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Although there have been recent advances in the molecular pathology of ependymomas, little is known about the underlying molecular evolution during its development. Here, we assessed the clinical, pathological and molecular evolutionary process of ependymoma recurrence in a 9-year-old patient who had seven recurrences of supratentorial ependymoma and died from intracranial multiregional recurrences at the age of 19 years old. Whole-genome sequencing (WGS) of 7 tumor samples (1 primary and 6 subsequent recurrent tumors) was performed to elucidate the mutation landscape and identify potential driver mutations for tumor evolution. The genetic profiles of the seven tumor specimens showed significant heterogeneity and suggested a highly branched evolutionary pattern. The mutational signatures and chromothripsis changed with treatments. Strikingly, adhesion G protein-coupled receptor L3 (ADGRL3, also known as Latrophilins 3, LPNH3) was found to be consistently mutated during the entire disease process. However, Sanger sequencing of other 78 ependymoma patients who underwent surgery at our institution showed no genetic alteration of ADGRL3, as found in the present case. The mRNA levels of ADGRL3 were significantly lower in ependymomas (n = 36), as compared with normal brain tissue (n = 3). Grade III ependymomas had the lowest ADGRL3 expression. Moreover, ependymomas with lower mRNA level of ADGRL3 had shorter overall survival. Our findings, therefore, demonstrate a rare evolutionary process of ependymoma involving ADGRL3.

We reviewed a study addressing the development and validation of a prediction model for moderately severe and severe acute pancreatitis in pregnancy. We identified some statistical deficiencies in this article. In addition, we believe that the role of cholesterol as a predictor should be described in more detail.

e14014 Background: Nearly all patients (pts) with glioblastoma (GBM) will suffered relapse or disease progression after resection and adjuvant radiotherapy and temozolomide (TMZ). Anlotinib is a new multikinase inhibitors (MKI) blocking angiogenesis and tumor cell proliferation simultaneously and a prospective phase II study was performed to explore the potency of the combination anlotinib and TMZ for pts with relapse or progression GBM. Here, we reports the preliminary results of this study. Methods: This is a prospective, single-arm, open label, phase II study (NCT04547855). Eligible pts were diagnosed with histologically confirmed glioblastoma and experienced relapse or progression for the first time from surgery (including biopsy, partial resection and total resection) and radiotherapy-TMZ therapy (STUPP regimen). Other criteria included 18 to 75 years age, Karnofsky performance status (KPS) ≥ 60% and adequate organ function. The primary endpoint was progression free survival at 6 months (6m-PFS). All pts received orally TMZ (150 mg/m2) from D1-D7 every 2 weeks and anlotinib (12mg, QD) from D1-D14 every 3 weeks until disease progression or unacceptable toxicities. Results: From July 2020 to November 2021, 25 pts were enrolled. The median age was 49 (rang: 23, 62) and the median KPS was 80 (range: 60, 100). Most pts had poor prognostic factors that 17 pts (70.8%) had unmethylated MGMT promoter and 22 pts (91.6%) were IDH wild-type, which 24 pts detected IDH and MGMT status. At the data cutoff date on January 2022, the 6m-PFS was 25.2% and the median PFS was 4.2 months (95% CI, 3.4-5.0m). The median OS reached 9.1 months (95% CI, 8.1-10.2). Tumor response was assessed for all pts. 7 pts achieved partial response and the objective response rate was 28%. 10 pts had stable disease and the disease control rate was 68%. The most common grade 3 or worse adverse events (AEs) was lympyhopenia (48.0%), which may be caused by TMZ. No death was attributed to AEs. Conclusions: Combination of anlotinib and dose-intense temozolomide was tolerable in the treatment of recurrent or progressive glioblastoma. Preliminary results indicated that the efficacy was promising for those miserable pts with worse prognosis factors. Further investigation was ongoing. Clinical trial information: NCT04547855.

The present study was designed to examine effects of Sinomenine (SM) on glioma cells growth in vivo and in vitro. Cells growth and apoptosis were detected by MTT assay, TUNEL assay and flow cytometric analysis. In the study, SM treatment led to growth inhibition on a series of glioma cell lines, including U87, U373, U251, Hs683 and T98G. SM prevented U87 growth in the nude mice as well. Inhibitory effects of SM on U87 cells proliferation in vitro and in vivo were more effective than that of temozolomide (TMZ), and SM has synergistic effects with TMZ in the glioma therapy. SM induced apoptotic death in U87 cells via activation of caspase-3, caspase-8 and caspase-9, and down-regulation of HIAP, Bcl-2 and survivin. Moreover, we observed SM decreased the expression of phosphorylated STAT3 (p-STAT3) both in vivo and in vitro. Interestingly, using a specific activator of STAT3, we demonstrated overexpression of p-STAT3 impaired, SM mediated growth inhibition and apoptosis induction in the U87 cells. In summary, our results indicate SM induced growth suppression of human glioma cells through inhibiting phosphorylation of STAT3.

Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1) is the active catalytic component of prolyl 4-hydroxylase and plays a crucial role in modulating extracellular matrix hemostasis. P4HA1 has been reported to promote tumor progression by enhancing invasion and angiogenesis. Overexpression of P4HA1 is associated with decreased survival for patients with breast and prostate cancer. However, the prognostic significance of P4HA1 for glioma patients remains undefined.The expression of P4HA1 in 290 gliomas (WHO grade II-IV) and 10 normal brain tissues was examined with TMA-based immunohistochemistry assay. The correlation between P4HA1 expression and clinicopathological parameters as well as the prognosis of glioma patients was investigated.Cytoplasmic expression of P4HA1 is high in 37.93% of all glioma cases, with 44.98% in high-grade gliomas and 19.75% in low-grade gliomas respectively. Increased P4HA1 level was correlated with advanced histological grade (p0.01) and old age (p=0.01). Upregulation of P4HA1, as well as histological grade, was an independent risk factor for unfavorable prognosis. Subgroup analysis demonstrated that high P4HA1 expression was significantly associated with poor prognosis for high-grade gliomas (p0.01) but not for low-grade gliomas.P4HA1 was upregulated in gliomas. High expression of P4HA1 was correlated with the malignancy of gliomas and could serve as a prognostic indicator for patients with high-grade gliomas.

We investigated the functional status of adult supratentorial superficial low-grade glioma (ASS-LGG) after surgery and analyzed its relevant factors to guide the therapeutic strategy and improve the life quality of these patients. Clinical materials from January 2008 to December 2010 in 104 adults with ASS-LGG were analyzed retrospectively. The follow-up period ranged from 6 months to 1.5 years. The logistic regression was used to evaluate the preoperative and postoperative variation of functional status in patients to disclose the relevant factors affecting postoperative functional status, such as age, gender, the duration of symptom, size and location of the tumor, hemisphere, resection degree, and tumor pathologic grade and preoperative Karnofsky performance status (Pre-KPS). Four out of nine candidate factors are related to the postoperative functional status. They are age less than 40 years, the size of tumor less than 5 cm in diameter, tumor located in the right hemisphere, and limited resection of tumor in the eloquent area. It seems more meaningful to evaluate the functional status of the patients with ASS-LGG on the basis of these clinical features, involving age, tumor size, location, and extent of resection.

Glioma is the most frequent primary central nervous system tumor. Although the current first-line medicine, temozolomide (TMZ), promotes patient survival, drug resistance develops easily. Thus, it is important to investigate novel therapeutic reagents to solidify the treatment effect. β-Elemene (bELE) is a compound from a Chinese herb whose anticancer effect has been shown in various types of cancer. However, its role in the inhibition of glioma stem-like cells (GSLCs) has not yet been reported. We studied both the in vitro and the in vivo inhibitory effect of bELE and TMZ in GSLCs and parental cells and their combined effects. The molecular mechanisms were also investigated. We also optimized the delivery methods of bELE. We found that bELE selectively inhibits the proliferation and sphere formation of GSLCs, other than parental glioma cells, and TMZ exerts its effects on parental cells instead of GSLCs. The in vivo data confirmed that the combination of bELE and TMZ worked better in the xenografts of GSLCs, mimicking the situation of tumorigenesis of human cancer. Notch1 was downregulated with bELE treatment. Our data also demonstrated that the continuous administration of bELE produces an ideal effect to control tumor progression. Our findings have demonstrated, for the first time, that bELE could compensate for TMZ to kill both GSLCs and nonstem-like cancer cells, probably improving the prognosis of glioma patients tremendously. Notch1 might be a downstream target of bELE. Therefore, our data shed light on improving the outcomes of glioma patients by combining bELE and TMZ.

The flow behavior, microstructure evolution and softening mechanism of an AA7085 aluminum alloy are investigated by isothermal hot compression tests at 450 °C with the strain rates of 0.001 s−1 and 0.1 s−1. Optical microscopy (OM), electron back-scattered diffraction (EBSD) and transmission electron microscopy (TEM) are used to characterize microstructure evolution during deformation. The results reveal that the flow stress curves exhibit a single peak and then two types of flow stress curves are found in the present study. Microstructure characterization reveals that dynamic recovery (DRV) and recrystallization (DRX) occur in the both conditions. The microstructure discrepancy becomes significant with increasing strain rate after a certain strain level (e≥0.3). In the case of 0.001 s−1, the dynamic recovery is thought to precede continuous dynamic recrystallization. As the strain rate increased, the absence of dynamic recovery provides enough stored energy for discontinuous dynamic recrystallization (DDRX), resulting in a retardation in the occurrence of continuous dynamic recrystallization (CDRX).

The flow behavior and microstructure evolution of 6A82 aluminum alloy (Al–Mg–Si–Cu) with high copper content were studied on a Gleeble–1500 system by isothermal hot compression test in the temperature range from 320 to 530 °C and the strain rate range from 0.001 to 10 s−1. The results reveal that the flow stress of the alloy exhibits a continuous flow softening behavior at low temperatures of 320–390 °C, whereas it reaches steady state at high temperatures (≥460 °C), which are influenced greatly by the Zener–Hollomon parameter (Z) in the hyperbolic sine with the hot deformation activation energy of 325.12 kJ/mol. Microstructure characterizations show that prominent dynamic recrystallization and coarsening of dynamic precipitation may be responsible for the continuous flow softening behavior. Due to deformation heating at high strain rates (≥1 s−1), dynamic recrystallization is more prominent in the specimen deformed at 530 °C and 10 s−1 than in the specimen deformed at 460 °C and 0.1 s−1 even though they have very close ln Z values.

