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Mutation of isocitrate dehydrogenase 1 (IDH1) is shown to induce DNA hypermethylation and to remodel the epigenome to resemble that of gliomas with the CpG island methylator phenotype. Cancer induction by isocitrate dehydrogenase mutation Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 have been identified in gliomas, the most common form of brain tumour, and in other cancers including leukaemias. The mutated enzymes produce 2-hydroxyglutarate (2HG), which is a potential oncometabolite. Three papers in this issue of Nature examine the mechanisms through which IDH mutations promote cancers. Lu et al . show that 2HG-producing IDH mutants can prevent the histone demethylation that is required for progenitor cells to differentiate, potentially contributing to tumour-cell accumulation. Turcan et al . show that IDH1 mutation in primary human astrocytes induces DNA hypermethylation and reshapes the methylome to resemble that of the CIMP phenotype, a common feature of gliomas and other solid tumours. Koivunen et al . show that the ( R )-enantiomer of 2HG (but not the ( S )-enantiomer) can stimulate the activity of the EGLN prolyl 4-hydroxylases, leading to diminished levels of hypoxia-inducible factor (HIF), which in turn can enhance cell proliferation. These papers establish a framework for understanding gliomagenesis and highlight the interplay between genomic and epigenomic changes in human cancers. Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology 1 , 2 , 3 . Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 ( IDH1 ), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.

Purpose Management of patients with large brain metastases poses a clinical challenge, with poor local control and high risk of adverse radiation events when treated with single-fraction stereotactic radiosurgery (SF-SRS). Hypofractionated SRS (HF-SRS) may be considered, but clinical data remains limited, particularly with Gamma Knife (GK) radiosurgery. We report our experience with GK to deliver mask-based HF-SRS to brain metastases greater than 10 cc in volume and present our control and toxicity outcomes. Methods Patients who received hypofractionated GK radiosurgery (HF-GKRS) for the treatment of brain metastases greater than 10 cc between January 2017 and June 2022 were retrospectively identified. Local failure (LF) and adverse radiation events of CTCAE grade 2 or higher (ARE) were identified. Clinical, treatment, and radiological information was collected to identify parameters associated with clinical outcomes. Results Ninety lesions (in 78 patients) greater than 10 cc were identified. The median gross tumor volume was 16.0 cc (range 10.1-56.0 cc). Prior surgical resection was performed on 49 lesions (54.4%). Six- and 12-month LF rates were 7.3% and 17.6%; comparable ARE rates were 1.9% and 6.5%. In multivariate analysis, tumor volume larger than 33.5 cc (p = 0.029) and radioresistant histology (p = 0.047) were associated with increased risk of LF (p = 0.018). Target volume was not associated with increased risk of ARE (p = 0.511). Conclusions We present our institutional experience treating large brain metastases using mask-based HF-GKRS, representing one of the largest studies implementing this platform and technique. Our LF and ARE compare favorably with the literature, suggesting that target volumes less than 33.5 cc demonstrate excellent control rates with low ARE. Further investigation is needed to optimize treatment technique for larger tumors.

