BACKGROUND AND OBJECTIVES:To study the effect on tumor control and serviceable hearing in patients with vestibular schwannoma treated with upfront Gamma Knife Radiosurgery (Upfront GKRS group) compared with patients undergoing initial conservative management (Conservative group). METHODS:Between 2013 and 2017, patients with newly diagnosed Vestibular Schwannoma with a maximum diameter of 20 mm were asked to participate in this single-center, open-label 1:1 randomized clinical trial with parallel group design. Outcomes were assessed by differences in tumor control and hearing preservation at 5-year follow-up between the upfront GKRS group, vs the conservative group, with serviceable hearing defined as Gardner-Robertson class 1-2. RESULTS:Fifty-two patients with serviceable hearing were included and randomly assigned to upfront GKRS group (n = 24) or conservative group (n = 28). The groups were well-balanced at baseline. At 5-year follow-up, 24 of 24 patients in the upfront GKRS group (12 Gy) had tumor control, with 14 of 28 patients in the conservative group needing active treatment. Sixty-five percent of patients in upfront GKRS group had serviceable hearing compared with 50% in the conservative group (P = .388). No major adverse events were registered in either group for the duration of this study. CONCLUSION:The results of this randomized controlled trial demonstrate tumor control after GKRS in newly diagnosed Vestibular Schwannoma, although no significant difference of hearing preservation was observed in upfront GKRS compared with conservative management. TRIAL REGISTRATION:NCT01938677.

BACKGROUND AND OBJECTIVES:Craniopharyngiomas are rare intracranial tumors associated with a high recurrence rate. Gamma Knife radiosurgery (GKRS) is a widely used modality to treat these tumors, either as primary or secondary treatment. Long-term control is desired, yet available evidence on the long-term efficacy of GKRS remains unknown because of the limited follow-up periods in existing studies. The aim of this study was to assess long-term outcomes of GKRS-treated craniopharyngiomas in a nationwide consecutive cohort. METHODS:All patients with craniopharyngiomas who were treated by GKRS at the Karolinska University Hospital between 1968 and 2010 were included. Progression-free survival (PFS), overall survival (OS), and potential predictors of tumor growth and survival were assessed. RESULTS:A total of 44 patients were included. Follow-up times ranged from 4 to 55 years, with a mean of 21 years and a median of 19 years. PFS was 64% at 5 years, 50% at 10 years, 45% at 20 years, and 40% at 30 years. No growth occurred after 30 years in patients who had been progression free until that point. 69% of recurrences required further treatment. OS was 91% at 5 years, 79% at 10 years, 64% at 20 years, and 64% at 30 years. Tumor volume was an independent predictor of tumor growth (OR 1.69, P = .020), and age (OR 1.07, P = .018) and tumor volume (OR 1.21, P = .049) were independent predictors of survival. CONCLUSION:GKRS demonstrates sustained long-term efficacy in treating craniopharyngiomas, with a PFS rate of 40% at 30 years and no tumor growth observed beyond this point. Initial tumor volume should be assessed when planning GKRS treatment and follow-up of craniopharyngioma patients because it is a significant predictor of both tumor growth and OS.

Gamma Knife radiosurgery (GKRS) is a well-established treatment for residual or growing pituitary adenomas (PAs) post-partial resection. However, some PAs grow even after initial GKRS, for which the efficacy of repeat GKRS is unclear. The primary objective of this study was to determine long-term progression-free survival (PFS) following repeated GKRS in patients with PA. The secondary objective was to determine predictors of tumor progression in these patients. Single-center, population-based consecutive cohort study of patients with recurrent PAs treated with repeated GKRS due to tumor progression between 1999 and 2022 at the Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden. PFS and predictors of tumor growth were assessed. 23 patients were included, with a median follow-up time of 6.3 years. The 5-year PFS rate was 57

In May 1968, Lars Leksell and Erik-Olof Backlund achieved a pioneering breakthrough by performing the first Gamma Knife radiosurgery (GKRS) on a craniopharyngioma (CP). Today, more than 50 years later, this patient remains under continuous monitoring, providing the longest documented follow-up of a GKRS-treated CP. This case report provides a complete record of the patient's preoperative presentation, surgical assessment, GKRS, and an extensive long-term follow-up with multiple interventions. The investigation involved analysis of archived and digitalized patient records and radiological images. The patient was a 21-year-old female who presented with amenorrhea and low levels of gonadotropins. Pneumoencephalography showed a calcified 2 × 2.5 cm mass located in the suprasellar region, indicative of a CP. Subsequent stereotactic puncture confirmed a predominantly solid nature of the CP. Given the size and composition of the tumor, the surgical team opted for GKRS. Dose planning was performed manually, with coordinates determined using Leksell's stereotactic frame. The tumor was targeted with a total dose of 50 Gy using 179 beams of 60 Co. Over the subsequent 55 years, the patient underwent radiological and clinical follow-ups. Throughout this period, 4 cystic tumor recurrences occurred and were managed by stereotactic puncture and Yttrium-90 instillation radiotherapy. The solid component remained stable without repeated GKRS. The patient suffered lateral quadrant anopsia and endocrinological deficits, necessitating pharmaceutical intervention. Despite these challenges, the patient is still living an active life at age 76 years. This case stands as historic evidence of long-term safety and efficacy of GKRS for CPs.