Background: The radiochemotherapy regimen concomitantly employing temozolomide (TMZ) chemotherapy and radiotherapy (RT) 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma (GBM). However, its median overall survival (OS) is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen. Methods: A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide (early TMZ group) or standard concomitant radiochemotherapy regimen (control group). Overall response was assessed based on objective tumor assessments, administration of corticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event (AE), and neurological condition were measured for 24 months of follow-up. The primary efficacy endpoint of this study was overall survival (OS). The secondary endpoint was progression free survival (PFS). Results: The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group (log-rank test P = 0.021). In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively (P < 0.05). The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group (log-rank test P = 0.695). AEs occurred in 29 (55.8%) and 31(73.8%) patients respectively in early and control groups, including nausea (15.4% vs. 33.3%), vomiting (7.7% vs. 28.6%), fever (7.7% vs. 11.9%), and headache (3.8% vs. 23.8%). Only 30.8% and 33.3% were drug-related, respectively. Conclusions: Addition of TMZ chemotherapy in the early break of the standard concomitant radiochemotherapy regimen was well tolerated and significantly improved the OS of the GBM patients, compared with standard concomitant radiochemotherapy regimen. However, a larger randomized trial is warranted to verify these results.

CD44 is a molecular marker associated with cancer stem cell populations and treatment resistance in glioma. More effective therapies will result from approaches aimed at targeting glioma cells high in CD44.Glioma-initiating cell lines were derived from fresh surgical glioblastoma samples. Expression of tissue transglutaminase 2 (TGM2) was attenuated through lentivirus-mediated short hairpin RNA knockdown. MTT assay [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] was used to evaluate the growth inhibition induced by TGM2 inhibitor. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling was used to evaluate cell apoptosis following TGM2 inhibition. CD44(+) glioma stem cells were sorted by flow cytometry. A nude mice orthotopic xenograft model was used to evaluate the in vivo effect of TGM2 inhibitor.TGM2 was highly expressed in CD44-high glioblastoma tissues and tumor-derived glioma-initiating cell lines. TGM2 knockdown impaired cell proliferation and induced apoptosis in CD44-high glioma-initiating cell lines. Further studies indicated that expression of inhibitor of DNA binding 1 protein (ID1) is regulated by TGM2 and might be an important mediator for TGM2-regulated cell proliferation in CD44-high glioma-initiating cell lines. TGM2 inhibitor reduces ID1 expression, suppresses cell proliferation, and induces apoptosis in CD44-high glioma-initiating cell lines. Furthermore, TGM2 is highly expressed in CD44(+) glioma stem cells, while pharmacological inhibition of TGM2 activity preferentially eliminates CD44(+) glioma stem cells. Consistently, TGM2 inhibitor treatment reduced ID1 expression and induced apoptosis in our orthotopic mice xenograft model, which can be translated into prolonged median survival in tumor-bearing mice.TGM2 regulates ID1 expression in glioma-initiating cell lines high in CD44. Targeting TGM2 could be an effective strategy to treat gliomas with high CD44 expression.

// Qun-Ying Yang 1, * , Cheng-Cheng Guo 1, * , Mei-Ling Deng 2 , Jian Wang 1 , Jing Wang 1 , Fu-hua Lin 1 , Ji Zhang 1 , Xiao-Bing Jiang 1 , Yong-Gao Mou 1 , Zhong-Ping Chen 1 1 State Key Laboratory of Oncology in South China, Department of Neurosurgery/Neuro-Oncology at The Cancer Center of Sun Yat-sen University, Collaborative Innovation Center of Oncology, Guangzhou 510060, China 2 State Key Laboratory of Oncology in South China, Department of Radiotherapy at The Cancer Center of Sun Yat-sen University, Collaborative Innovation Center of Oncology, Guangzhou 510060, China * These authors have contributed equally to this work Correspondence to: Zhong-Ping Chen, email: chenzhp@sysucc.org.cn Keywords: primary intracranial germ cell tumor, clinical diagnosis, diagnostic radiotherapy, diagnostic chemotherapy Received: January 27, 2016 Accepted: June 10, 2016 Published: June 22, 2016 ABSTRACT Background and Objective: Primary intracranial germ cell tumors (GCTs) are a class of heterogeneous tumors. Surgery can quickly relieve tumor compression and provide histological diagnosis. It is very difficult to treat some patients who are unable to be pathologically diagnosed. We aimed to analyze clinically diagnosed GCTs patients. Methods: Patients clinically diagnosed as primary intracranial GCTs were included in this study. Results: From 2002 to 2015, 42 patients clinically diagnosed with primary intracranial GCTs received chemotherapy and/or radiotherapy. Patients were assigned to diagnostic chemotherapy group (25 cases), diagnostic radiotherapy group (5 cases) and gamma knife radiosurgery group (12 cases) based on their initial anti-tumor therapy. The 5-year survival rates were 85.8%, 75.0% and 63.6%, respectively. There were no statistically significant difference ( p value = 0.44). Patients were assigned to the group (30 cases) with secretory tumors and the group (12 cases) with non-secretory tumors based on their levels of tumor makers. The 5- year survival rates were 80.7% and 68.6%, respectively. There were no statistically significant difference ( p value = 0.49).The major adverse reactions were grade III - IV bone marrow suppression with an incidence of 35.2% and grade II- III nausea/vomiting with an incidence of 45.8%. Conclusion: Surgical removal of tumor or biopsy is recognized as the most accurate method to determine the pathological property of tumor. But for some patients who can not be pathologically diagnosed, they can receive comprehensive treatments such as chemotherapy combined with radiotherapy, and some of them can still have good responses.

