Georges Sinclair

Increased Survival Using Delayed Gamma Knife Radiosurgery for Recurrent High-Grade Glioma: A Feasibility Study

OBJECTIVE The current study retrospectively assessed delayed gamma knife radiosurgery (GKRS) in the management of high-grade glioma recurrences. METHODS A total of 55 consecutive patients with high-grade glioma comprising 68 World Health Organization (WHO) III and WHO IV were treated with GKRS for local recurrences between 2001 and 2007. All patients had undergone microsurgery and radiochemotherapy, considered as standard therapy for high-grade glioma. Complete follow-up was available in all patients; median follow-up was 17.2 months (2.5-114.2 months). Median tumor volume was 5.2 mL, prescription dose was 20 Gy (14-22 Gy), and median max dose was 45 Gy (30-77.3 Gy). RESULTS The patients with WHO III tumors showed a median survival of 49.6 months with and a 2-year survival of 90%. After GKRS of the recurrences, these patients showed a median survival of 24.2 months and a 2-year survival of 50%. The patients with WHO IV tumors had a median survival of 24.5 months with a 2-year survival of 51.4%. After the recurrence was treated with GKRS, the median survival was 11.3 months and a 2-year survival: 22.9% for the WHO IV patients. CONCLUSION The current study shows a survival benefit for high-grade glioma recurrences when GKRS was administered after standard therapy. This is a relevant improvement compared with earlier studies that had had not been able to provide a beneficial effect timing radiosurgery in close vicinity to EBRT.

Fractionated SRT using VMAT and Gamma Knife for brain metastases and gliomas — a planning study

Stereotactic radiosurgery using Gamma Knife (GK) or linear accelerators has been used for decades to treat brain tumors in one fraction. A new positioning system, Extend™, was introduced by Elekta AB for fractionated stereotactic radiotherapy (SRT) with GK. Another option for fractionated SRT is advanced planning and delivery using linacs and volumetric modulated arc therapy (VMAT). This project aims to assess the performance of GK Extend™ for delivering fractionated SRT by comparing GK treatments plans for brain targets performed using Leksell GammaPlan (LGP) with VMAT treatment plans. Several targets were considered for the planning: simulated metastasis- and glioma-like targets surrounding an organ at risk (OAR), as well as three clinical cases of metastases. Physical parameters such as conformity, gradient index, dose to OARs, and brain volume receiving doses above the threshold associated with risk of damaging healthy tissue, were determined and compared for the treatment plans. The results showed that GK produced better dose distributions for target volumes below 15 cm3 , while VMAT results in better dose conformity to the target and lower doses to the OARs in case of fractionated treatments for large or irregular volumes. The volume receiving doses above a threshold associated with increased risk of damage to normal brain tissue was also smaller for VMAT. The GK consistently performed better than VMAT in producing a lower dose-bath to the brain. The above is subjected only to margin-dependent fractionated radiotherapy (CTV/PTV). The results of this study could lead to clinically significant decisions regarding the choice of the radiotherapy technique for brain targets. PACS numbers: 87.53.Ly, 87.55.D.Stereotactic radiosurgery using Gamma Knife (GK) or linear accelerators has been used for decades to treat brain tumors in one fraction. A new positioning system, Extend™, was introduced by Elekta AB for fractionated stereotactic radiotherapy (SRT) with GK. Another option for fractionated SRT is advanced planning and delivery using linacs and volumetric modulated arc therapy (VMAT). This project aims to assess the performance of GK Extend™ for delivering fractionated SRT by comparing GK treatments plans for brain targets performed using Leksell GammaPlan (LGP) with VMAT treatment plans. Several targets were considered for the planning: simulated metastasis‐ and glioma‐like targets surrounding an organ at risk (OAR), as well as three clinical cases of metastases. Physical parameters such as conformity, gradient index, dose to OARs, and brain volume receiving doses above the threshold associated with risk of damaging healthy tissue, were determined and compared for the treatment plans. The results showed that GK produced better dose distributions for target volumes below 15 cm3, while VMAT results in better dose conformity to the target and lower doses to the OARs in case of fractionated treatments for large or irregular volumes. The volume receiving doses above a threshold associated with increased risk of damage to normal brain tissue was also smaller for VMAT. The GK consistently performed better than VMAT in producing a lower dose‐bath to the brain. The above is subjected only to margin‐dependent fractionated radiotherapy (CTV/PTV). The results of this study could lead to clinically significant decisions regarding the choice of the radiotherapy technique for brain targets. PACS numbers: 87.53.Ly, 87.55.D‐

