Adjuvant Temozolomide Chemotherapy With or Without Interferon Alfa Among Patients With Newly Diagnosed High-grade Gliomas: A Randomized Clinical Trial.

Importance: High-grade gliomas (HGGs) constitute the most common and aggressive primary brain tumor, with 5-year survival rates of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. The add-on efficacy of interferon alfa is unclear for the treatment of HGG. Objectives: To compare the therapeutic efficacy and toxic effects of the combination of temozolomide and interferon alfa and temozolomide alone in patients with newly diagnosed HGG. Design, Setting, and Participants: This multicenter, randomized, phase 3 clinical trial enrolled 199 patients with newly diagnosed HGG from May 1, 2012, to March 30, 2016, at 15 Chinese medical centers. Follow-up was completed July 31, 2021, and data were analyzed from September 13 to November 24, 2021. Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed HGG and had received no prior chemotherapy, radiotherapy, or immunotherapy for their HGG. Interventions: All patients received standard radiotherapy concurrent with temozolomide. After a 4-week break, patients in the temozolomide with interferon alfa group received standard temozolomide combined with interferon alfa every 28 days. Patients in the temozolomide group received standard temozolomide. Main Outcomes and Measures: The primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability. Results: A total of 199 patients with HGG were enrolled, with a median follow-up time of 66.0 (95% CI, 59.1-72.9) months. Seventy-nine patients (39.7%) were women and 120 (60.3%) were men, with ages ranging from 18 to 75 years and a median age of 46.9 (95% CI, 45.3-48.7) years. The median OS of patients in the temozolomide plus interferon alfa group (26.7 [95% CI, 21.6-31.7] months) was significantly longer than that in the standard group (18.8 [95% CI, 16.9-20.7] months; hazard ratio [HR], 0.64 [95% CI, 0.47-0.88]; P = .005). Temozolomide plus interferon alfa also significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation (24.7 [95% CI, 20.5-28.8] months) compared with temozolomide (17.4 [95% CI, 14.1-20.7] months; HR, 0.57 [95% CI, 0.37-0.87]; P = .008). Seizure and influenzalike symptoms were more common in the temozolomide plus interferon alfa group, with 2 of 100 (2.0%) and 5 of 100 (5.0%) patients with grades 1 and 2 toxic effects, respectively (P = .02). Finally, results suggested that methylation level at the IFNAR1/2 promoter was a marker of sensitivity to temozolomide plus interferon alfa. Conclusions and Relevance: Compared with the standard regimen, temozolomide plus interferon alfa treatment could prolong the survival time of patients with HGG, especially the MGMT promoter unmethylation variant, and the toxic effects remained tolerable. Trial Registration: ClinicalTrials.gov Identifier: NCT01765088.

Recurrence benefit from supramarginal resection in brain metastases of lung adenocarcinoma.

Background: There is growing evidence that brain metastases (BM) have no well-defined boundaries and that conventional microsurgical circumferential dissection of BM is often inadequate to prevent local tumor recurrence. Previous studies have suggested that supramarginal resection can significantly improve local tumor control. We retrospectively analyzed the local tumor control in a series of patients with BM from lung adenocarcinoma. Methods: We retrospectively analyzed 48 patients with BM for lung adenocarcinoma in Shenzhen Second People's Hospital from May 2015 to May 2020. 26 resected lesions were located in eloquent areas and underwent standard gross total resection (GTR group); 22 resected lesions were located in ineloquent areas, after standard gross total resection, the periphery was expanded and resected by 5 mm (MTR group). The postoperative tumor recurrence was compared between the two groups. Results: During the follow-up period, the local recurrence rates in the GTR group and the MTR group were 61.5% and 27.3% (p = 0.022), respectively. Within 6 months after surgery, the local recurrence rates in the GTR group and the MTR group were 42.3% and 13.6% (p = 0.029), respectively. Within 12 months after surgery, the local recurrence rates in the GTR group and the MTR group were 57.7% and 22.7% (p = 0.014), respectively. The median progression-free survival time after surgery was 7.0 months (95% CI 4.0-10.0 months) in the GTR group and 14.0 months (95% CI 11.4-16.6 months) in the MTR group (Log-Rank p = 0.008). Compared with the MTR group, the HR of local recurrence in the GTR group was 3.74 (95% CI 1.38-10.39, p = 0.010). Cox multivariable analysis showed no other factors associated with local recurrence except for the surgical method (p = 0.012). Conclusions: On the basis of conventional surgical total resection, expanded peripheral resection of 5 mm around the brain metastases of lung adenocarcinoma can significantly reduce the local recurrence rate and prolongs the progression-free survival time.

