation or intermediate-dose cytarabine (10 g/m²) were offered as second consolidation. Patients with a matched donor could receive an allogeneic transplantation in a risk-adapted manner.
After double induction therapy including intermediate-dose cytarabine (10 g/m²), mitoxantrone, etoposide, and amsacrine, complete remission was achieved in 66% of patients. In the primary efficacy analysis population, a consolidation with either I-MAC or H-MAC did not result in significant differences in the 5-year overall (30% v 33%; P = .77) or disease-free survival (37% v 38%; P = .86) according to the intention-to-treat analysis. Besides a prolongation of neutropenia and higher transfusion demands in the H-MAC arm, rates of serious adverse events were comparable in the two groups.
In young adults with AML receiving intermediate-dose cytarabine induction, intensification of the cytarabine dose beyond 12 g/m² within first consolidation did not improve treatment outcome.
This study investigated the prognostic and predictive significance of
IDH
1 and
IDH
2 mutations in low-grade astrocytomas (LGA). The presence and consistency of
IDH
mutations during the progression ...of LGA to secondary high-grade gliomas (sHGG) were detected. Samples of patients with LGA and sHGG were investigated. The genomic regions around
IDH1
codon 132 and
IDH2
codon 172 were PCR amplified and directly sequenced. Furthermore, the
MGMT
promoter status was provided using the methylation-specific PCR. Our population comprised 71 patients with a total of 45 pairs of LGA and their consecutive sHGG. Median follow-up was 9.6 years.
IDH
mutations were found in 36/45 LGA (80%) and their sHGG without changes in the mutation status. A total of 71 patients with LGA were analyzed according to clinical and molecular tumor-related factors: 56/71 patients (78.8%) had an
IDH
mutation without significant influence on the progression-free or overall survival (OS), and 22/71 (31%) of the patients received postoperative radiotherapy (RT) after diagnosis of LGA. Patients with early RT but without
IDH
mutations had the shortest survival. Our study shows that
IDH
mutation status is stable during the progression course of LGA to sHGG. The presence of
IDH
mutations fails to demonstrate a significant influence on survival in the multivariate analysis of LGA patients. Early RT appears to be beneficial only LGA patients with
IDH
-mutations.
We present an analysis of prognostic factors derived from a trial in patients with acute myeloid leukemia older than 60 years. The AML96 trial included 909 patients with a median age of 67 years ...(range, 61-87 years). Treatment included cytarabine-based induction therapy followed by 1 consolidation. The median follow-up time for all patients is 68 months (5.7 years). A total of 454 of all 909 patients reached a complete remission (50%). Five-year overall survival (OS) and disease-free survival were 9.7% and 14%, respectively. Multivariate analyses revealed that karyotype, age, NPM1 mutation status, white blood cell count, lactate dehydrogenase, and CD34 expression were of independent prognostic significance for OS. On the basis of the multivariate Cox model, an additive risk score was developed that allowed the subdivision of the largest group of patients with an intermediate-risk karyotype into 2 groups. We are, therefore, able to distinguish 4 prognostic groups: favorable risk, good intermediate risk, adverse intermediate risk, and high risk. The corresponding 3-year OS rates were 39.5%, 30%, 10.6%, and 3.3%, respectively. The risk model allows further stratification of patients with intermediate-risk karyotype into 2 prognostic groups with implications for the therapeutic strategy. This study was registered at www.clinicaltrials.gov as #NCT00180115.
Summary
Multi drug resistance (MDR) is a major obstacle for cancer therapy. The three major candidates accounting for the development of MDR in acute myeloid leukaemia (AML) are multi drug resistance ...gene (MDR1), multi drug resistance‐related protein gene (MRP1) and lung resistance protein gene (LRP). So far, the differential impact of resistance gene expression on treatment outcome in AML is not clear. Therefore, we examined MDR1, MRP1 and LRP gene expression at diagnosis in 331 adult AML patients in the context of other known prognostic factors, such as age, disease status, cytogenetics and FMS‐like tyrosine kinase 3 (FLT3)‐internal tandem duplication mutational status. Median observation time was longer than 5 years 64·1 months (40·0–87·6). MDR1 expression proved to be an independent prognostic factor for outcome of induction therapy (P < 0·001) and overall survival (P = 0·02), whereas MRP1 expression was an independent predictor for disease‐free survival (P = 0·01) in the multivariate analysis. This prognostic impact of both resistance genes was also found in patients with intermediate risk cytogenetics. LRP expression, however, had no impact on treatment outcome in AML. Our study shows that resistance gene expression should be considered together with age, cytogenetics and FLT3 mutational status for risk‐adapted treatment strategies in AML in the future.
To assess the safety and effectiveness of bis-chloroethylnitrosourea (BCNU) wafers in elderly patients with recurrent glioblastoma (GBM).
Patients with recurrent GBM operated on between 2007 and 2014 ...were divided into 3 groups: >65 years with BCNU wafer implantation, >65 years without BCNU wafer implantation, and ≤65 years with BCNU wafer implantation. We compared survival and complications.
A total of 79 patients were identified: 24 in the older BCNU group (median age 68.2 years, 33.3% with a methylated MGMT promoter), 16 in the older non-BCNU group (median age 68.6 years, 31.3% with a methylated MGMT promoter), and 39 in the younger BCNU group (median age 56.8 years). Survival after progression was 9.2 months in the elderly BCNU group and 7.6 months in the elderly non-BCNU group (p = 0.34); overall survival was 17.2 and 15.9 months, respectively (p = 0.35). We found a tendency toward a higher rate of seizures and pneumonia in the older BCNU group.
BCNU wafer implantation after resection of recurrent GBM is a reasonably safe treatment in patients aged >65 years. Seizures and systemic infections may occur more frequently, but the trade-off is still favorable as survival may be influenced positively. Higher age should not be regarded as a contraindication for BCNU wafers.
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