The role of radiosurgery in the acute management of fourth ventricle compression due to brain metastases

Background: Approximately 20–30% of all intracranial metastases are located in the posterior fossa. The clinical evolution hinges on factors such as tumor growth dynamics, local topographic conditions, performance status, and prompt intervention. Fourth ventricle (V4) compression with secondary life-threatening obstructive hydrocephalus remains a major concern, often requiring acute surgical intervention. We have previously reported on the application of adaptive hypofractionated Gamma Knife Radiosurgery in the acute management of critically located metastases, a technique known to us as rapid rescue radiosurgery (3R). We report the results of 3R in the management of posterior fossa lesions and ensuing V4 decompression. Case Descriptions: Four patients with V4 compression due to posterior fossa metastases were treated with 3R by three separate gamma knife radiosurgical sessions (GKRS) over a period of seven days. Mean V4 volume was 1.02 cm3 at GKRS 1, 1.13 cm3 at GKRS 2, and 1.12 cm3 at GKRS 3. Mean tumor volume during the week of treatment was 10 cm3 at both GKRS 1 and 2 and 9 cm3 at GKRS 3. On average, we achieved a tumor volume reduction of 52% and a V4 size increase of 64% at the first follow-up (4 weeks after GKRS 3). Long-term follow-up showed continued local tumor control, stable V4 volume, and absence of hydrocephalus. Conclusion: For this series, 3R was effective in terms of rapid tumor ablation, V4 decompression, and limited radiation-induced toxicity. This surgical procedure may become an additional tool in the management of intractable posterior fossa metastasis with V4 compression.

Gamma knife radiosurgery in the management of endolymphatic sac tumors

Background: Although widely regarded as rare epithelial tumors with a low grade of malignancy, endolymphatic sac tumors (ELST) often lead to disabling petrous bone destruction and significantly impairing symptoms at the time of primary diagnosis and/or recurrence. ELST is not uncommon in von Hippel Lindau (VHL) patients. Although open surgery is regarded as the best treatment option, recurrence remains a challenge, particularly when gross tumor resection (GTR) is deemed unachievable due to topographic conditions. Tumor recurrence successfully treated with fractionated radiotherapy and radiosurgery have been reported in selected cases. We present the case of a patient with recurrent ELST treated with salvage gamma knife radiosurgery (GKRS) adding a review of current literature. Case Description: A 65-year-old patient underwent GKRS of an unresectable, recurrent ELST. Tumor volumetric analysis showed almost 15% increase in tumor volume in the 4 months between the pre-GKRS magnetic resonance imaging (MRI) and the stereotactic MRI (s-MRI) at treatment. Follow-up MRI at 12 and 20 months showed significant decrease in local tumor volume, decreased contrast enhancement and no perifocal edema. The patients general and neurological status remains stable to the present day. Conclusion: In the present case, GKRS was effective in the management of a recurrent ELST over the course of 20 months. Because of ELSTs recurrence potential, long-term follow up is required. The present case as well as previous reports might suggest a possible salvage/adjunctive role of radiosurgery in the management of ELST. Further studies are deemed necessary.