Primary central nervous system germ cell tumors (CNS-GCTs) in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS-GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years (range, 2.7 to 18.0 years) at diagnosis; 43 (75.4%) had non-germinomatous germ cell tumors (NGGCTs) and 14 (24.6%) had germinomas; 44 (77.2%) had localized disease and 13 (22.8%) had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB (cisplatin, etoposide, and bleomycin) protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months (range, 1.2 to 139 months). Fourteen patients died of relapse or disease progression. The 3-year event-free survival (EFS) and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs (P = 0.064). The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively (P = 0.042). Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS-GCTs.

Glioblastoma multiforme (GBM) is a lethal solid cancer in adults. Temozolomide (TMZ) is a first-line chemotherapeutic agent but the efficacy is limited by intrinsic and acquired resistance in GBM. Triptolide (TPL), a derivative from traditional Chinese medicine, demonstrated anti-tumor activity. In this study, we explored the interaction of TPL and TMZ in glioma-initiating cells (GICs) and the potential mechanism. A GIC line (GIC-1) was successfully established. Cell viability of GIC-1 after treatment was measured using a CCK-8 assay. The interaction between TPL and TMZ was calculated from Chou–Talalay equations and isobologram. Self-renewal was evaluated with tumor sphere formation assay. Apoptosis was assessed with flow cytometry and western blot. Luciferase assay was employed to measure NF-κB transcriptional activity. The expression of NF-κB downstream genes, NF-κB nuclear translocalization and phoshorylation of IκBα and p65 were evaluated using western blot. We found that GIC-1 cells were resistant to TMZ, with the expected IC50 of 705.7 μmol/L. Co-treatment with TPL yielded a more than three-fold dose reduction of TMZ. TPL significantly increased the percentage of apoptotic cells and suppressed the tumor sphere formation when combined with TMZ. Phosphorylation of IκBα and p65 coupled with NF-κB nuclear translocalization were notably inhibited after a combined treatment. Co-incubation synergistically repressed NF-κB transcriptional activity and downstream gene expression. TPL sensitizes GICs to TMZ by synergistically enhancing apoptosis, which is likely resulting from the augmented repression of NF-κB signaling. TPL is therefore a potential chemosensitizer in the treatment of GBM.

Objectives Malignant gliomas are common primary brain tumors with dismal prognosis. The blood–brain barrier and unacceptable systemic toxicity limit the employment of chemotherapeutic agents. BCNU-impregnated biodegradable polymers (Gliadel®) have been demonstrated to prolong the survival of patients with malignant gliomas. Until now, no biodegradable drug delivery system has been commercially available in China. In the present study, we evaluated the safety of implants with high-dose BCNU in Chinese patients with recurrent malignant gliomas. Patients and methods Adults with supratentorial recurrent malignant glioma were eligible. High-dose BCNU-loaded PLGA implants (20 mg of BCNU in each implant) were placed in the debulking cavity. The implants were investigated by a classical 3 + 3 design. Four levels of BCNU, up to 12 implants, were evaluated. Pharmacokinetic sampling was performed. The toxicity of the implants and the survival of patients were recorded. Results Fifteen recurrent patients were enrolled with 12 glioblastomas and 3 anaplastic gliomas. Among 15 patients, 3 were treated with 3 implants (60 mg of BCNU), 3 with 6 implants (120 mg), 3 with 9 implants (180 mg) and 6 with 12 implants (240 mg). No dose-limiting toxicity was observed in the cohort of patients. Subgaleal effusion was the most common adverse event, presenting in 7 patients (46.7%). The median overall survival (OS) was 322 days (95% CI, 173–471 days). The 6-month, 1-year and 2-year survival rates were 66.7%, 40% and 13.3%, respectively. Conclusions The high-dose BCNU-loaded PLGA implants were safe for Chinese patients with recurrent malignant gliomas and further investigation for efficacy is warranted.

O6-methylguanine DNA methyltransferase (MGMT) can remove DNA alkylation adducts, thereby repairing damaged DNA and contributing to the drug resistance of gliomas to alkylating agents. In addition, glioma stem-like cells (GSCs) have been demonstrated to be involved in the recurrence and treatment resistance of gliomas. In this study, we aimed to investigate MGMT expression and regulatory mechanisms in GSCs and the association of MGMT with temozolomide (TMZ) sensitivity. GSCs were enriched from one MGMT-positive cell line (SF-767) and 7 MGMT-negative cell lines (U251, SKMG-4, SKMG-1, SF295, U87, MGR1, and MGR2) through serum-free clone culture. GSCs from the U251G, SKMG-4G, SF295G, and SKMG-1G cell lines became MGMT-positive, but those from the U87G, MGR1G, and MGR2G cell lines remained MGMT-negative. However, all the GSCs and their parental glioma cell lines were positive for nuclear factor-κB (NF-κB). In addition, GSCs were more resistant to TMZ than their parental glioma cell lines (P < 0.05). However, there was no significant difference in the 50% inhibition concentration (IC50) of TMZ between MGMT-positive and MGMT-negative GSCs (P > 0.05). When we treated the MGMT-positive GSCs with TMZ plus MG-132 (an NF-κB inhibitor), the antitumor activity was significantly enhanced compared to that of GSCs treated with TMZ alone (P < 0.05). Furthermore, we found that MGMT expression decreased through the down-regulation of NF-κB expression by MG-132. Our results show that MG-132 may inhibit NF-κB expression and further decrease MGMT expression, resulting in a synergistic effect on MGMT-positive GSCs. These results indicate that enhanced MGMT expression contributes to TMZ resistance in MGMT-positive GSCs.