ObjectiveData supporting dose escalation for node-positive cervical cancer are currently limited to small retrospective studies. The goal of this study was to assess whether radiation dose was associated with lymph node control or gastrointestinal toxicity in patients with node-positive cervical cancer.MethodsA total of 390 patients with carcinoma of the uterine cervix were treated between October 1997 and October 2017. Patients included in our analysis were those with squamous cell carcinoma or adenocarcinoma who were node-positive, treated definitively, and with at least one follow-up visit and post-treatment imaging scan. We excluded those without follow-up and those treated with palliative intent. All patients were treated with external beam radiation to pelvic±para-aortic fields with concurrent weekly cisplatin. All lymph nodes present at the time of treatment were stratified by size as <2 cm or ≥2 cm. Acute and late gastrointestinal toxicity were recorded for all patients.ResultsA total of 77 patients with 206 lymph nodes were identified. Median stage at presentation was FIGO IIB. Thirteen patients underwent definitive surgical resection followed by adjuvant radiation, of which 12 were treated to doses ≤5040 (range 2700–5940) cGy. Sixty-four patients were treated with definitive chemoradiation, of which 42 (66%) received ≤5040 (range 4500–5040) cGy and 22 (34%) received >5040 (range 5300–6640) cGy. Patients with pre-chemoradiation lymph nodes ≥2 cm had inferior lymph node control compared with patients with pre-chemoradiation lymph node <2 cm at 12 months (77% vs 100%, p=0.002). Radiation dose >5040 cGy was not significantly associated with improved lymph node control compared with ≤5040 cGy when analyzing all patients (12 months, 100% vs 89%, p=0.112). In patients with pre-chemoradiation lymph nodes ≥2 cm, radiation dose >5040 cGy was associated with improved lymph node control (12 months, 100% vs 60%, p=0.020). Acute grade ≥2 gastrointestinal toxicity was not associated with radiation dose >5040 cGy (20% vs 13%, p=0.424). Two patients developed grade ≥2 late gastrointestinal toxicity, both of whom were treated to ≤5040 cGy.ConclusionsThis series supports the role of dose escalation for patients with lymph nodes ≥2 cm. Dose escalation is associated with improved control in patients with larger lymph nodes, and is not associated with greater gastrointestinal toxicity.

INTRODUCTION Planning for stereotactic radiosurgery (SRS) for patients with meningiomas can be confounded by difficulty in identifying the tumor boundary, especially in those who have had prior surgery. Recent data have suggested the benefit of 68-GA-DOTATATE PET scans in delineation of meningioma in comparison to MRI alone. METHODS We reviewed patients who had the diagnosis of grade II meningioma and who had MRI and 68Ga-DOTATATE PET imaging over a 12-month period. Images were imported into Velocity treatment planning software and separated into two different sessions, one in which only the MRI was accessible, and a second which had the PET scan fused to the MRI. Three different users were asked to contour the residual meningioma as gross tumor volume (GTV) first with MRI alone, and then on a separate session with the PET/MRI fusion. The volume of each GTV pre-and post- PET fusion was compared and Dice index was generated to measure overlap. RESULTS A total of 4 patients with 6 GTV targets were identified. PET fusion identified additional lesions in close proximity to the initial GTV targets in 2 patients by all three individuals. One of the lesions was in the skull anterior to the mastoid air cells. The second was a nodular dural based lesion along the left high parietal convexity adjacent to a prior craniectomy and mesh duraplasty site. Across all observers, GTV volumes were significantly increased when PET fusion was used. The average volume (in cc) increase was 111.6% ± 66.2%. The average Dice index was 0.58 ± 0.17. CONCLUSION 68Ga-DOTATATE PET scan when fused with MRI improved the visualization of meningiomas in patients undergoing SRS. A larger experience is needed to confirm this trend, and to report the clinical and imaging outcomes. We have begun to use DOTATATE-PET imaging on a regular basis when imaging patients with meningiomas for SRS.

The authors' recommendation of PCI for all patients after resection of T1N0 or T2N0 small-cell lung cancers is made despite the fact that the highest reported risk of developing brain metastasis in patients with resected T1 tumours is 11%.2-4 The anticipated 5-year survival rate for patients with pathological stage I disease is 74%, and the anticipated rate of initial intracranial failure in a cumulative series of 111 patients is 7%.3 No studies have shown a survival advantage with the addition of PCI for this small but important subset of patients with resected small-cell lung cancer.