Identification of neoepitopes recognized by tumor-infiltrating lymphocytes (TILs) from patients with glioma

Neoepitope-specific T-cell responses have been shown to induce durable clinical responses in patients with advanced cancers. We explored the recognition patterns of tumor-infiltrating T lymphocytes (TILs) from patients with glioblastoma multiforme (GBM), the most fatal form of tumors of the central nervous system. Whole-genome sequencing was used for generating DNA sequences representing the entire spectrum of ‘private’ somatic mutations in GBM tumors from five patients, followed by 15-mer peptide prediction and subsequent peptide synthesis. For each mutated peptide sequence, the wildtype sequence was also synthesized and individually co-cultured with autologous GBM TILs, which had been expanded in vitro with a combination of interleukin (IL)-2, IL-15 and IL-21. After seven days of culture, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α) and/or IL-17A production was measured by ELISA in culture supernatants, and used as an epitope-specific immune response readout. Mutated peptides that induced a strong cytokine response were considered to contain legitimate neoepitopes. TILs from 5/5 patients with GBM exhibited specific immune reactivity profiles to the nominal target peptides, defined by IFN-γ and/or TNF-α production, as well as IL-17A. Neoepitopes, defined by mutated peptides inducing IFN-γ and/or TNF-α production without or only minimal reactivity to the wildtype sequences, were found for each individual patient. CD8+ TILs dominated the patients’ responses to private neoepitopes. The present study shows that neoepitope-specific TIL reactivity constitutes an important arm of anti-tumor immune responses in patients with GBM, and thus a powerful tool for developing next-generation personalized immunotherapies.

Mutant Epitopes in Cancer

Targeted immunotherapy in cancer is a rapidly expanding and evolving field with a developmental history spanning at least three decades. Beginning with the identification and characterisation of tumour-specific antigens (TSA)—protein molecules which are exclusively present on the surface of cancer cells—and very recently the dawn of neoantigen-specific immune-cell reactivity—championed by immune checkpoint blockade therapy—demonstrates that immune-based interventions will shape the future of cancer therapy. Neoantigens arise from naturally processed host protein molecules—eventually presented as immunogenic peptides to the immune system. However, a deeper understanding concerning the generation and recognition of neoantigens is indispensable in order to better understand the immunological and biological underpinnings in diagnostics and therapeutic applications in to enhance healthcare for patients with cancer.

Cumulative Intracranial Tumor Volume Augments the Prognostic Value of Diagnosis-Specific Graded Prognostic Assessment Model for Survival in Patients with Melanoma Cerebral Metastases

BACKGROUND The diagnosis‐specific graded prognostic assessment scale (ds‐GPA) for patients with melanoma brain metastasis (BM) utilizes only 2 key prognostic variables: Karnofsky performance status and the number of intracranial metastases. We wished to determine whether inclusion of cumulative intracranial tumor volume (CITV) into the ds‐GPA model for melanoma augmented its prognostic value. OBJECTIVE To determine whether or not CITV augments the ds‐GPA prognostic scale for melanoma. METHODS We analyzed the survival pattern of 344 melanoma patients with BM treated with stereotactic radiosurgery (SRS) at separate institutions and validated our findings in an independent cohort of 201 patients. The prognostic value of ds‐GPA for melanoma was quantitatively compared with and without the addition of CITV using the net reclassification index (NRI > 0) and integrated discrimination improvement (IDI) metrics. RESULTS The incorporation of CITV into the melanoma‐specific ds‐GPA model enhanced its prognostic accuracy. Addition of CITV to the ds‐GPA model significantly improved its prognostic value, with NRI > 0 of 0.366 (95% CI: 0.125‐0.607, P = .002) and IDI of 0.024 (95% CI: 0.008‐0.040, P = .004). We validated these findings that CITV improves the prognostic utility of melanoma ds‐GPA in an independent cohort of 201 melanoma cohort. CONCLUSION The prognostic value of the ds‐GPA scale for melanoma BM is enhanced by the incorporation of CITV.

Salvage gamma knife radiosurgery in the management of dysembryoplastic neuroepithelial tumors: Long-term outcome in a single-institution case series

