Purpose
Patients with recurrent glioblastoma (rGBM) have a poor prognosis, with survival ranging from 25 to 40 weeks. Antiangiogenic agents are widely used, showing a variable response. In this ...study, we explored the efficacy of carmustine plus bevacizumab (BCNU/Bev) for treating rGBM.
Methods/patients
In this study, we assessed 59 adult patients with histologically confirmed rGBM who were treated with BCNU/Bev as second-line regimen. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were evaluated according to their molecular expression profile, including
CD133
mRNA expression,
MGMT
methylation (
pMGMT
),
PDGFR
amplification,
YKL40
mRNA expression,
IDH1/2
condition,
p53
and
EGFRvIII
mutation status.
Results
Median follow-up was 18.6 months, overall RR to the combination was 56.3%, and median PFS was 9.0 months (95% CI 8.0–9.9). OS from time of diagnosis was 21.0 months (95% CI 13.2–28.7) and from starting BCNU/Bev it was 10.7 months (95% CI 9.5–11.8).
IDH1/2
mutations were found in 30.5% of the patients,
pMGMT
in 55.9% and high
CD133
mRNA expression in 57.6%. Factors which positively affected PFS included performance status (
p
= 0.015),
IDH
+ (
p
= 0.05),
CD133
mRNA expression (
p
= 0.009) and
pMGMT
+ (
p
= 0.007). OS was positively affected by
pMGMT
+ (
p
= 0.05). Meanwhile,
YKL40
negatively affected PFS (
p
= 0.01) and OS (
p
= 0.0001). Grade ≥ 3 toxicities included hypertension (22%) and fatigue (12%).
Conclusions
BCNU/Bev is a safe and tolerable treatment for rGBM. Patients with
MGMT
+
/IDH
+ derive the greatest benefit from the treatment combination in the second-line setting. Nonetheless, high
YKL40
expression discourages the use of antiangiogenic therapy.
The mutant regulator of APX2 1-1 (rax1-1) was identified in Arabidopsis thaliana that constitutively expressed normally photooxidative stress-inducible ASCORBATE PEROXIDASE2 (APX2) and had ≥50% ...lowered foliar glutathione levels. Mapping revealed that rax1-1 is an allele of γ-GLUTAMYLCYSTEINE SYNTHETASE 1 (GSH1), which encodes chloroplastic γ-glutamylcysteine synthetase, the controlling step of glutathione biosynthesis. By comparison of rax1-1 with the GSH1 mutant cadmium hypersensitive 2, the expression of 32 stress-responsive genes was shown to be responsive to changed glutathione metabolism. Under photo-oxidative stress conditions, the expression of a wider set of defense-related genes was altered in the mutants. In wild-type plants, glutathione metabolism may play a key role in determining the degree of expression of defense genes controlled by several signaling pathways both before and during stress. This control may reflect the physiological state of the plant at the time of the onset of an environmental challenge and suggests that changes in glutathione metabolism may be one means of integrating the function of several signaling pathways.
Drug metabolizing enzymes like cytochrome P450 (CYP) play an important role in determining the susceptibility of organs or tissue to the toxic effects of drugs or other xenobiotics. There is some ...evidence indicating that individual isoforms of CYPs are over-expressed in different types of malignant tumors including that of oesophagus, pancreas, breast, lung, colon and stomach. Nevertheless, it is not clear if this change in expression is previous or after the appearance of malignancy. This is important in order to clarify the possible role of xenobiotics in the development of gastric cancer. On the other hand, it has been reported that a high salt ingestion leads to histological changes in rat stomach mucosa including enhanced cell proliferation, lipid peroxidation and intestinal metaplasia. The aim of this study is to explore the expression and activity of CYP families involved in the metabolism of carcinogens in normal rat stomach mucosa and intestinal metaplasia induced by high NaCl ingestion. Male Wistar rats were exposed to diets containing different NaCl concentrations (0.6% control group, 6%, 12%, 18% and 24%) for 12 weeks and histological changes as well as CYP modulation were monitored in gastric mucosa. Chronic gastritis, regenerative hyperplasia and focal metaplasia were noted in animals receiving the 12%, 18% and 24% NaCl diets. In the same groups, induction of CYP1A1 and CYP3A2 was produced, mainly in areas of metaplasia. The expression of xenobiotic metabolizing enzymes in the gastric mucosa might contribute to chemical activation in the stomach, metabolizing both exogenous and endogenous compounds implicated in the development of gastric cancer.
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