Background Intracranial solitary fibrous tumors (SFTs), formerly hemangiopericytomas (HPCs), are rare, aggressive dural-based mesenchymal tumors. While adjuvant radiation therapy has been suggested to improve local tumor control (LTC), especially after subtotal resection, the role of postoperative stereotactic radiosurgery (SRS) and the optimal SRS dosing strategy remain poorly defined. Methods PubMed, EMBASE, and Web of Science were systematically searched according to PRISMA guidelines for studies describing postoperative SRS for intracranial SFTs. The search strategy was defined in the authors’ PROSPERO protocol (CRD42023454258). Results 15 studies were included describing 293 patients harboring 476 intracranial residual or recurrent SFTs treated with postoperative SRS. At a mean follow-up of 21–77 months, LTC rate after SRS was 46.4–93% with a mean margin SRS dose of 13.5–21.7 Gy, mean maximum dose of 27-39.6 Gy, and mean isodose at the 42.5–77% line. In pooled analysis of individual tumor outcomes, 18.7% of SFTs demonstrated a complete SRS response, 31.7% had a partial response, 18.9% remained stable (overall LTC rate of 69.3%), and 30.7% progressed. When studies were stratified by margin dose, a mean margin dose > 15 Gy showed an improvement in LTC rate (74.7% versus 65.7%). Conclusions SRS is a safe and effective treatment for intracranial SFTs. In the setting of measurable disease, our pooled data suggests a potential dose response of improving LTC with increasing SRS margin dose. Our improved understanding of the aggressive biology of SFTs and the tolerated adjuvant SRS parameters supports potentially earlier use of SRS in the postoperative treatment paradigm for intracranial SFTs.

Introduction To assess tumor control and survival in patients treated with stereotactic radiosurgery (SRS) for 10 or more metastatic brain tumors. Methods Patients were retrospectively identified. Clinical records were reviewed for follow-up data, and post-treatment MRI studies were used to assess tumor control. For tumor control studies, patients were separated based on synchronous or metachronous treatment, and control was assessed at 3-month intervals. The Kaplan–Meier method was employed to create survival curves, and regression analyses were employed to study the effects of several variables. Results Fifty-five patients were treated for an average of 17 total metastases. Forty patients received synchronous treatment, while 15 received metachronous treatment. Univariate analysis revealed an association between larger brain volumes irradiated with 12 Gy and decreased overall survival (p = 0.0406); however, significance was lost on multivariate analysis. Among patients who received synchronous treatment, the median percentage of tumors controlled was 100%, 91%, and 82% at 3, 6, and 9 months, respectively. Among patients who received metachronous treatment, the median percentage of tumors controlled after each SRS encounter was 100% at all three time points. Conclusions SRS can be used to treat patients with 10 or more total brain metastases with an expectation of tumor control and overall survival that is equivalent to that reported for patients with four or fewer tumors. Development of new metastases leading to repeat SRS is not associated with worsened tumor control or survival. Survival may be adversely affected in patients having a higher volume of normal brain irradiated.

