Journal of Neuro-Oncology最新文献

Purpose: There is an unmet need for new treatments for many central nervous system tumors. An expanding body of research supports the use of laser interstitial thermal therapy (LITT) in the treatment of gliomas, recurrent brain metastases, and radiation necrosis.

Methods: In this review, we highlight emerging indications for LITT, including its use adjacent to eloquent structures, in the posterior fossa, and for meningioma and tumors of the vertebral column. We conclude by providing an overview of current research into post-LITT response assessment and adjunctive therapies.

Results: Evidence has continued to accumulate regarding the safety of LITT in locations as varied as the motor cortex, posterior fossa, and vertebral column, as well as for novel pathologies such as meningioma. Regardless of disease histology, most patients leave the hospital within 12-48 h of LITT and can rapidly return to systemic and radiation therapies. Emerging data has allowed for a characterization of post-LITT imaging findings, and receipt of LITT should not preclude subsequent clinical trial enrollment, especially as hyperthermia modulates blood-brain barrier permeability and may synergize with immunotherapies.

Conclusion: As LITT is incorporated into neurosurgical oncology practice, novel use cases will continue to emerge. Given that laser ablation is associated with shortened length of stay and decreased debility relative to open resection, development of radiographic response assessment criteria for LITT-treated lesions is urgently needed so that patients may more rapidly receive definitive management or proceed to clinical trial enrollment. Prospective evaluation of LITT and adjunctive combination therapies is ongoing.

Background: Even a gross total resection of a benign epidermoid tumor (ET) carries a high risk of recurrence. The management strategy mostly involves redo surgical excision but at a significant cost of morbidity and mortality. The role of adjuvant radiation therapies in this scenario is still undefined.

Objective: To evaluate the feasibility, safety, efficacy, and complication profile of radiosurgery as a standalone or adjuvant therapy for intracranial epidermoid in the published literature.

Methodology: Following PRISMA guidelines, a comprehensive search of the databases PubMed, Embase, Scopus, and Web of Science in published English language was conducted. We included studies with radiosurgery for benign ET and in patients with malignant transformation of ET (MTET). All studies were evaluated for tumor characteristics, pattern of treatment, dosimetric profile, outcome, and complications. We included all studies with at least one outcome of interest i.e. local control (LC); progression-free survival (PFS); symptomatic toxicity; disease progression; retreatment; and overall survival (OS); and cause-specific mortality.

Results: The search revealed 403 articles, of which 6 and 8 studies with patients of benign ET and MTET respectively were included. 25 (65.7%) patients received primary SRS. 27 patients presented with hyperactive cranial nerve syndromes; 77.7% gained complete improvement. The overall median age was 46.7 years (22-67) and the median tumor volume ranged from 0.38 to 6.2cc in benign ET. Volumetric reduction was seen in 6 cases; progression was seen in 2 cases while ET remained stable in the rest. Mean follow-up duration ranged from 33.7 to 60 months, and no recurrence was reported at the latest follow-up in any case of benign ET. 9.5% of patients suffered from transient cranial nerve deficits with no prolonged adverse radiation effect. OS in the MTET group was 6 to 60 months following GKRS with 50% of patients alive at the latest follow-up.

Conclusion: SRS may be a promising treatment option for a conventionally benign and radioresistant ET making a meaningful change in the natural history of the disease. It is a valuable adjuvant technique in patients with MTET.

Purpose: Availability data are scarce and primarily retrospective in patients with brain metastasis (BM) from gastrointestinal (GI) cancers. The objective of this cohort was to determine prognostic factors for survival outcomes in patients with BM from GI cancers.

Methods: METACER is a national multicentric prospective cohort study which included patients with BM diagnosis during a histologically proven digestive cancer follow-up between 2010 and 2014. The primary endpoint was overall survival (OS). The secondary endpoints were Progression-Free survival (PFS), prognostic factors, and BM-free survival as time from disease diagnosis to BM diagnosis.

