Grade II and III gliomas are generally slowly progressing brain cancers, many of which eventually transform into more aggressive tumors. Despite recent findings of frequent mutations in IDH1 and ...other genes, knowledge about their pathogenesis is still incomplete. Here, combining two large sets of high-throughput sequencing data, we delineate the entire picture of genetic alterations and affected pathways in these glioma types, with sensitive detection of driver genes. Grade II and III gliomas comprise three distinct subtypes characterized by discrete sets of mutations and distinct clinical behaviors. Mutations showed significant positive and negative correlations and a chronological hierarchy, as inferred from different allelic burdens among coexisting mutations, suggesting that there is functional interplay between the mutations that drive clonal selection. Extensive serial and multi-regional sampling analyses further supported this finding and also identified a high degree of temporal and spatial heterogeneity generated during tumor expansion and relapse, which is likely shaped by the complex but ordered processes of multiple clonal selection and evolutionary events.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Extended endonasal transsphenoidal surgery (eTSS) offers a wide surgical field for various parasellar lesions; however, intraoperative high-flow cerebrospinal fluid (CSF) leakage is inevitable. ...Therefore, secure sellar reconstruction methods are essential to prevent postoperative CSF leakage. Although collagen matrix has been applied for dural reconstruction in neurosurgery, its suitability for application in extended eTSS remains unclear. Eighteen patients underwent modified shoelace dural closure using collagen matrix after lesionectomy via extended eTSS. In this technique, a collagen matrix, which was placed subdurally (inlay graft), was continuously sutured with both open dural edges like a shoelace. Then, another collagen matrix was placed epidurally (onlay graft), and rigid reconstruction was performed using the septal bone and a resorbable fixation mesh. Postoperative CSF leakage did not occur in 17 patients but did occur in 1 patient with tuberculum sellae meningioma. In this case, the CSF leakage point was detected just around the area between the coagulated dura and the adjacent collagen matrix. The collagen matrix harvested from this area was pathologically examined; neovascularization and fibroblastic infiltration into the collagen matrix were not detected. On the other hand, neovascularization and fibroblast infiltration into the collagen matrix were apparent on the surface of the collagen matrix harvested from the non-CSF leakage area. Our novel dural closure technique using collagen matrix could be an effective option for sellar reconstruction in extended eTSS; however, it should be applied in patients in whom normal dural edges are preserved.
The criteria for indication of salvage stereotactic radiosurgery (SRS) for local progression following multi-fraction (mf) SRS of brain metastases (BMs) remain controversial, along with the optimal ...planning scheme. Herein, we described a case of BMs from pan-negative lung adenocarcinoma (LAC), in which the two lesions of local progression following initial eight-fraction (8-fr) SRS were re-treated with 5-fr SRS with the biologically effective dose (BED10) of ≥80 Gy, based on the linear-quadratic (LQ) formula with an alpha/beta ratio of 10. The re-SRS resulted in the alleviation of symptoms and favorable tumor responses with minimal adverse effects during the 7.3-month follow-up. In the lesions of local progression, the gross tumor volume (GTV) coverage with 49.6 Gy (BED10 80 Gy) was generally insufficient, and the GTV dose wes relatively homogeneous with ≥87% isodose covering. In contrast, the 5-fr re-SRS was performed with sufficient GTV coverage with ≤68% isodose of 43 Gy (BED10 80 Gy). Taken together, sufficient GTV coverage with a BED10 of ≥80 Gy and steep dose increase inside the GTV boundary, that is, extremely inhomogeneous GTV dose, are important in 8-fr SRS for ensuring excellent local control of BMs from pan-negative LAC. For local progression following mfSRS that does not fulfill both criteria, re-SRS with the above planning scheme can be an efficacious and safe treatment option for at least six months, especially in cases in which the prior SRS was performed with a dose/fractionation under adequate consideration of brain tolerance. The BED10 seems to be the most suitable for estimating the anti-tumor efficacies of SRS doses in 3-8 fr, similar to that of a single fraction of 24 Gy.
