Stereotactic Radiosurgery for Benign Cavernous Sinus Meningiomas: A Multicentre Study and Review of the Literature.

Cavernous sinus meningiomas (CSMs) remain a surgical challenge due to the intimate involvement of their contained nerves and blood vessels. Stereotactic radiosurgery (SRS) is a safe and effective minimally invasive alternative for the treatment of small- to medium-sized CSMs. Objective: To assess the medium- to long-term outcomes of SRS for CSMs with respect to tumour growth, prevention of further neurological deterioration and improvement of existing neurological deficits. This multicentric study included data from 15 European institutions. We performed a retrospective observational analysis of 1222 consecutive patients harbouring 1272 benign CSMs. All were treated with Gamma Knife stereotactic radiosurgery (SRS). Clinical and imaging data were retrieved from each centre and entered into a common database. All tumours with imaging follow-up of less than 24 months were excluded. Detailed results from 945 meningiomas (86%) were then analysed. Clinical neurological outcomes were available for 1042 patients (85%). Median imaging follow-up was 67 months (mean 73.4, range 24-233). Median tumour volume was 6.2 cc (+/-7), and the median marginal dose was 14 Gy (+/-3). The post-treatment tumour volume decreased in 549 (58.1%), remained stable in 336 (35.6%) and increased in only 60 lesions (6.3%), yielding a local tumour control rate of 93.7%. Only 27 (2.8%) of the 60 enlarging tumours required further treatment. Five- and ten-year actuarial progression-free survival (PFS) rates were 96.7% and 90.1%, respectively. Tumour control rates were higher for women than men (p = 0.0031), and also for solitary sporadic meningiomas (p = 0.0201). There was no statistically significant difference in outcome for imaging-defined meningiomas when compared with histologically proven WHO Grade-I meningiomas (p = 0.1212). Median clinical follow up was 61 months (mean 64, range 6-233). Permanent morbidity occurred in 5.9% of cases at last follow-up. Stereotactic radiosurgery is a safe and effective method for treating benign CSM in the medium term to long term.

Ten-year follow-up after Gamma Knife radiosurgery of meningioma and review of the literature.

OBJECTIVES: With regard to the generally slow growth of meningioma, it is essential to analyse clinical treatment results in a long-term perspective. The purpose of the present analysis is to provide clinical data after Gamma Knife radiosurgery of meningioma in a 10-year perspective together with a review of the current literature. METHODS: The current study is a retrospective analysis of 86 consecutive Swedish patients with meningiomas treated using Gamma Knife radiosurgery at the Karolinska Hospital Stockholm between March 1991 and May 2001. A total of 130 tumours were treated in 115 treatment sessions. The median radiological follow-up was 10 years (1.8-16.5 years), and the median clinical follow-up was 9.4 years (2.1-17.4 years). RESULTS: After a median follow-up period of 10 years, local tumour control was achieved in 87.8% of meningiomas (108/123 tumours). The median latency between initial treatment and local (in-field) recurrence (n = 15) was 5.8 years (1.9-11.5). Recurrences adjacent but outside the initial radiation field occurred in 15.1% of patients (13/86) at a median of 7.5 years (1.3-15.7). New meningiomas were seen in 10.5% after a median of 5.4 years (0.9-10.8). In 72% of patients, no further treatment was required, 17.4% (15/86) underwent a second Gamma Knife treatment, 4.7% (4/86) required later open surgery and 5.8% (5/86) required both secondary treatments. Eighty-six percent of patients were neurologically unchanged or improved. A significantly lower rate of local (in-field) recurrences was seen in meningiomas treated with a prescription dose of > 13.4 Gy (7.1% vs. 24%, p = 0.02). CONCLUSIONS: The current retrospective analysis provides a 10-year follow-up and comprises one of the longest available follow-up studies of radiosurgically treated meningiomas. The current series documents a persistent high local tumour control after Gamma Knife treatment, while providing an estimation of a necessary minimum dose for long-term tumour control in meningiomas. The study confirms the validity of previous short-term data in a long-term perspective.

A translational concept of immuno-radiobiology.