Zhen-ye Li,2 Xiang-heng Zhang,1 Yu Chen,1 Jian-gui Guo,1 Ke Sai,1 Qun-ying Yang,1 Zhong-ping Chen,1 Yong-gao Mou11State Key Laboratory of Oncology in South China, Department of Neurosurgery, Sun Yat-sen University Cancer Center, Guangzhou, 2Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of ChinaBackground: B7-H4, a member of the inhibitory B7 family, is shown to have a profound inhibitory effect on the proliferation, activation, cytokine secretion, and development of cytotoxicity of T cells and may be involved in immune evasion in cancer patients. Although B7-H4 expression has been detected in non-small cell lung cancer (NSCLC), there are no published reports on the expression of B7-H4 in brain metastases from NSCLC.Methods: We examined the expression of B7-H4 by immunohistochemistry in 49 cases of brain metastatic NSCLC, 18 cases of matched primary NSCLC, and 20 cases of NSCLC patients who had neither brain metastases nor other distant metastases.Results: B7-H4 was highly expressed in 20 (40.8%) out of 49 brain metastases and two (11.1%) out of 18 matched primary tumors. The expression of B7-H4 in brain metastases appeared to be significantly higher than their matched primary tumors (P = 0.016). We also found that patients with high B7-H4 expression in their primary NSCLC have a higher risk of developing brain metastases (P = 0.022). Univariate analyses showed that median overall survival was significantly shorter in patients with high B7-H4 expression in brain metastases (P = 0.002). Multivariate analyses showed that B7-H4 was a significant independent prognostic indicator (P = 0.003).Conclusion: NSCLC patients with high B7-H4 expression may benefit from aggressive treatment and close surveillance. Furthermore, our study suggests that B7-H4 may play an important role in the metastatic process of NSCLC and is promising to be a new immune checkpoint molecule for future antitumoral immunotherapy.Keywords: B7-H4, brain metastases, non-small cell lung cancer, immunotherapy

To explore the survival of newly diagnosed malignant gliomas patients on combined modality therapy of surgery, radiotherapy and chemotherapy.The data of 122 newly diagnosed malignant glioma patients on combined modality therapy at our center between 2000 and 2010 were retrospectively reviewed and analyzed. The median age was 40 years old (range: 5 - 75) and median Karnofsky performance status score (KPS) 80 (range: 60 - 100). Combined modality therapy consisted of surgery (maximal safety tumor resection), followed by fractionated focal irradiation for a total dose of 54 - 60 Gy and then 4 - 6 cycles of adjuvant chemotherapy including temozolomide or nitrosourea-based regimens or other ones without temozolomide and nitrosourea. The overall and progression-free survivals were analyzed by the Kaplan-Meier method and the influencing factors screened by Cox proportional hazard model.There were grade IV (n = 70) and grade III (n = 52). The median survival periods were 17.0 months for grade IV patients and 36.0 months for grade III ones. The 2, 3, 4 and 5-year survival rates were 32.0% vs 64.8%, 19.6% vs 47.8%, 11.8% vs 32.0% and 5.9% vs 25.4% (P0.01) for grades IV and III patients respectively. The median progression-free survivals were 9.0 vs 12.0 months and 1, 2 and 3-year progression-free survival rates 30.8% vs 50.0%, 12.3% vs 31.4% and 9.2% vs 17.7% (P0.01) respectively. Multivariate analysis revealed that histologic type was an independent prognostic factor.Combined modality therapy of surgery, adjuvant radiotherapy and chemotherapy may improve the survival of patients with malignant gliomas.

Background Maintenance chemotherapy is one strategy pursued in recent years with intent to break through the chemotherapy plateau for advanced non-small cell lung cancer (NSCLC). However, given the toxicity, platinum-based combinations are rarely given for this purpose. We carried out the present prospective study of triplet platinum-based combination sequential chemotherapy in advanced NSCLC to investigate if patients could tolerate and benefit from such intensive treatment. Methods From Dec 2003 to Dec 2007, 190 stage IIIB and IV NSCLC patients in Sun yat-sen University sequentially received the 3 platinum-based combination (TP- NP-GP) treatment (T: paclitaxol 175 mg/m2 d1; N: vinorelbine 25 mg/m2 d1 and 8; G: gemcitabine 1 g/m2 d1 and 8; P: cisplatin 20 mg/m2 d1-5; repeated every 3 weeks). Patients were followed up to at least 3 years to obtain survival data. Treatment toxicities and the quality of life (QOL) were assessed during the whole treatment. Results There were 187 patients evaluable. The TP, NP and GP response rates with sequential use were 42.8% (80/187), 41.1% (65/158) and 28.8% (21/73) respectively. Median survival time was 18.2 months and the 1, 2 and 3 year overall survival (OS) rates were 78.7%, 38.5% and 21.3%. Patients receiving>6 cycles of chemotherapy had significantly longer OS and TTP (MST 25.3 vs. 14.5 months, TTP 15.1 vs. 9.1 months). The QOL on the whole for the patients was improved after chemotherapy. Conclusions The sequential chemotherapy strategy with triplet platinum-based combination regimens can improve the survival outcome and the quality of life of advanced non-small cell lung cancer patients.