Chronic giant cranial diploe hematoma in hemophiliac.

Cranial diploe hematoma is a hematoma that occurs between the inner and outer layer of the skull and is often in infants and young children. Hemophilia A is an inherited X-linked bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII) . Epidemiological survey results show that the prevalence of hemophilia in 24 provinces and cities in China is 2.73/100,000, while only about 5% of patients are registered . Hemophilia is mainly characterized by bleeding, which can occur anywhere in the pa-tient's body and manifest as intracranial, gastrointestinal, or pharyngeal bleeding, which can be life-threatening in severe cases. This article shares a case of a patient with he-mophilia A complicated by a chronic giant diploe hematoma.

Guideline conformity to the Stupp regimen in patients with newly diagnosed glioblastoma multiforme in China.

Aims: To determine how consistently Chinese glioblastoma multiforme (GBM) patients were treated according to the Stupp regimen. Patients and methods: The proportion of treatments conforming to the Stupp regimen and reasons for nonconformity were evaluated in 202 newly diagnosed GBM patients. Results: Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations were temozolomide dosages >75 mg/m2 (58/120; 48.3%) and treatment durations <42 days (84/120; 70.0%) in the concomitant phase and temozolomide dosages <150 mg/m2 (89/101; 88.1%) in the maintenance phase. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments. Conclusion: Increased conformity to the Stupp regimen is needed for GBM patients in China.

Lay abstract In 2005 the European Organization for Research and Treatment of Cancer 26981 study led to US FDA approval for the use of temozolomide in combination with radiotherapy to treat glioblastoma multiforme (GBM). The Stupp regimen consists of fractionated focal irradiation in daily fractions of 2 Gy given 5 days/week for 6 weeks (a total of 60 Gy), plus concomitant daily temozolomide (75 mg/m²/day, 7 days/week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150­200 mg/m²/day for 5 days during each 28-day cycle). In 2012 the Chinese guidelines for the diagnosis and treatment of glioma of the CNS recommended the Stupp regimen as first-line therapy for newly diagnosed GBM. In the present study, compliance of GBM treatments with the Stupp regimen in 28 Chinese centers from 2012­2016 was evaluated. Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations related to temozolomide dosages and treatment durations in the concomitant and maintenance phases. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments.

Long Noncoding RNA WEE2-AS1 Plays an Oncogenic Role in Glioblastoma by Functioning as a Molecular Sponge for MicroRNA-520f-3p.

The long noncoding RNA WEE2 antisense RNA 1 (WEE2-AS1) plays an oncogenic role in hepatocellular carcinoma and triple negative breast cancer progression. In this study, we investigated the expression and roles of WEE2-AS1 in glioblastoma (GBM). Furthermore, the molecular mechanisms behind the oncogenic actions of WEE2-AS1 in GBM cells were explored in detail. WEE2-AS1 expression was detected using quantitative real-time polymerase chain reaction. The roles of WEE2-AS1 in GBM cells were evaluated by the cell counting kit-8 assay, flow cytometric analysis, Transwell cell migration and invasion assays, and tumor xenograft experiments. WEE2-AS1 expression was evidently enhanced in GBM tissues and cell lines compared with their normal counterparts. An increased level of WEE2-AS1 was correlated with the average tumor diameter, Karnofsky Performance Scale score, and shorter overall survival among GBM patients. Functionally, depleted WEE2-AS1 attenuated GBM cell proliferation, migration, and invasion in vitro, promoted cell apoptosis, and impaired tumor growth in vivo. Mechanistically, WEE2-AS1 functioned as a molecular sponge for microRNA-520f-3p (miR-520f-3p) and consequently increased specificity protein 1 (SP1) expression in GBM cells. A series of recovery experiments revealed that the inhibition of miR-520f-3p and upregulation of SP1 could partially abrogate the influences of WEE2-AS1 downregulation on GBM cells. In conclusion, WEE2-AS1 can adsorb miR-520f-3p to increase endogenous SP1 expression, thereby facilitating the malignancy of GBM. Therefore, targeting the WEE2-AS1miR-520f-3pSP1 pathway might be a promising therapy for the management of GBM in the future.

Effect of metformin on cell proliferation, apoptosis, migration and invasion in A172 glioma cells and its mechanisms.