Results: METACER included 130 patients, with colorectal cancer (CRC) (N = 105) and eso-gastric (N = 25) cancer (EGC). The median OS was 6.6 months: 7.1 months (95%CI: 4.7-9.7) in CRC patients and 5.2 months, (95%CI: 1.9-7.6) in EG patients (p = 0.827). In multivariate analysis, cerebral BM location (versus cerebellar), BM surgery, performance status (0-1 versus 2), and a unique BM were significantly associated with prolonged OS. BM-free survival were 30.8 months (95%CI:25.2-36.9) in CRC patients and 7.8 months (95%CI:3.8-13.6) in EGC patients (p < 0.001). In synchronous metastatic disease, BM-free survival were 18.6 months (95%CI:13.1-25.2) in CRC patients and 3.7 months (95%CI:0.03-7.8) in EGC patients (p < 0.001).

Conclusion: BM in GI cancers are of poor prognosis. BM surgery should be considered in case of unique brain lesion. In metastatic settings, EGC patients have shorter BM-free survival than CRC patients.

Purpose:  Chordomas are malignant tumors of the axial spine and skull base, and they are notorious for their poor treatment response. Differentiating these tumors from comparatively less malignant chondrosarcomas is crucial for treatment and prognostication. Both tumor types differ in their developmental origin. Chordomas are considered to be derived from notochordal remnants and chondrosarcomas from mesenchymal cells. Here, we evaluated the differential expression of developmental transcription factors in these skull base tumors.

Methods:  Histopathologically-confirmed tumor biopsies were obtained from 12 chordoma and 7 chondrosarcoma patients. Following RNA extraction, samples were submitted to real-time quantitative PCR (RT-qPCR) for the evaluation of 32 evolutionary conserved genes that are known to associate with notochord, mesoderm, and axial spine development. Gene expression levels were normalized to housekeeping genes ACTB and RS27a.

Results:  Fifteen genes were either exclusively expressed (n = 12) or overexpressed (n = 3; 2.21-4.43 fold increase) in chordoma, compared to chondrosarcoma. Brachyury and CD24 were highly and exclusively expressed in chordoma. Other novel genes exclusive to chordomas included chordin, HOXA5 and ACAN. Vice versa, ten genes were either exclusively expressed (n = 2) or overexpressed (n = 8; 0.01-0.66 fold increase) in chondrosarcoma, compared to chordoma.

Conclusion:  As chordoma patients demonstrate a worse prognosis compared to chondrosarcoma patients, the differential expression of chordin, HOXA5 and ACAN and CD24 could be relevant for the pathophysiology of chordomas and may have diagnostic and treatment value. Further study on role of these genes in tumorigenesis is therefore warranted.

Purpose: This systematic review aimed to collate and synthesize the available literature on the abscopal effect in Glioblastoma multiforme (GBM) neoplasms, focusing on the reported biochemical mechanisms driving the abscopal effect.

Methods: A systematic search was conducted in PubMed, Cochrane Database of Systematic Reviews, and Epistemonikos from inception to May 1, 2023. Studies exploring the abscopal effect in GBM were included. The Clinical Relevance Assessment of Animal Preclinical research (RAA) tool was used to assess methodological quality of preclinical studies. Data on preclinical models, biochemical mechanisms, and outcomes were extracted and synthesized systrmatically.

Results: Out of a total of 7 studies, five preclinical studies met the inclusion criteria. The studies utilized various in vivo mouse models, including bilateral tumor models and immunohumanized mice. Key biochemical mechanisms identified included immunogenic cell death, danger-associated molecular pattern release, macrophage activation, and enhanced T cell responses. Combinatorial approaches involving oncolytic virotherapy, nanoparticle-based treatments, radiation therapy, and immune checkpoint inhibitors showed promise in inducing abscopal effects. Significant tumor growth inhibition and improved survival were reported in treated animals. However, the RAA analysis highlighted concerns regarding research transparency and internal validity across studies.

Conclusions: This systematic review highlighted the potential of the abscopal effect in GBM, demonstrating its ability to enhance anti-tumor immune responses both locally and systemically. The synergistic effects of combinatorial approaches showed promise for improving outcomes. However, the low methodological quality of existing studies underscored the need for more rigorous preclinical research. Future studies should focus on improving research transparency, exploring the abscopal effect in other primary CNS neoplasms, and translating these findings into clinical trials to assess safety and efficacy in humans.