There are no accurate mass screening methods for early detection of central nervous system (CNS) tumors. Recently, liquid biopsy has received a lot of attention for less-invasive cancer screening. ...Unlike other cancers, CNS tumors require efforts to find biomarkers due to the blood–brain barrier, which restricts molecular exchange between the parenchyma and blood. Additionally, because a satisfactory way to collect urinary biomarkers is lacking, urine-based liquid biopsy has not been fully investigated despite the fact that it has some advantages compared to blood or cerebrospinal fluid-based biopsy. Here, we have developed a mass-producible and sterilizable nanowire-based device that can extract urinary microRNAs efficiently. Urinary microRNAs from patients with CNS tumors (n = 119) and noncancer individuals (n = 100) were analyzed using a microarray to yield comprehensive microRNA expression profiles. To clarify the origin of urinary microRNAs of patients with CNS tumors, glioblastoma organoids were generated. Glioblastoma organoid-derived differentially expressed microRNAs (DEMs) included 73.4% of the DEMs in urine of patients with parental tumors but included only 3.9% of those in urine of noncancer individuals, which suggested that many CNS tumor-derived microRNAs could be identified in urine directly. We constructed the diagnostic model based on the expression of the selected microRNAs and found that it was able to differentiate patients and noncancer individuals at a sensitivity and specificity of 100 and 97%, respectively, in an independent dataset. Our findings demonstrate that urinary microRNAs extracted with the nanowire device offer a well-fitted strategy for mass screening of CNS tumors.
Background
A variety of revascularization techniques have been reported for the management of moyamoya disease to prevent risks of stroke. STA (superficial temporal artery)–MCA (middle cerebral ...artery) microanastomosis, single or double bypass, with temporal muscle or galeal onlay graft has been the standard operative procedure.
Method
Our rationale of revascularization surgery has been a combination of STA-MCA double bypass using the frontal and the parietal branches of STA and transfer of a highly vascularized thick galeal flap with maintained STA vasculature.
Conclusion
This STA-enhanced vascularized galeal flap graft is extremely effective for revascularization of moyamoya disease.
Stereotactic radiosurgery (SRS) with >5 fraction (fr) has been increasingly adopted for brain metastases (BMs), given the current awareness of limited brain tolerance for ≤5 fr. The target ...volume/configuration change and/or deviation within the cranium during fractionated SRS can be unpredictable and critical uncertainties affecting treatment accuracy, plus the effect of these events on the long-term outcome remains uncertain. Herein, we describe a case of two challenging BMs treated by 10 fr SRS with a unique dose-gradient optimization strategy, in which the large cystic tumor revealed an intriguing correlation of such inter-fractional change with late radiographic sequela, suggesting a dose threshold for attaining long-term local tumor control and being immune to symptomatic brain necrosis. A 63-year-old man presented with two cystic lesions located in the left parietal lobe (19.9 cm
) and pons (1.1 cm
) one month after surgery for esophageal squamous cell carcinoma. The principles for 10 fr SRS were as follows: (1) very inhomogeneous gross tumor volume (GTV) dose covered by 53 Gy, biologically effective dose with an alpha/beta ratio of 10 (BED
) of ≥80 Gy; (2) moderate dose spillage margin outside the GTV boundary: 2-2.5 mm outside the GTV margin was covered by 37 Gy, BED
of ≈50 Gy; (3) concentrically-laminated, steep dose increase inside the GTV boundary: 2 mm inside the GTV margin was covered by ≥62 Gy, BED
of ≥100 Gy. At the completion of SRS, the parietal lesion showed significant shrinking and dorsomedial shifting with slight evisceration of the GTV, followed by marked regression of the parietal lesion within four months. At 13.5 months, a cystic change was noted at the dorsal part of the remnant. At 16.7 months, ventral enhancement gradually expanded without enlargement of the dorsal cystic component. On the T2-weighted images, the dorsal low-intensity remnant and ventral iso-intensity blurry-demarcated component were contrasting. Pathological examinations during and after lesionectomy at 17.4 months revealed necrosis only. At 30.5 months, the patient had a left visual field defect without recurrence. In contrast, the pons lesion showed no notable change during 10 fr SRS and nearly complete remission over six months with its sustainment without radiation injury at 30.5 months. Taken together, 10 fr SRS with a sufficient BED
can provide superior tumor response and safety for BM that is not amenable to ≤5 fr SRS. Although a very inhomogeneous GTV dose can contribute to early and adequate tumor shrinkage and subsequent local tumor eradication, significant tumor shrinkage during fractionated SRS (fSRS) inevitably results in unnecessary higher dose exposure to the surrounding brain, which could lead to late radiation injury requiring intervention. The optimum dose should be determined through further investigation, in consideration of the dynamic and unpredictable nature of the actual absorbed doses to both the tumor and the surrounding brain.
