Effect of MGMT gene methylation status on chemoradiotherapy and prognosis in elderly patients with glioblastoma / 中华放射肿瘤学杂志

Objective:To investigate the effect of O-6-methylguananine-DNA methyltransferase (MGMT) gene promoter methylation status on the treatment and prognosis of elderly patients newly-diagnosed with glioblastoma (GBM).Methods:Clinical data of 65 newly-diagnosed GBM patients admitted to Tianjin Huanhu Hospital from January 2012 to December 2018 were retrospectively analyzed. All patients received intensity-modulated radiotherapy after surgery and 49 patients received temozolomide (TMZ) monotherapy. All patients were divided into the MGMT(+ ) group and MGMT(-) group according to the methylation status of MGMT promoter. Kaplan- Meier method and log-rank test were used for univariate survival analysis, and Cox regression model was used for multivariate prognostic analysis. Results:The median overall survival (OS) for all patients was 18.0 months. The median OS was 27.0 months and 15.3 months in the MGMT(+ ) group and MGMT(-) group, respectively. Univariate analysis revealed that tumor number, MGMT promoter methylation, postoperative concurrent chemoradiotherapy were significantly related to clinical prognosis ( P=0.029, P=0.001 and P<0.001). In multivariate analysis, tumor number and postoperative concurrent chemoradiotherapy were identified as significant prognostic factors for OS ( P=0.037, P=0.004). In the MGMT(+ ) group, the median OS was 27.0 months for patients receiving concurrent chemoradiotherapy and 12.0 months for radiotherapy alone ( P=0.040). In the MGMT(-) group, the median OS was 17.0 months for concurrent chemoradiotherapy patients and 10.0 months for radiotherapy alone ( P=0.122). Conclusions:MGMT promoter methylation status is significantly associated with longer OS in elderly GBM patients. Conventional fractional radiotherapy combined with concurrent and sequential TMZ chemotherapy probably yields better survival benefits.

A FKBP5 mutation is associated with Paget's disease of bone and enhances osteoclastogenesis

Paget's disease of bone (PDB) is a common metabolic bone disease that is characterized by aberrant focal bone remodeling, which is caused by excessive osteoclastic bone resorption followed by disorganized osteoblastic bone formation. Genetic factors are a critical determinant of PDB pathogenesis, and several susceptibility genes and loci have been reported, including SQSTM1, TNFSF11A, TNFRSF11B, VCP, OPTN, CSF1 and DCSTAMP. Herein, we report a case of Chinese familial PDB without mutations in known genes and identify a novel c.163G>C (p.Val55Leu) mutation in FKBP5 (encodes FK506-binding protein 51, FKBP51) associated with PDB using whole-exome sequencing. Mutant FKBP51 enhanced the Akt phosphorylation and kinase activity in cells. A study of osteoclast function using FKBP51V55L KI transgenic mice proved that osteoclast precursors from FKBP51V55L mice were hyperresponsive to RANKL, and osteoclasts derived from FKBP51V55L mice displayed more intensive bone resorbing activity than did FKBP51WT controls. The osteoclast-specific molecules tartrate-resistant acid phosphatase, osteoclast-associated receptor and transcription factor NFATC1 were increased in bone marrow-derived monocyte/macrophage cells (BMMs) from FKBP51V55L mice during osteoclast differentiation. However, c-fos expression showed no significant difference in the wild-type and mutant groups. Akt phosphorylation in FKBP51V55L BMMs was elevated in response to RANKL. In contrast, IκB degradation, ERK phosphorylation and LC3II expression showed no difference in wild-type and mutant BMMs. Micro-CT analysis revealed an intensive trabecular bone resorption pattern in FKBP51V55L mice, and suspicious osteolytic bone lesions were noted in three-dimensional reconstruction of distal femurs from mutant mice. These results demonstrate that the mutant FKBP51V55L promotes osteoclastogenesis and function, which could subsequently participate in PDB development.

Clinical features and prognostic factors of brain metastasis from colorectal cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>The aim of this study was to analyze the clinical features and prognostic factors in patients with brain metastasis from colorectal cancer (CRC).</p><p><b>METHODS</b>Clinical materials of 45 colorectal cancer patients who developed brain metastasis were collected, and the data and follow-up data of those patients were retrospectively analyzed.</p><p><b>RESULTS</b>Most brain metastases were from rectal cancer (64.4%), and 80.0% of the 45 cases had extracranial metastases. The most common extracranial metastatic site was the lung (57.8%), followed by the liver (35.6%). All the brain metastases in patients with liver metastases were supratentorial, while in contrast, 44.8% of the patients without liver metastasis had subtentorial metastasis, showing a significant difference between them (P<0.05). The interval time from diagnosis of CRC to the development of brain metastases in case of Dukes D stage was 12.0 months, significantly shorter than that in the cases of Dukes A stage (24.0 months), B (36.0 months) and C (29.0 months) (P<0.05). The interval time was also shorter in the patients who developed extracranial metastasis within one year than those more than one year (12.0 months vs. 38.0 months)( P<0.05). The median survival time of patients with brain metastasis from colorectal was 6.0 months, with a 1-year survival rate of 21.1% and 2-year survival rate of 3.3% only. Univariate analysis showed that the median survival of patients with a KPS score of ≥70 was 8.0 months, significantly higher than 2.0 months in those with a KPS score of <70 (P<0.05). The median survival of patients with one or two brain metastases was 8.0 months, significantly higher than 4.0 months of those with >2 brain metastases (P<0.05). The median survival time after diagnosis of brain metastasis was 4.0 months for those who received monotherapy (only steroids, only chemotherapy or only radiotherapy), significantly shorter than 10.0 months of patients who received chemoradiotherapy, and 12.0 months of those who underwent surgery (P<0.05). Comparing each two differently treated groups, the survival time of surgery combined with chemotherapy or radiotherapy group was significantly different from that of all of other groups (P<0.05). The median survival time of chemoradiotherapy group was longer than that of monotherapy, but the difference was not significant (P>0.05). Multivariate analysis showed that brain metastases >2 and treatment modality type are independent prognostic factors for survival.</p><p><b>CONCLUSIONS</b>Patients initially diagnosed with a Dukes D stage primary colorectal tumor and occurrence of extracranial metastasis (especially, pulmonary metastasis) within one year are associated to an increased risk of brain metastases and have a shorter survival time. Most brain metastases in patients with liver metastases are supratentorial, while many patients without liver metastasis have subtentorial metastasis. Brain metastases >2 and the type of treatment modality are independent prognostic factors for survival. The prognosis of patients who received chemoradiotherapy is better than those treated only with chemotherapy or radiotherapy. Some subsets of patients may benefit from surgery plus chemotherapy/radiotherapy.</p>