BACKGROUND: Traditional concepts of radiobiology model the direct radiation-induced cellular cytotoxicity but are not focused on late and sustained effects of radiation. Recent experimental data show the close involvement of immunological processes. METHODS: Based on systematic PubMed searches, experimental data on immunological radiation effects are summarized and analyzed in a non-quantitative descriptive manner to provide a translational perspective on the immuno-modulatory impact of radiation in cancer. RESULTS: Novel experimental findings document that sustained radiation effects are ultimately mediated through systemic factors such as cytotoxic CD8+ T cells and involve a local immuno-stimulation. Increased tumor infiltration of CD8+ T cell is a prerequisite for long-term radiation effects. CD8+ T cell depletion induces radio-resistance in experimental tumors. The proposed sequence of events involves radiation-damaged cells that release HMGB1, which activates macrophages via TLR4 to a local immuno-stimulation via TNF, which contributes to maturation of DCs. The mature DCs migrate to lymph nodes where they trigger effective CD8+ T cell responses. Radiation effects are boosted, when the physiological self-terminating negative feedback of immune reactions is antagonised via blocking of TGF-ß or via checkpoint inhibition with involvement of CD8+ T cells as common denominator. CONCLUSION: The concept of immuno-radiobiology emphasizes the necessity for a functional integrity of APCs and T cells for the long-term effects of radiotherapy. Local irradiation at higher doses induces tumor infiltration of CD8+ T cells, which can be boosted by immunotherapy. More systematic research is warranted to better understand the immunological effects of escalating radiation doses.

Cytokine patterns in cancer patients: A review of the correlation between interleukin 6 and prognosis.

OBJECTIVE: In tumor patients, IL-6 appears to be one component of a consistent cancer-associated cytokine network resulting in both a systemic immune stimulation and a microenvironment of cancer-induced immune suppression that ultimately protects the cancer cells. IL-6 has been associated with prognosis in cancer patients, but so far a systemical analysis has not been carried out. METHODS: The present meta-analysis studies the relation between IL-6 serum levels and the prognosis of cancer patients in the available clinical literature of 100 articles published between 1993 and 2013 comprising 11,583 patients. RESULTS: The IL-6 serum level was described as significantly correlating with survival in 82/101 series comprising 85.6% of patients (9917/11,583) with 23 different cancer types. A total of 64 studies dichotomized patient cohorts according to various cut-off IL-6 serum levels: in 59/64 of these series corresponding to 94.5% of the reported patients (7694/8142) significant correlations between IL-6 serum level and survival were seen. The median survival of cancer patients had been determined above various cut-off levels of serum IL-6 in 24 dichotomized studies (26 cohorts). There was a highly significant inverse correlation between median survival of the cohorts with IL-6 serum level above cut-off (1272 patients) and their corresponding IL-6 cut-off values (Spearman R -0,48 p= < 0.001) following a linear regression when both parameters were log-transformed (p < 0.001). A significant correlation between increasing serum IL-6 and tumor stage or metastases was described in 39/44 studies and 91% of published patients (4221/4636) where clinical parameters had been specified. CONCLUSIONS: Closely associated with the patient's clinical condition and independent of the cancer histology, the increased IL-6 serum level uniformly appears to correlate with survival as paraneoplastic condition in later cancer stages independent of the cancer type. Modifications of this paraneoplastic immune reaction may offer new therapeutic options in cancer.

Cytokine patterns in patients with cancer: a systematic review.

Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types, but owing to the heterogeneity of cancer theories of common reaction mechanisms seem to be obsolete. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor α (TNFα), transforming growth factor ß (TGFß), interferon-γ, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4). Clinical data were analysed in a non-quantitative descriptive manner and interpreted with regard to experimentally established physiological cytokine interactions. The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFα, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFß. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12-interferon-γ-HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient's prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer.

Capsulotomy for refractory anxiety disorders: long-term follow-up of 26 patients.

OBJECTIVE: The objective of the present study was to evaluate the long-term efficacy and safety of capsulotomy in patients with anxiety disorders. METHOD: Twenty-six patients who had undergone bilateral thermocapsulotomy were followed up 1 year after the procedure and after a mean of 13 years. Primary diagnoses were generalized anxiety disorder (N=13), panic disorder (N=8), and social phobia (N=5). Measures of psychiatric status included symptom rating scales and neuropsychological testing. Ratings were done by psychiatrists not involved in patient selection or postoperative treatment. A quantitative magnetic resonance imaging (MRI) evaluation was conducted to search for common anatomic denominators. Seventeen of the 23 patients who were alive at long-term follow-up were followed up in person, and one was interviewed by telephone; the relatives of these 18 patients were interviewed. RESULTS: The reduction in anxiety ratings was significant both at 1-year and long-term follow-up. Seven patients, however, were rated as having substantial adverse symptoms; the most prominent adverse symptoms were apathy and dysexecutive behavior. Neuropsychological performance was significantly worse in the patients with adverse symptoms. No common anatomic denominator could be found in responders in the analysis of MRI scans. CONCLUSIONS: Thermocapsulotomy is an effective treatment for selected cases of nonobsessive anxiety but may carry a significant risk of adverse symptoms indicating impairment of frontal lobe functioning. These findings underscore the importance of face-to-face assessments of adverse symptoms.