Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumours stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma — the most frequent primary brain tumour — and can transiently normalize tumour vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.

Angiogenesis in brain tumours

Summary Background We aimed to examine whether stereotactic radiosurgery without whole-brain radiotherapy (WBRT) as the initial treatment for patients with five to ten brain metastases is non-inferior to that for patients with two to four brain metastases in terms of overall survival. Methods This prospective observational study enrolled patients with one to ten newly diagnosed brain metastases (largest tumour Findings We enrolled 1194 eligible patients between March 1, 2009, and Feb 15, 2012. Median overall survival after stereotactic radiosurgery was 13·9 months [95% CI 12·0–15·6] in the 455 patients with one tumour, 10·8 months [9·4–12·4] in the 531 patients with two to four tumours, and 10·8 months [9·1–12·7] in the 208 patients with five to ten tumours. Overall survival did not differ between the patients with two to four tumours and those with five to ten (HR 0·97, 95% CI 0·81–1·18 [less than non-inferiority margin], p=0·78; p non-inferiority vs 18 [9%] with five to ten; p=0·89). Four patients died, mainly of complications relating to stereotactic radiosurgery (two with one tumour and one each in the other two groups). Interpretation Our results suggest that stereotactic radiosurgery without WBRT in patients with five to ten brain metastases is non-inferior to that in patients with two to four brain metastases. Considering the minimal invasiveness of stereotactic radiosurgery and the fewer side-effects than with WBRT, stereotactic radiosurgery might be a suitable alternative for patients with up to ten brain metastases. Funding Japan Brain Foundation.

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Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study

Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that "glioblastoma" represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.

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Emerging insights into the molecular and cellular basis of glioblastoma

Pathophysiology of Parkinsonism

Objective Atypical meningioma (AM) patients often undergo gross total resection (GTR) at the time of presentation, but subsequent prognosis and optimal management remain unclear. We sought to define the long-term recurrence rate of AMs after GTR, along with factors predicting recurrence, including postoperative radiation. Methods We performed a retrospective review of 108 AMs after GTR at our institution from 1993 to 2004. Recurrence risk factors were analyzed using multivariate Cox regression. Results There were 600 patient-years of imaging follow-up on 48 men and 60 women. Of 108 tumors, 30 (28%) recurred 3 to 144 months after GTR (mean, 36 months). Actuarial tumor recurrence rates were 7% (1 year), 41% (5 years), and 48% (10 years). Of 108 patients, 8 received postoperative radiation without recurrence (P = 0.1). Multivariate analysis including age, sex, postoperative radiation, tumor location, MIB-1 labeling index, and 6 atypical-defining histological features identified recurrence-predicting factors: older age (hazard ratio, 1.6/decade; P = 0.01), sheeting (hazard ratio, 2.2; P = 0.025), and prominent nucleoli (hazard ratio, 2.1; P = 0.034). Recursive partitioning identified a subset, men with mitoses and prominent nucleoli, with 70% recurrence (n = 14). All patients with recurrences received radiation, and 22 of 30 patients underwent craniotomies (average, 2.7 craniotomies per patient with recurrence; range, 1-7 craniotomies). Only 1 of 22 re-resected meningiomas underwent malignant transformation. Of 30 patients with recurrence, 10 experienced tumor-induced mortality an average of 7 years after recurrence (range, 1-14 years). Conclusion After GTR without postoperative radiation, AMs have a high recurrence rate. Most recurrences occurred within 5 years after resection. Recurrences caused numerous reoperations per patient and shortened survival. Our finding suggesting lower recurrence rates in patients undergoing immediate postoperative radiation should be investigated in larger, prospective series.

Long-term recurrence rates of atypical meningiomas after gross total resection with or without postoperative adjuvant radiation.

BACKGROUD:

The authors investigated whether expression of c-Met protein in glioblastomas is associated with overall survival and biologic features representing tumor invasiveness in patients with glioblastomas.



METHODS:

Paraffin-embedded specimens of glioblastomas from 62 patients treated in a single institution were assessed by immunohistochemical (IHC) analysis of c-Met expression. On the basis of the clinical data for these patients, the association between c-Met expression and clinicobiologic features representing tumor invasiveness was analyzed.



RESULTS:

c-Met overexpression was detected in 29.0% (18 of 62) of glioblastomas. In patients with c-Met overexpression, the median survival was 11.7 months (95% confidence interval [95% CI], 9.9 months-13.5 months), compared with a median survival of 14.3 months (95% CI, 7.6 months-21.0 months) for patients whose tumors had no or little expression of c-Met (P = .031). On the radiographic analysis, 9 of 18 patients (50%) with tumors overexpressing c-Met demonstrated invasive and multifocal lesions on the initial magnetic resonance images, whereas only 9 of 44 patients (20.5%) with tumors that expressed no or little c-Met demonstrated these features (P = .030). Using immunohistochemistry, we also found a significant association between c-Met expression and matrix metalloproteinase-2,-9 (P = .020 and P = .013). Furthermore, Myc overexpression was found to be closely correlated with c-Met overexpression on IHC analysis (P = .004).