Purpose: Bevacizumab, an anti-VEGF monoclonal antibody, has become a mainstay therapeutic in the management of malignant glioma. It is unknown if the risk of intracranial hemorrhage (ICH), a major complication associated with bevacizumab use, is dose-dependent.

Methods: This was a single institution retrospective analysis of patients treated with bevacizumab for the management of gliomas between 2009 and 2022. Incidence rates of ICH between patients receiving low-dose (< 5 mg/kg/week) and conventional-dose (5 mg/kg/week) bevacizumab regimens were compared via competing risk analysis over time. We evaluated post-progression survival (PPS) as a secondary outcome using multivariate Cox regression.

Results: One hundred and seventy-three patients were identified (low-dose group, n = 51, conventional-dose group, n = 122) for inclusion in our analysis. Cumulative incidence rates of all cases of ICH and clinically symptomatic cases of ICH were higher in the conventional-dose (17.2% for all cases, 13.7% for symptomatic) relative to the low-dose group (3.9% for all cases, 2.0% for symptomatic); p-value 0.0296 for all cases, p-value 0.0274 for symptomatic cases. On multivariate Fine-Gray regression, conventional-dose bevacizumab therapy remained significantly associated with increased risk for symptomatic ICH (SHR 8.0560; p-value 0.0442). No difference in PPS was observed between the low-dose versus conventional-dose groups.

Conclusions: Conventional-dose bevacizumab therapy (5 mg/kg/week) is associated with increased incidence of ICH in patients with malignant glioma compared to lower dose bevacizumab (< 5 mg/kg/week) in this single center retrospective cohort. No difference in PPS was observed between the low-dose versus conventional-dose groups.

Background: Irinotecan demonstrates anti-tumor efficacy in preclinical glioma models but clinical results are modest due to drug delivery limitations. Convection enhanced delivery (CED) improves drug delivery by increasing intratumoral drug concentration. Real-time magnetic resonance imaging of infusate delivery during CED may optimize tumor coverage. This phase 1 trial examines the safety and tolerability of liposomal irinotecan and gadolinium delivered via CED using real-time MRI guidance in recurrent high-grade glioma patients.

Methods: Initially, a 3 + 3 dose-escalating, single dose trial was planned with 4 cohorts based on a fixed drug dose and volume. After 9 patients, a protocol amendment allowed for variable volume and dose of the study agent based on tumor size. The amended design specified 'personalized' drug volume but fixed concentration of 20 mg/mL of liposomal irinotecan in the first cohort escalating to 40 mg/mL in the second cohort.

Results: Eighteen patients with recurrent WHO grade 3 or 4 gliomas (diameter 1-4 cm) were treated. Based on the tumor volume, the total dose of liposomal irinotecan was 20-680 mg in a total volume of 2-17 ml. Technical challenges were overcome by real-time MRI guidance and protocol amendment. The only dose-limiting toxicity (DLT) was a grade 3 stroke. Safety and survival information is presented.

Conclusions: CED of liposomal irinotecan using real-time MRI in patients with recurrent high-grade glioma is feasible. Image-guidance allowed for improved placement of CED cannulas and optimal tumor coverage. Our results warrant further study with repeat CED dosing.

Purpose: Sarcomas metastasizing to the spine are a rare entity. Ideally an En-bloc resection is necessary to achieve durable local control (LC) rates. However, anatomical constraints often limit the degree of tumor resection. Because of this, other therapeutic modalities either replacing or as an adjuvant to resection are necessary. Stereotactic radiosurgery (SRS) is a reasonable candidate therapy.

Methods: We conducted a systematic review of the literature using the following databases: PubMed, Science Direct, and Cochrane library. We used a combination of the following terms connected by boolean operators: "Metastatic Sarcoma, Sarcoma of the Spine, Spine Sarcoma, Metastasis, stereotactic radiosurgery, SRS." All retrospective and prospective cohorts, as well as randomized control trials reporting on patients with histopathologically confirmed metastatic sarcomas of the bony elements of the vertebrae, thecal sac, cord, or associated soft tissues of the spine were included. We excluded animal studies, case reports, case series, patients < 18 (pediatric cohorts), review articles and meta-analyses. No date filters were applied to our search.