To investigate correlation between the expression of TGF-β1 and the amount of Treg cell in glioma, and evaluate their clinical values in predicting the prognosis of glioma.Double immunohistochemistry staining was used to detect the expression of TGF-β1, CD4 and Foxp3 in 135 specimens of human gliomas (WHO I 18, WHO II 45, WHO III 53, WHO IV 19) and 15 normal brain.OF the 135 specimans of glioma, 58 showed low TGF-β1 expression and 77 (57.03%) showed high TGF-β1 expression while ws not expression in normal brain tissue. Average Treg cell density in glioma was 2. 031/HP, but there was no expression of Treg in normal brain tissue. Expression of TGF-β1 was positively correlated with the mount of Treg in glioma tissues (r = 0.294, P0.01). Compared with the low grade, The levels of TGF-β1 and the amount of Treg cells with significant higher in high-grade glioma, however the mount of Treg had no correlations with Sex, KPS score. The Laplan-Meier analysis showed that there wer significant difference in overall survival (OS) between the TGF-β1 high-expression and low-expression group (P0.001). Cox multivariate analysis showed that TGF-β1 and Treg were not independent prognostic factors (P0.05).Intratumoral of TGF-β1 may relate to the infiltration of Treg cells in glioma tissues. The level of TGF-β1 was obviously increased in high grade. Glioma patients with TGF-β1 or Trg high expression have poorer prognosis, while TGF-β1 and Treg cannot serve as independent prognostic factors of glioma survival time.

The incidence of brain metastasis (BM) from colorectal carcinoma (CRC) is increasing. The objectives of the present study were to explore the clinical characteristics and potential prognostic factors in CRC patients with BM. Between April 1991 and December 2010, all CRC patients treated in the Sun Yat-sen University Cancer Center were retrospectively reviewed and 60 patients were identified to have BM (36 males and 24 females). The association between patients and their tumor characteristics, treatment modality, and survival were statistically analyzed. The median age at diagnosis of BM was 62.5 years. Fifty-three patients (88.3%) developed extracranial metastases at diagnosis of BM. The cause of death was systemic disease in 19 patients and neurological disease in 23 patients. Brain metastases were primarily treated with either whole brain radiation therapy (WBRT; 15 patients), stereotactic radiosurgery (SRS; nine patients), or surgical resection (seven patients). Ten patients received WBRT and SRS, and 19 patients (31.7%) were treated with steroids alone. The median survival after diagnosis of BM was 8 months (95% confidence interval = 4.2–11.8 months). Recursive partitioning analysis (RPA) class, the number of brain lesions, and treatment modality type were significantly associated with survival. Although BM from CRC is a late-stage phenomenon with an extremely poor prognosis, some subsets of patients would benefit from a multidisciplinary management strategy. A low RPA class and a limited number of brain lesions may predict increased survival after therapy for CRC patients with BM.

Nimotuzumab is a humanized monoclonal antibody targeted against epidermal growth factor receptor (EGFR). Recent clinical studies show that patients with malignant gliomas could benefit from nimotuzumab treatment. The aim of the present study was to evaluate the efficacy and side effects of nimotuzumab in combination with chemotherapy for patients with malignant gliomas.The patients received 200 mg of nimotuzumab infusion intravenously over 60 minutes once weekly for the first eight weeks and then once every two weeks until unacceptable toxicity or tumor progression occurred. Individualized chemotherapy was administered based on O(6)-methylguanine-DNA methyltransferase (MGMT) expression and previous chemotherapy responses in combined with nimotuzumab.Fourteen patients received a total of 122 times of nimotuzumab ranging from 2 to 20 (median 7.5 times). Combined chemotherapy regimens included: continuous 21-day temozolomide (10 cases), standard 5-day temozolomide (2 cases), teniposide plus cisplatin (1 case), and teniposide plus nimustine (1 case). Partial response (PR) and stable disease (SD) were found in 3 patients (21.4%)and 6 patients (42.9%), respectively. Disease control rate (PR + SD) was 64.3%. The median progression-free survival (PFS) was 4 months (95%CI: 0.7 - 7.3) and PFS at 6 months was 30.6%. The most common toxicities include grade I-II neutropenia (2 cases), thrombocytopenia (2 cases), lymphopenia (1 case), nausea and vomitting (3 case) and asymptomatic transaminase increase (1 case). One patient developed grade IV neutropenia and thrombocytopenia. One patient developed nimotuzumab-related acneiform rash.Nimotuzumab in combination with chemotherapy has moderate activity in patients with malignant gliomas and the toxicities are well tolerable, therefore, worth further investigation.

Background. Radiation-induced temporal lobe necrosis is a rare and serious late complication in irradiated patients with nasopharyngeal carcinoma (NPC). Treatment of radiation-induced temporal lobe necrosis with surgery has been seldom thoroughly investigated. Methods. We retrospectively analyzed the clinical data of 14 patients with radiation-induced temporal lobe necrosis treated with surgical intervention. Results. Radiation-induced temporal lobe necrosis pre- sented as obvious cystic formation or as heterogeneous enhanced nodule on MRI. Among 3 patients with 18 F-fluoro- deoxyglucose ( 18 F-FDG) PET-CT scan, increased uptake of 18 F-FDG was observed in 2 cases. Four patients were anes- thestized nasotracheally and 1 was through tracheostomy dur- ing surgery because of other radiation complications, including trismus and skull base osteoradionecrosis. The temporal approach was applied in all cases, with the removal of bone flap in 11 patients. During follow-up, 1 patient died of exhaustion. Conclusions. Surgery benefits selected patients with NPC with radiation-induced temporal lobe necrosis. The goals of surgery are to relieve the increased intracranial pressure and to establish the accurate diagnosis. V