Abstract BACKGROUND This study evaluates the outcomes of WHO grade II meningiomas treated with stereotactic radiosurgery (SRS) using a large, multi-institutional European database. We aim to investigate the long-term tumor control rate and morbidity associated with SRS. METHODS Data from 355 consecutive patients treated between 1992 and 2022 at 16 European radiosurgery centers were retrospectively analyzed. After excluding 40 patients due to loss to follow-up, results from 315 patients were included. Clinical and imaging data were independently collected by each center and uniformly entered into a multicenter database. RESULTS The median age of patients was 56 years, with 54% being female. The median follow-up duration was 46.3 ± 36.9 months. Tumors had prior surgical treatment and biopsy in 99% and 1% of cases, respectively. Tumors received previous radiotherapy or SRS in 27.4% of cases. SRS was performed due to local progression in 89.6% of cases, residual tumor in 6.4%, and distant progression in 4.0%. SRS characteristics included a median target volume of 5.1 cm³ and a median margin dose of 16 Gy (53.5% isodose). The 3-year local control rate was 72.0%, with a progression-free survival rate of 66.6% and an overall survival rate of 89.7%. Transient and permanent morbidity rates were 6.4% and 3.5%, respectively. Multivariate analysis identified previous radiotherapy and age as significant factors influencing these outcomes. CONCLUSIONS This study is the largest to date on SRS in WHO grade II meningiomas. Our data shows that SRS is a viable and safe treatment option for residual and recurrent WHO grade II meningiomas

Lars Leksell was instrumental in stereotactic radiosurgery that he invented. Not only did he create stereotactic radiosurgery conceptionally, but, with the Gamma Knife, he also developed its technical prerequisites. Leksell died in 1986. Late in his life, he wrote the book “Brain fragments” in Swedish not as a true biography but as an episodic novel of his life. Hence, the current book is not new, but the current translation is. Leksell's son Dan translated his father's memories discretely but closely. These are the memories of one of the most formative neurosurgeons of the 20th century. In impressive simplicity and modesty, the stations of his life are shaped by the craftsmanship of the surgeon and by the creativity of the inventor, and are defined by the frustration and success of the academic neurosurgeon, all, by essence, being the expression of his joy of life. His ludic drive, courage, and the aesthetic of technical perfection were Leksell's incitement, which appear today as ingenious.

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.

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-β 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.

In December of 2016, a Consensus Conference on unruptured AVM treatment, involving 24 members of the three European societies dealing with the treatment of cerebral AVMs (EANS, ESMINT, and EGKS) was held in Milan, Italy. The panel made the following statements and general recommendations: (1) Brain arteriovenous malformation (AVM) is a complex disease associated with potentially severe natural history; (2) The results of a randomized trial (ARUBA) cannot be applied equally for all unruptured brain arteriovenous malformation (uBAVM) and for all treatment modalities; (3) Considering the multiple treatment modalities available, patients with uBAVMs should be evaluated by an interdisciplinary neurovascular team consisting of neurosurgeons, neurointerventionalists, radiosurgeons, and neurologists experienced in the diagnosis and treatment of brain AVM; (4) Balancing the risk of hemorrhage and the associated restrictions of everyday activities related to untreated unruptured AVMs against the risk of treatment, there are sufficient indications to treat unruptured AVMs grade 1 and 2 (Spetzler–Martin); (5) There may be indications for treating patients with higher grades, based on a case-to-case consensus decision of the experienced team; (6) If treatment is indicated, the primary strategy should be defined by the multidisciplinary team prior to the beginning of the treatment and should aim at complete eradication of the uBAVM; (7) After having considered the pros and cons of a randomized trial vs. a registry, the panel proposed a prospective European Multidisciplinary Registry.

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.

Chemotherapy has made substantial progress in the therapy of systemic cancer, but the pharmacological efficacy is insufficient in the treatment of brain metastases. Fractionated whole brain radiotherapy (WBRT) has been a standard treatment of brain metastases, but provides limited local tumor control and often unsatisfactory clinical results. Stereotactic radiosurgery using Gamma Knife, Linac or Cyberknife has overcome several of these limitations, which has influenced recent treatment recommendations. This present review summarizes the current literature of single session radiosurgery concerning survival and quality of life, specific responses, tumor volumes and numbers, about potential treatment combinations and radioresistant metastases. Gamma Knife and Linac based radiosurgery provide consistent results with a reproducible local tumor control in both single and multiple brain metastases. Ideally minimum doses of ≥18Gy are applied. Reported local control rates were 90-94% for breast cancer metastases and 81-98% for brain metastases of lung cancer. Local tumor control rates after radiosurgery of otherwise radioresistant brain metastases were 73-90% for melanoma and 83-96% for renal cell cancer. Currently, there is a tendency to treat a larger number of brain metastases in a single radiosurgical session, since numerous studies document high local tumor control after radiosurgical treatment of >3 brain metastases. New remote brain metastases are reported in 33-42% after WBRT and in 39-52% after radiosurgery, but while WBRT is generally applied only once, radiosurgery can be used repeatedly for remote recurrences or new metastases after WBRT. Larger metastases (>8-10cc) should be removed surgically, but for smaller metastases Gamma Knife radiosurgery appears to be equally effective as surgical tumor resection (level I evidence). Radiosurgery avoids the impairments in cognition and quality of life that can be a consequence of WBRT (level I evidence). High local efficacy, preservation of cerebral functions, short hospitalization and the option to continue a systemic chemotherapy are factors in favor of a minimally invasive approach with stereotactic radiosurgery.