Results: Our final analysis included 5 studies ranging from 2009 to 2024 reporting on 260 patients and 371 associated lesions. Leiomyosarcoma was the most frequently reported histologic subtype (60%). Most lesions were localized to the thoracic spine (48.6%). 75% of studies reported a median dose < 30 Gy, and achieved biologically equivalent doses (BEDs) ranging from < 50-100. Pooled 1-year median survival was 64.5% (IQR: 61.8-75.10). Pooled 1-year median LC was 86% (IQR: 79.4-88.5). Three of five studies (60%) for OS and 4/5 (80%) for LC had data availability suitable for meta-analysis. The 1-year OS and LC rates proportions across these studies were 67% (proportion = 0.67, 95% CI: 0.57-0.75, p = 0.07, I² = 63%), and 84% (proportion = 0.84, 95% CI: 0.78-0.89, p = 0.10, I² = 52%) respectively. Median follow up across all studies was 18 months (IQR:12.7-31.3).

Conclusions: SRS is a reasonable alternative therapy in either the up front, salvage or adjuvant setting which can facilitate durable LC.

Purpose: BRAF and MEK inhibitors are used to treat a range of paediatric tumours including low-grade gliomas. The ubiquitous nature of the BRAF/MAPK/MEK pathway means such treatments are not without side effects such as renal tubulopathies and hyperglycaemia. This study aims to describe the endocrine dysfunction observed in a cohort of children treated with BRAF and MEK inhibitors at the largest paediatric centre in the UK utilising these treatments.

Methods: Electronic data for patients treated with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) from January 2019 to May 2022 were retrospectively reviewed. Outcomes included diagnosis of glucose dysregulation, the presence of hyponatraemia (< 135 mmol/l) and sodium nadir during treatment.

Results: A total of 55 patients were included for analysis. Nine patients had at least one hyponatraemic episode during treatment of whom three had coexisting central diabetes insipidus. A statistically significant difference (p-value = 0.037) with regards to the plasma sodium nadir during treatment was observed between patients with diabetes insipidus (median = 134 (132-137) mmol/l) and patients without (median = 137 (127-141 mmol/l). Six patients were diagnosed with a form of glucose dysregulation (e.g. insulin resistance, type 2 diabetes), of whom four were diagnosed during treatment with dabrafenib, all with hypothalamo-pituitary lesions.

Conclusion: Clinicians using such treatments need to be aware of these potential effects, particularly the risk of hyponatraemia in patients with pre-existing central diabetes insipidus and monitor for these accordingly, including performing measurements of sodium and glucose prior to, during and after treatment.

Purpose: High-grade gliomas (HGG) represent a challenging subset of brain tumors characterized by aggressive nature and poor prognosis. Histopathology remains to be the standard for diagnosis, however, it is invasive, prone to sampling errors, and may not capture the full tumor heterogeneity and evolution over time. In recent years, there has been a growing interest in the potential utility of circulating biomarkers, obtained through minimally-invasive liquid biopsies, providing an opportunity for diagnosis, prognostication, monitoring treatment response and developing targeted therapies.

Methods: We have reviewed the literature on circulating biomarkers for HGG, including circulating tumor cells (CTCs), circulating tumor-derived exosomes/extracellular vesicles (ctEVs), circulating tumor-derived DNA (ctDNA), circulating tumor-derived miRNA (ctmiRNA), and circulating tumor-derived proteins.

Results: CTCs provide real-time information about tumor characteristics for molecular profiling and monitoring treatment response, yet their low numbers in circulation makes detection challenging. ctEVs carry a range of biomolecules and are easily detectable. However, they are not exclusively released from tumor cells and heterogeneity in their content requires standardized isolation and analysis methods. ctDNA is another promising biomarker with its levels correlating with the disease stage. However, its low concentration in blood requires highly sensitive techniques for identification and differentiation from normal cell-free DNA. ctmiRNA and tumor-derived proteins show promise but are limited by their susceptibility to dilution and lack of specificity in current technology.

Conclusion: This review highlights the transformative potential of circulating biomarkers in the management of HGG, with implications for improving patient outcomes, optimizing treatment strategies, and advancing precision oncology in neuro-oncology practice.