The purpose of the present study was to determine the effects of metformin on the inhibition of proliferation, apoptosis, invasion and migration of A172 human glioma cells in vitro and determine the underlying mechanism. The effects of metformin at different concentrations (0, 0.1, 1 and 10 mmol/l) on the inhibition of A172 cell proliferation were detected using a 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide assay. Cell apoptosis was detected by flow cytometry. Caspase­3 activity was analyzed by spectrophotometry. The invasion and migration of cells were detected by Transwell assays. The levels of Bcl­2­associated X protein (Bax), B­cell lymphoma 2 (Bcl­2), AMP­activated protein kinase (AMPK), phosphorylated­(p)AMPK and mechanistic target of rapamycin (mTOR) protein expression were detected by western blot analysis, and changes in the malondialdehyde (MDA) content and activity of superoxide dismutase (SOD) were determined. Compared with the control group, metformin significantly increased the inhibition of proliferation and apoptosis, and significantly reduced the invasion and migration of A172 cells in dose­ and time­dependent manners (P<0.05). In addition, compared with the control group, metformin significantly enhanced the activity of caspase­3, increased the expression of AMPK/pAMPK/Bax proteins and reduced the expression of mTOR/Bcl­2 proteins (P<0.05). Metformin increased the MDA content and reduced the activity of SOD in a dose­dependent manner (P<0.05). Metformin may inhibit glioma cell proliferation, migration and invasion, and promote its apoptosis; the effects may be associated with the AMPK/mTOR signaling pathway and oxidative stress.

Primary cerebellopontine angle ependymoma with spinal metastasis in an adult patient: A case report.

Subtentorial ependymoma is a common central nervous system tumor in young children, but is uncommon in adults. Ependymoma often arises from the cells lining the fourth ventricle. The present study reports a rare case of primary ependymoma that originated from the cerebellopontine angle, with local extension to the two internal auditory canals and remote spinal metastasis, in an adult male. A 50-year-old male presented with headache, tinnitus and bilateral hearing loss that had persisted for 4 months. Magnetic resonance imaging (MRI) revealed a mass in each of the cerebellopontine angles, which had spread to each internal auditory canal and wrapped the VII/VIII cranial nerve complex. A gross total resection was performed to remove the mass in the right side. Histological examination confirmed that the tumor was a World Health Organization grade II papillary ependymoma. Notably, the patient complained of urine retention post-surgery and massive occupational lesions in T3-T4 and L5-S2 were found on full spinal cord MRI. The patient then received combination therapy consisting of temozolomide, and whole-brain and spinal cord radiation. In the final follow-up examination, performed 13 months after treatment, slight shrinkage of the T3 lesion was observed, and no progression of the left cerebellopontine angle and S5-L2 lesions were identified on MRI. In summary, although this clinical entity is rare, the diagnosis of ependymoma and the possibility of spinal cord metastasis should be considered in subtentorial tumors.

Inhibition of tumor cell migration and invasion through knockdown of Rac1 expression in medulloblastoma cells.

Medulloblastoma is one of the common malignant brain tumors in children or young adults and its overall disease-free 5-year survival rate is approximately 50% due to tumor progression, invasion, and metastasis. This study aimed to determine whether one of Rho GTPases, Rac1 can affect the morphology, motility, and invasion of medulloblastoma cells through knockdown of Rac1 expression. Medulloblastoma Daoy cells were used to manipulate Rac1 expression using Rac1 shRNA, Rac1N17, and Rac1L61 constructs. Reverse transcriptase-PCR and western blot were used to detect expression of Rac1 mRNA and protein, respectively. Invasion and migration assays were performed to assess invasion and migration capacity of Daoy cells, respectively. The data showed that Rac1 mRNA and protein were overexpressed in Daoy cells. Deletion of Rac1 decreased the cross-linked actin network and pseudopodia and also inhibited the number of migration cells migrated or invaded to the other side of the filter compared to control cells. These data indicated that the invasion and migration in Daoy cells were inhibited by deletion of Rac1, and suggest that targeting Rac1 by Rac1 shRNA may further be evaluated and used as a potential anticancer strategy to treat medulloblastoma.

Clinical research and surgical treatment of posttraumatic epilepsy.

In order to investigate the susceptible factors of posttraumatic epilepsy (PTE) and the surgical treatment, the relative factors of 18 cases of intractable PTE and 35 cases of non-PTE patients with posttraumatic seizures (PTS) and the surgical treatment of PTE patients were studied retrospectively. The results showed that there was significant difference in the degree of unconsciousness after head injury, incidence of intracerebral hematoma and acute subdural hematoma between PTE group and non-PTE group. Of the 18 cases of PTE undergoing surgical treatment, the effectiveness of 11 cases was satisfactory and that of the remaining 7 was not. Between the two groups, there was difference in the localization of interictal epileptic discharge (IED) and ictal discharge (ID) as demonstrated by preoperative EEG. It was concluded that PTE was associated with the severity of head injury and intracranial hematoma. The localization of epileptogenic loci by preoperative EEG presumably contributed to the PTE surgical effects.