Objective To improve the efficiency of frame-based and frameless Gamma Knife® Icon™ (GKI) treatments by analyzing the workflows of both treatment approaches and identifying steps that lead to prolonged patient in-clinic or treatment time. Methods The treatment processes of 57 GKI patients, 16 frame-based and 41 frameless cases were recorded and analyzed. For frame-based treatments, time points were recorded for various steps in the process, including check-in, magnetic resonance imaging (MRI) completion, plan approval, and treatment start/end times. The time required for completing each step was calculated and investigated. For frameless treatments, the actual and planned treatment times were compared to evaluate the patient tolerance of the treatment. In addition, the time spent on room cleaning and preparation between treatments was also recorded and analyzed. Results For frame-based cases, the average in-clinic time was 6.3 hours (ranging from 4 to 8.7 hours). The average time from patient check-in to plan approval was 4.2 hours (ranging from 2.8 to 5.5 hours), during which the frame was placed, stereotactic reference MRI images were taken, target volumes were contoured, and the treatment plan was developed and second-checked. For patients immobilized with a mask, treatment pauses triggered by the intra-fractional motion monitoring system resulted in a significantly longer actual treatment time than the planned time. In 50 (or 55%) of the 91 frameless treatments, the patient on-table time was longer than the planned treatment time by more than 10 minutes, and in 19 (or 21%) of the treatments the time difference was larger than 20 minutes. Major treatment interruptions, defined as pauses leading to a longer than 10-minute delay, were more commonly encountered in patients with a planned treatment time longer than 40 minutes, which accounted for 64% of the recorded major interruptions. Conclusion For frame-based cases, the multiple pretreatment steps (from patient check-in to plan approval) in the workflow were time-consuming and resulted in prolonged patient in-clinic time. These pretreatment steps may be shortened by performing some of these steps before the treatment day, e.g., pre-planning the treatment using diagnostic MRI scans acquired a few days earlier. For frameless patients, we found that a longer planned treatment time is associated with a higher chance of treatment interruption. For patients with a long treatment time, a planned break or consideration of fractionated treatments (i.e., 3 to 5 fractionated stereotactic radiosurgery) may optimize the workflow and improve patient satisfaction.Objective To improve the efficiency of frame-based and frameless Gamma Knife® Icon™ (GKI) treatments by analyzing the workflows of both treatment approaches and identifying steps that lead to prolonged patient in-clinic or treatment time. Methods The treatment processes of 57 GKI patients, 16 frame-based and 41 frameless cases were recorded and analyzed. For frame-based treatments, time points were recorded for various steps in the process, including check-in, magnetic resonance imaging (MRI) completion, plan approval, and treatment start/end times. The time required for completing each step was calculated and investigated. For frameless treatments, the actual and planned treatment times were compared to evaluate the patient tolerance of the treatment. In addition, the time spent on room cleaning and preparation between treatments was also recorded and analyzed. Results For frame-based cases, the average in-clinic time was 6.3 hours (ranging from 4 to 8.7 hours). The average time from patient check-in to plan approval was 4.2 hours (ranging from 2.8 to 5.5 hours), during which the frame was placed, stereotactic reference MRI images were taken, target volumes were contoured, and the treatment plan was developed and second-checked. For patients immobilized with a mask, treatment pauses triggered by the intra-fractional motion monitoring system resulted in a significantly longer actual treatment time than the planned time. In 50 (or 55%) of the 91 frameless treatments, the patient on-table time was longer than the planned treatment time by more than 10 minutes, and in 19 (or 21%) of the treatments the time difference was larger than 20 minutes. Major treatment interruptions, defined as pauses leading to a longer than 10-minute delay, were more commonly encountered in patients with a planned treatment time longer than 40 minutes, which accounted for 64% of the recorded major interruptions. Conclusion For frame-based cases, the multiple pretreatment steps (from patient check-in to plan approval) in the workflow were time-consuming and resulted in prolonged patient in-clinic time. These pretreatment steps may be shortened by performing some of these steps before the treatment day, e.g., pre-planning the treatment using diagnostic MRI scans acquired a few days earlier. For frameless patients, we found that a longer planned treatment time is associated with a higher chance of treatment interruption. For patients with a long treatment time, a planned break or consideration of fractionated treatments (i.e., 3 to 5 fractionated stereotactic radiosurgery) may optimize the workflow and improve patient satisfaction.

Neurologic complications from radiotherapy can be immediate or can occur many years after treatment. A known complication of radiotherapy to the supraclavicular and axillary lymph nodes is brachial plexus neuropathy. Although not a common injury, phrenic nerve dysfunction has been reported in association with radiation-induced brachial neuropathy. We describe a patient who developed asymmetric diaphragmatic weakness secondary to phrenic nerve paralysis 37 years after receiving mantle radiation for Hodgkin lymphoma. The patient did not have an associated brachial plexus neuropathy or a secondary malignancy involving the phrenic nerves. A radiation-induced injury was the most likely cause.

Background Accumulating evidence suggests that brachial plexopathy following head and neck cancer radiotherapy may be underreported and that this toxicity is associated with a dose–response. Our purpose was to determine whether the dose to the brachial plexus (BP) can be constrained, without compromising regional control. Methods The radiation plans of 324 patients with oropharyngeal carcinoma (OPC) treated with intensity-modulated radiation therapy (IMRT) were reviewed. We identified 42 patients (13%) with gross nodal disease <1 cm from the BP. Normal tissue constraints included a maximum dose of 66 Gy and a D 05 of 60 Gy for the BP. These criteria took precedence over planning target volume (PTV) coverage of nodal disease near the BP. Results There was only one regional failure in the vicinity of the BP, salvaged with neck dissection (ND) and regional re-irradiation. There have been no reported episodes of brachial plexopathy to date. Conclusions In combined-modality therapy, including ND as salvage, regional control did not appear to be compromised by constraining the dose to the BP. This approach may improve the therapeutic ratio by reducing the long-term risk of brachial plexopathy.