Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults

QUESTION: What is the role of temozolomide in the management of adult patients (aged 65 and under) with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level I: Concurrent and post-irradiation Temozolomide (TMZ) in combination with radiotherapy and post-radiotherapy as described by Stupp et al. is recommended to improve both PFS and OS in adult patients with newly diagnosed GBM. There is no evidence that alterations in the dosing regimen have additional beneficial effect. QUESTION: Is there benefit to adjuvant temozolomide treatment in elderly patients (\u3e 65 years old?). TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level III: Adjuvant TMZ treatment is suggested as a treatment option to improve PFS and OS in adult patients (over 70 years of age) with newly diagnosed GBM. QUESTION: What is the role of local regional chemotherapy with BCNU biodegradable polymeric wafers in adult patients with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level III: There is insufficient evidence for the use of BCNU wafers following resection in patients with newly diagnosed glioblastoma who undergo the Stupp protocol after surgery. Further studies of higher quality are suggested to understand the role of BCNU wafer and other locoregional therapy in the setting of Stupp Protocol. QUESTION: What is the role of bevacizumab in the adult patient with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level I: Bevacizumab in general is not recommended in the initial treatment of adult patients with newly diagnosed GBM. It continues to be strongly recommended that patients with newly diagnosed GBM be enrolled in properly designed clinical trials to assess the benefit of novel chemotherapeutic agents compared to standard therapy

Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas

Local recurrence of glioblastomas is a major cause of patient mortality after definitive treatment. This review discusses the roles of the chemokine stromal cell-derived factor-1 and its receptor CXC chemokine receptor 4 (CXCR4) in affecting the sensitivity of glioblastomas to irradiation. Blocking these molecules prevents or delays tumour recurrence after irradiation by inhibiting the recruitment of CD11b+ monocytes/macrophages that participate in revascularising the tumour. We review the literature pertaining to the mechanism by which revascularisation occurs following tumour irradiation using experimental models. Areas of interest and debate in the literature include the process by which endothelial cells die after irradiation and the identity/origin of the cells that reconstitute the tumour blood vessels after injury. Understanding the processes that mediate tumour revascularisation will guide the improvement of clinical strategies for preventing recurrence of glioblastoma after irradiation

IL-24 Inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis

© 2015 Panneerselvam et al. Background The stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling pathway plays a key role in lung cancer metastasis and is molecular target for therapy. In the present study we investigated whether interleukin (IL)-24 can inhibit the SDF-1/CXCR4 axis and suppress lung cancer cell migration and invasion in vitro. Further, the efficacy of IL-24 in combination with CXCR4 antagonists was investigated. Methods Human H1299, A549, H460 and HCC827 lung cancer cell lines were used in the present study. The H1299 lung cancer cell line was stably transfected with doxycycline-inducible plasmid expression vector carrying the human IL-24 cDNA and used in the present study to determine the inhibitory effects of IL-24 on SDF-1/CXCR4 axis. H1299 and A549 cell lines w ere used in transient transfection studies. The inhibitory effects of IL-24 on SDF1/CXCR4 and its downstream targets were analyzed by quantitative RT-PCR, western blot, luciferase reporter assay, flow cytometry and immunocytochemistry. Functional studies included cell migration and invasion assays. Principal Findings Endogenous CXCR4 protein expression levels varied among the four human lung cancer cell lines. Doxycycline-induced IL-24 expression in the H1299-IL24 cell line resulted in reduced CXCR4 mRNA and protein expression. IL-24 post-transcriptionally regulated CXCR4 mRNA expression by decreasing the half-life of CXCR4 mRNA ( > 40%). Functional studies showed IL-24 inhibited tumor cell migration and invasion concomitant with reduction in CXCR4 and its downstream targets (pAKTS 473 , pmTORS 2448 , pPRAS40 T246 and HIF-1α). Additionally, IL-24 inhibited tumor cell migration both in the presence and absence of the CXCR4 agonist, SDF-1. Finally, IL-24 when combined with CXCR4 inhibitors (AMD3100, SJA5) or with CXCR4 siRNA demonstrated enhanced inhibitory activity on tumor cell migration. Conclusions IL-24 disrupts the SDF-1/CXCR4 signaling pathway and inhibits lung tumor cell migration and invasion. Additionally, IL-24, when combined with CXCR4 inhibitors exhibited enhanced anti-metastatic activity and is an attractive therapeutic strategy for lung metastasi

Management of patients with recurrence of diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline

TARGET POPULATION: These recommendations apply to adult patients with recurrent low-grade glioma (LGG) with initial pathologic diagnosis of a WHO grade II infiltrative glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). QUESTION: Do pathologic and molecular characteristics predict outcome/malignant transformation at recurrence? RECOMMENDATIONS: IDH STATUS AND RECURRENCE: (Level III) IDH mutation status should be determined as LGGs with IDH mutations have a shortened time to recurrence. It is unclear whether knowledge of IDH mutation status provides benefit in predicting time to progression or overall survival. TP53 STATUS AND RECURRENCE: (Level III) TP53 mutations occur early in LGG pathogenesis, remain stable, and are not recommended as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis. MGMT STATUS AND RECURRENCE: (Level III) Assessment of MGMT status is recommended as an adjunct to assessing prognosis as LGGs with MGMT promoter methylation are associated with shorter PFS (in the absence of TMZ) and longer post-recurrence survival (in the presence of TMZ), ultimately producing similar overall survival to LGGs without MGMT methylation. The available retrospective reports are conflicting and comparisons between reports are limited CDK2NA STATUS AND RECURRENCE: (Level III) Assessment of CDK2NA status is recommended when possible as the loss of expression of the CDK2NA via either methylation or loss of chromosome 9p is associated with malignant progression of LGGs. PROLIFERATIVE INDEX AND RECURRENCE: (Level III) It is recommended that proliferative indices (MIB-1 or BUdR) be measured in LGGs as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival. 1P/19Q STATUS AND RECURRENCE: There is insufficient evidence to make any recommendations. QUESTION: What role does chemotherapy have in LGG recurrence? RECOMMENDATIONS: TEMOZOLOMIDE AND RECURRENCE: (Level III) Temozolomide is recommended in the therapy of recurrent LGG as it may improve clinical symptoms. Oligodendrogliomas and tumors with 1p/19q co-deletion may derive the most benefit. PCV AND RECURRENCE: (Level III) PCV is recommended in the therapy of LGG at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas. CARBOPLATIN AND RECURRENCE : (Level III) Carboplatin is not recommended as there is no significant benefit from carboplatin as single agent therapy for recurrent LGGs. OTHER TREATMENTS (NITROSUREAS, HYDROXYUREA/IMANITIB, IRINOTECAN, PACLITAXEL) AND RECURRENCE: There is insufficient evidence to make any recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess these chemotherapeutic agents. QUESTION: What role does radiation have in LGG recurrence? RECOMMENDATIONS: RADIATION AT RECURRENCE WITH NO PREVIOUS IRRADIATION: (Level III) Radiation is recommended at recurrence if there was no previous radiation treatment. RE-IRRADIATION AT RECURRENCE: (Level III) It is recommended that re-irradiation be considered in the setting of LGG recurrence as it may provide benefit in disease control. SURGERY AT RECURRENCE: There is insufficient evidence to make any specific recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess the role of surgery at recurrence

Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline

PURPOSE To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. METHODS ASCO convened an Expert Panel and conducted a systematic review of the literature. RESULTS Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. RECOMMENDATIONS Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status # 50 or Karnofsky Performance Status, 70 with no systemic therapy options do not derive benefit from radiation therapy. Additional information is available at www.asco.org/neurooncology-guidelines

The Mobilization and Recruitment of C-Kit+ Cells Contribute to Wound Healing after Surgery

Delayed wound healing is a serious clinical problem in patients after surgery. A recent study has demonstrated that bone marrow-derived c-kit-positive (c-kit+) cells play important roles in repairing and regenerating various tissues and organs. To examine the hypothesis that surgical injury induces the mobilization and recruitment of c-kit+ cells to accelerate wound healing. Mice were subjected to a left pneumonectomy. The mobilization of c-kit+ cells was monitored after surgery. Using green fluorescent protein (GFP+) bone marrow-transplanted chimera mice, we investigated further whether the mobilized c-kit+ cells were recruited to effect wound healing in a skin puncture model. The group with left pneumonectomies increased the c-kit+ and CD34+ stem cells in peripheral blood 24 h after surgery. At 3 days after surgery, the skin wound size was observed to be significantly smaller, and the number of bone marrow-derived GFP+ cells and GFP+/c-kit+ cells in the wound tissue was significantly greater in mice that had received pneumonectomies, as compared with those that had received a sham operation. Furthermore, some of these GFP+ cells were positively expressed specific markers of macrophages (F4/80), endothelial cells (CD31), and myofibroblasts (αSMA). The administration of AMD3100, an antagonist of a stromal-cell derived factor (SDF)-1/CXCR4 signaling pathway, reduced the number of GFP+ cells in wound tissue and completely negated the accelerated wound healing. Surgical injury induces the mobilization and recruitment of c-kit+ cells to contribute to wound healing. Regulating c-kit+ cells may provide a new approach that accelerates wound healing after surgery