Background: Dysembryoplastic neuroepithelial tumors (DNT/DNET) are rare epileptogenic tumors. Microsurgery remains the best treatment option, although case reports exist on the use of gamma knife radiosurgery (GKRS) in selected cases. We investigated the long-term outcome of GKRS-treated DNTs at our institution in the context of current diagnostic and treatment options. Case Descriptions: We conducted a retrospective review of three consecutive adult patients (≥18 years) treated with salvage GKRS between 2002 and 2010 at Karolinska University Hospital, Stockholm, Sweden. The case series was supplemented by a review of current literature. A 20-year-old male underwent subtotal resection (STR) in 1997 and 2002 of DNT resulting in temporary control of intractable epilepsy despite antiepileptic drug treatment (AED). Long-term seizure control was obtained after GKRS of two separate residual DNT components along the surgical margin (2005 and 2010). A 27-year-old male undergoing gross total resection of the contrast-enhancing portion of a DNT (1999) resulted in temporary control of intractable epilepsy despite AEDs; lasting clinical control of seizures was achieved in 2002 after GKRS of a small, recurrent DNT component. A 28-year-old male underwent STR of DNT (1994 and 2004) resulting in temporary control of intractable epilepsy. Lasting seizure control was gained after GKRS of a residual tumor (2005). Conclusion: GKRS as performed in our series was effective in terms of tumor and seizure control. No adverse radiation effects were recorded. Prospective studies are warranted to establish the role of GKRS in the treatment of DNTs.

Adaptive hypofractionated gamma knife radiosurgery in the acute management of large thymic carcinoma brain metastases

Background: Brain metastases often lead to serious neurological impairment and life threatening states. Their acute management remains complex, particularly in the case of rare malignancies with aggressive evolution. In large single lesions, open surgery followed by radiation to the surgical cavity is widely regarded as the best approach; yet in many cases, microsurgery is not feasible due to the lesions critical location and/or the number of brain metastases present. We report the effects of adaptive hypofractionated gamma knife radiosurgery in the acute management of critically located thymic carcinoma metastases. Case Description: A 50-year-old male with metastatic thymic carcinoma was treated with radiosurgery for two large supratentorial brain metastases (M3 and M4) adjacent to eloquent areas and one smaller cerebellar metastasis (M2). M3 and M4 were treated with adaptive hypofractionated gamma knife radiosurgery, showing a dramatic volume reduction 4 weeks after treatment completion without radiation-induced side effects. Thirteen months later, two new small, threatening supratentorial lesions (M5-M6) were treated with the same technique. Interestingly, M2 (treated with standard single fraction) and M5-M6 developed local adverse radiation events. The patients general and neurological status remained next to normal by the time of paper submission. Conclusion: The application of adaptive hypofractionated radiosurgery in this acute setting proved effective in terms of rapid tumor ablation, with salvage of neurological functionality and limited toxicity. We have called the overall procedure rapid rescue radiosurgery (RRR). A systematic study of past and ongoing RRR-treatments is warranted and in progress.

Mesothelin as a novel biomarker and immunotherapeutic target in human glioblastoma

Glioblastoma multiforme (GBM) presents the most malignant form of glioma, with a 5-year survival rate below 3% despite standard therapy. Novel immune-based therapies in improving treatment outcomes in GBM are therefore warranted. Several molecularly defined targets have been identified mediating anti-GBM cellular immune responses. Mesothelin is a tumor-associated antigen (TAA) which is expressed in several solid tumors with different histology. Here, we report the immunological significance of mesothelin in human malignant glioma. Expression of mature, surface-bound mesothelin protein was found to bein human GBM defined by immunofluorescence microscopy, and on freshly isolated, single cell suspension of GBM tumor cells and GBM tumor cell lines, determined by based on flow cytometric analysis. Peripheral blood (PB) from patients with GBM, stimulated with mesothelin peptides and IL-2, IL-15 and IL-21, exhibited increased antigen-specific IFN-γ and TNF-α production. Anti-mesothelin directed T-cell responses could also be detected in tumor - infiltrating lymphocytes (TIL) isolated from GBM speciments. Furthermore, T cells cultured in the presence of IL-2, IL-15 and IL-21 displayed enhanced mesothelin-specific CD4+ and CD8+ subset proliferation, based on ELISA and flow cytometric readouts. Mesothelin-specific IgG antibodies as well as (shed) mature mesothelin protein were detected in plasma samples from patients with GBM by indirect ELISA. Finally yet importantly, we identified distinct immune recognition hotspots within the mature mesothelin component, defined by peptide-specific IFN-γ responses from peripheral T-cells from patients with GBM. Mesothelin may therefore qualify as a viable target for immunotherapeutic approaches for patients with GBM.