Primary central nervous system (CNS) germ cell tumors (GCTs) are rare malignant neoplasms with various histological types. Excluding pure germinoma and mature teratoma, other types carry a poor prognosis. Previous investigations focused on combined modality treatment including chemotherapy to improve survival. This study was to analyze the efficacy and toxicity of chemotherapy combined with surgery and/or radiotherapy on CNS GCTs.A total of 23 patients with CNS GCTs were treated in Cancer Center of Sun Yat-sen University from May 2002 to Jun. 2006. The median age at diagnosis was 16 years. Alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (beta-HCG) levels were elevated in 19 patients (82.6%). All patients were treated with chemotherapy of PEB regimen combined with surgery and/or radiotherapy. PEB regimen was administered every 3 weeks with 20 mg/m(2) cisplatin (DDP) at Days 1-5 or 80-100 mg/m(2) at Day 1, 60-100 mg/m(2) etoposide (VP-16) or teniposide (VM-26) at Days 1-5, 10 mg/m(2) bleomycin (BLM) at Days 1 and 5.Of the 23 patients, 17 newly diagnosed patients received induction chemotherapy followed by radiotherapy or surgery/radiotherapy followed by adjuvant chemotherapy; 6 recurrent patients received salvage chemotherapy, of which 3 patients with disseminated tumor received salvage chemotherapy followed by craniospinal irradiation. The 23 patients completed a total of 61 cycles of PEB regimen with a median of 3 cycles. Chemotherapy alone gained a response rate of 87.0% and a complete remission rate of 30.4%. Craniospinal irradiation was performed in 14 patients and focal irradiation in 8 patients. One patient did not receive irradiation. Incomplete tumor resection or biopsy was performed in 13 patients. Fourteen patients (60.9%) were alive without evidence of diseases after combined modality treatment. With a median follow-up of 24 months, the 2-year survival rate was 67.4%. Main adverse events were late irradiation injury including aplastic anemia and hypothalamus syndrome (1 case), irradiation encephalopathy (1 case), and hypopituitarism (2 cases).The combined modality treatment including PEB regimen is highly effective in treating CNS GCTs patients, especially in the patients with elevated tumor markers. However, the long-term toxicities which related with craniospinal irradiation should not be ignored.

To investigate the therapeutic effect, long term survival and side effect on NSCLC patients treated with nadaplatin combined with paclitaxol and cisplatin combined with paclitaxol.NSCLC patients with stage IIIB or IV were randomized into two groups in this prospective clinical study. TN group: nadaplatin 30 mg/m2 dl-3, paclitaxol 175 mg/m2 dl, repeated every 4 weeks. TP group: DDP 30 mg/m2 dl-3, paclitaxol 175 mg/m2 dl, repeated every 4 weeks.Sixty patients were enrolled and 57 were evaluable with 30 in TN group and 27 in TP group. The overall response rate were 43.3% vs. 48.1% (P = 0.716), and the disease control rate were 86.7% vs. 88.8% in TN and TP group (P = 0.799), respectively. The median survival time was 14.3 vs. 13.0 months, and the 1- and 2-year survival rate was 62.5% vs. 59.1%, 0% vs. 5.8% in TN and TP group (P = 0.839), respectively. The rates of neutropenia and thrombocytopenia were similar in TN and TP groups whereas more patients in TP group than in TN group suffered from anemia (38.5% vs. 17.5%, P = 0.001), nausea and vomiting (82.6% vs. 35.6%, P = 0.000), fatigue (35.9% vs. 14.1%, P = 0.000) and peripheral neurotoxicity (50.0% vs. 21.9%, calculated by case, P = 0.023).Nadaplatin combined with paclitaxol is an effective treatment regimen for NSCLC patients. When compared with similar regimen with cisplatin, the response rate and survival were similar; however, nadaplatin regimen shows some superiority as regards some treatment side effect.

To analyse the clinical features of patients with B cell lymphoblastic lymphoma(BCLL) and the outcomes after modified BFM-90 protocol therapy.The clinical features of 14 patients with BCLL were analysed, and compared with that of T cell lymphoblastic lymphoma in the same period. The efficacy and toxicity of modified BFM-90 protocol were analysed.The 14 patients were aged 3 to 18 and diagnosed as BCLL by morphology and immunohistology. One case was in stage I , 2 stage III and 11 stage IV. Most common involved sites were lymph nodes (70% ), skin (50% ) and bone marrow (64% ). One patient received CHOP + HD-MTX, and 13 received modified BFM-90 protocol chemotherapy. Twelve patients (92.3%) achieved complete remission( CR) , 1 patient(7. 7% ) partial remission( PR). The median follow-up duration was 19. 5 months (2 to 44 months). At present 13 patients are alive except one PR patient who gave up treatment and died of disease. The major toxicity of the protocol was myelosuppression, but could be tolerated.The most common involvement sites of BCLL were lymph nodes, skin and bone marrow. The effectiveness is improved as treated with modified BFM-90 protocol.

High-grade gliomas (HGG) are extremely aggressive lesions and represent the most common primary malignant brain tumors without an effective therapy. Standard treatment for HGG usually includes surgery followed by radiotherapy and chemotherapy. However, the prognosis of patients with HGG remains dismal. We review the humanized epidermal growth factor receptor (EGFR) and the major EGFR target drugs in HGG treatments, focusing on the EGFR antibody nimotuzumab as a new therapeutic strategy in HGG. We found that nimotuzumab with or without radiotherapy, chemotherapy in newly diagnosed or recurrent HGG, such as glioblastoma multiforme (GBM), anaplastic astrocytomas (AA), and diffuse intrinsic pontine glioma (DIPG), might improve the response rate or the survival time. In conclusion, nimotuzumab is a very well-tolerated drug with acceptable toxicity, and it may have promising value in the combination treatment. As a result, multiple center randomized controlled Phase III clinical trials need to be conducted to confirm the efficacy and toxicity for nimotuzumab in HGG.