CONCLUSIONS:

The authors suggest that c-Met overexpression is associated with shorter survival time and poor treatment response in glioblastomas, the mechanism for which is elevated tumor invasiveness on the molecular and clinical phenotypes. This implies that more effective therapeutic strategies targeting c-Met receptors may have important clinical implication. Cancer 2009. © 2008 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.23972

Prognostic significance of c-Met expression in glioblastomas.

BACKGROUND

The objective of this prospective cohort study was to determine the efficacy of stereotactic radiosurgery (SRS) as a salvage treatment in patients with recurrent malignant gliomas.



METHODS

Between January 2000 and December 2006, 114 consecutive patients were treated with SRS as a salvage treatment for recurrent malignant gliomas at a single institution. Clinical outcome and its prognostic factors were analyzed and compared with the historical control group who were treated at the same institution between 1995 and 1999.



RESULTS

The median overall survival from the time of diagnosis was 37.5 months (95% confidence interval [95% CI], 11.7–63.2 months) for patients with grade 3 gliomas (according to World Health Organization criteria) and was 23months (95% CI, 16.2–29.3 months) for patients with glioblastomas. The median progression-free survival after SRS was 8.6 months (95% CI, 1.1–16.2 months) for patients with grade 3 gliomas and 4.6 months for patients with glioblastomas (95% CI, 4.0–5.2 months). With regard to treatment-related complications, radiation-induced necrosis was observed in 22 of 114 patients (24.4%). Compared with this historic control group, SRS significantly prolonged survival as a salvage treatment in patients with recurrent glioblastomas (23 months vs 12 months; P < .0001), but it was not found to provide a significant surgical benefit in patients with recurrent grade 3 gliomas (37.5 months vs 26 months; P = .789). On univariate analysis of prognostic factors, tumor volume (<10 mL) and low histologic grade were found to significantly influence better survival (P = .009 and P = .041, respectively).



CONCLUSIONS

SRS is a safe and effective modality in selected patients with recurrent small-sized glioblastomas. However, the efficacy of SRS for recurrent grade 3 gliomas needs to be further evaluated in well-designed clinical studies. Cancer 2008. © 2008 American Cancer Society.

Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas

BACKGROUND.

The objective of this retrospective cohort study was to define the efficacy and safety of fractionated radiotherapy (FRT) and stereotactic radiosurgery (SRS) for the treatment of patients with pituitary adenoma.



METHODS.

Between January 1995 and April 2006, 125 consecutive patients with pituitary adenomas (54 hormone-secreting adenomas and 71 nonsecretory adenomas) received FRT or underwent SRS. Sixty-four patients received FRT, for which the mean total dose was 50.4 grays (Gy) (range, 48–54 Gy), and 61 patients underwent gamma-knife SRS with mean marginal dose of 25.1 Gy (range, 9–30 Gy).



RESULTS.

After mean follow up of 36.7 months, the tumor volume was increased in only 4 patients (3.2%). The overall actuarial progression-free survival rate was 99% at 2 years and 97% at 4 years. No difference was observed between the FRT group and the SRS group in the control of tumor growth. Based on the endocrinologic results in the patients who had secretory adenomas, the overall hormone complete remission rate was 26.2% at 2 years and 76.3% at 4 years. The median time to complete remission was 26 months in the SRS group and 63 months in the FRT group (P = .0068). Hypopituitarism developed as a delayed complication in 11.5% of patients at a median of 84 months.



CONCLUSIONS.

Both FRT and SRS were efficient treatment modalities for the control of tumor growth in patients with pituitary adenomas. The current results indicated that single-dose radiosurgery more promptly produces an effect on the hypersecretion of pituitary hormones and may be recommended over FRT for suitable patients. Cancer 2007. © 2007 American Cancer Society.

The efficacy of fractionated radiotherapy and stereotactic radiosurgery for pituitary adenomas: long-term results of 125 consecutive patients treated in a single institution.

Jong Hyun Kim

Papers

Prognostic significance of c-Met expression in glioblastomas.

Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas

The efficacy of fractionated radiotherapy and stereotactic radiosurgery for pituitary adenomas: long-term results of 125 consecutive patients treated in a single institution.

Treatment of atypical meningioma.

Relationship between malignant subtypes of meningioma and clinical outcome.