The overall survival rate of children and adolescents with germ cell tumor is more than 75% after adopting combined therapy. However, the prognosis varies with stage, pathologic type, and primary tumor site. This study was to analyze the clinical characteristics and treatment outcome of children and adolescents with germ cell tumor, and to investigate the prognostic factors and therapeutic strategy.Clinical characteristics, treatment outcome, and prognostic factors of 44 children and adolescents with germ cell tumor, treated in Cancer Center of Sun Yat-sen University from Jan. 1997 to Dec. 2005, were analyzed. Survival rate was calculated by Kaplan-Meier method.Of the 44 patients, 25 received adjuvant chemotherapy after operation; 1 received operation alone; 18 received induction chemotherapy. Of the 18 patients, 7 received tumor resection after chemotherapy; 2 patients with primary mediastinal chorioepithelioma with multiple metastases received radiotherapy on residual disease after chemotherapy; 1 patient with postoperative abdominal metastasis and 1 with postoperative lung metastasis achieved complete remission after chemotherapy; 1 patient with mediastinal sinus tumor achieved partial remission after chemotherapy; 6 had poor response to chemotherapy and died of disease progression. Chemotherapy-treated patients received platinum-containing regimens for 2-7 cycles. The median follow-up was 32 months. The overall 3-year survival rate was 84.8%. The 3-year survival rate was 100% for stage I-II patients, 83.3% for stage III patients, 65.6% for stage IV patients, and 66.7% for relapsed patients. For previously untreated patients, the 3-year survival rate was 96.0% for gonadal germ cell tumor patients and 61.0% for extragonadal germ cell tumor patients.Surgery combined with platinum-containing chemotherapy can improve efficacy and survival of children and adolescents with germ cell tumor. For the patients with stage IV, relapsed, and metastatic tumors, novel therapeutic regimens with increased dose intensity need further investigation.

Pericardiocentesis and intrapericardial infusion of chemotherapeutic drugs is the main treatment of malignant pericardial effusion. This study was to observe the efficacy and side effect of intrapericardial infusion of etoposide (VP-16) and cisplatin (DDP) on malignant pericardial effusion of non-small cell lung cancer (NSCLC).Twenty-eight NSCLC patients with malignant pericardial effusion were treated with pericardiocentesis and intrapericardial infusion of VP-16 (200-300 mg) and DDP (80-100 mg). Intravenous chemotherapy were given 2 weeks after the pericardiocentesis.The overall response(OR) rate of the first-time treatment of the 28 patients was 85.7%, with complete response (CR) rate of 71.4%; the OR rate of the second-time treatment was 100%. Only 4 patients needed second-time pericardiocentesis. Sixteen patients developed gastrointestinal tract reaction (mainly grade I-II), 12 developed myelosuppression (mainly grade I), and 1 showed mild abnormal of transaminase. For the 24 naïve patients, the overall survival time was 14 months for stage IIIB and 10.9 months for stage IV; whereas for the 4 patients with relapsed disease, the overall survival time was 6 months (from the time of relapse).Intrapericardial infusion of VP-16 and DDP is an effective treatment for malignant pericardial effusion of NSCLC.

Background Although the incidence of glioma is relatively low, it is the most malignant tumor of the central nervous system. The prognosis of high-grade glioma patient is very poor due to the difficulties in complete resection and resistance to radio-/chemotherapy. Therefore, it is worth investigating the molecular mechanisms involved in glioma drug resistance. MicroRNAs have been found to play important roles in tumor progression and drug resistance. Our previous work showed that miR-181b is involved in the regulation of temozolomide resistance. In the current study, we investigated whether miR-181b also plays a role in antagonizing the effect of teniposide. Methods MiR-181b expression was measured in 90 glioma patient tissues and its relationship to prognosis of these patients was analyzed. Cell sensitivity to teniposide was tested in 48 primary cultured glioma samples. Then miR-181b stably overexpressed U87 cells were generated. The candidate genes of miR-181b from our previous study were reanalyzed, and the interaction between miR-181b and target gene MDM2 was confirmed by dual luciferase assay. Cell sensitivity to teniposide was detected on miR-181b over expressed and MDM2 down regulated cells. Results Our data confirmed the low expression levels of miR-181b in high-grade glioma tissues, which is related to teniposide resistance in primary cultured glioma cells. Overexpression of miR-181b increased glioma cell sensitivity to teniposide. Through target gene prediction, we found that MDM2 is a candidate target of miR-181b. MDM2 knockdown mimicked the sensitization effect of miR-181b. Further study revealed that miR-181b binds to the 3’-UTR region of MDM2 leading to the decrease in MDM2 levels and subsequent increase in teniposide sensitivity. Partial restoration of MDM2 attenuated the sensitivity enhancement by miR-181b. Conclusions MiR-181b is an important positive regulator on glioma cell sensitivity to teniposide. It confers glioma cell sensitivity to teniposide through binding to the 3’-UTR region of MDM2 leading to its reduced expression. Our findings not only reveal the novel mechanism involved in teniposide resistance, but also shed light on the optimization of glioma treatment in the future.