The presigmoid approach (PSA) is selected to obtain more lateral access to cerebellopontine angle tumors, brainstem cavernous malformations, or vertebrobasilar artery aneurysms than the standard ...retrosigmoid approach. However, mastoidectomy for the PSA can be considered time-consuming and to carry a higher risk of complications due to the anatomical complexity of the region. The authors established a method of minimized mastoidectomy focused on exposing Trautmann's triangle as the corridor for the PSA while maximizing procedural simplicity and safety and maintaining a sufficient operative view. The authors present their method of minimized mastoidectomy in a cadaver dissection and operative cases, showing potential as a useful option for the PSA.
Abstract
Background
Recent comprehensive studies have revealed several molecular alterations that are frequently found in meningiomas. However, effective treatment reagents targeting specific ...molecular alterations have not yet been identified because of the limited number of representative research models of meningiomas.
Methods
We performed organoid cultures using meningioma cells and meningioma tumor tissues. Using immunohistochemistry and molecular analyses consisting of whole-exome sequencing, RNA-seq, and DNA methylation analyses, we compared the histological findings and molecular profiling of organoid models with those of parental tumors. Further, using these organoid models together with a public database of meningiomas, we explored molecular alterations, which are a potent treatment target for meningioma.
Results
We established 18 organoid models comprising of two malignant meningioma cells (HKBMM and IOMM-Lee), 10 benign meningiomas, four malignant meningiomas, and two solitary fibrous tumors (SFTs). The organoids exhibited consistent histological features and molecular profiles with those of the parental tumors. Using a public database, we identified that upregulated forkhead box M1 (FOXM1) was correlated with increased tumor proliferation. Overexpression of FOXM1 in benign meningioma organoids increased organoid proliferation; depletion of FOXM1 in malignant organoids decreased proliferation. Additionally, thiostrepton, a FOXM1 inhibitor combined with radiation therapy, significantly inhibited the proliferation of malignant meningioma organoid models.
Conclusions
An organoid model for meningioma enabled us to elucidate the tumor biology of meningioma along with potent treatment targets for meningioma.
Purpose
The aim of this study was to assess the effect of the extent of resection (EOR) of tumors on survival in a series of patients with grade II and III gliomas (GII/III-gliomas) who underwent ...awake brain mapping.
Methods
We retrospectively analyzed 126 patients with GII/III-gliomas in the dominant and non-dominant hemisphere who underwent awake brain surgery at the same institution between December 2012 and May 2020.
Results
EOR cut-off values for improved progression-free survival (PFS) were determined by a receiver operator characteristic (ROC) analysis of 5-year PFS. The ROC for EOR showed a cut-off value of ≥ 85.3%. The median PFS rate of patients with GII/III-gliomas in the group with an EOR ≥ 100%, including supratotal resection (n = 47; median survival MS, not reached), was significantly higher than that in the group with an EOR < 90% (n = 52; MS, 43.1 months; 95% CI 37.7–48.5 months;
p
= 0.03). In patients with diffuse astrocytomas and anaplastic astrocytomas, the group with EOR ≥ 100%, including supratotal resection (n = 25; MS, not reached), demonstrated a significantly better PFS rate than did the group with an EOR < 100% (n = 45; MS, 35.8 months; 95% CI 19.9–51.6 months;
p
= 0.03). Supratotal or gross total resection was correlated with better PFS in
IDH
-mutant type of diffuse astrocytomas and anaplastic astrocytomas (n = 19; MS, not reached vs. n = 35; MS, 40.6 months; 95% CI 22.3–59.0 months;
p
= 0.02). By contrast, supratotal or gross total resection was not associated with longer PFS rates in patients with
IDH
-wild type of diffuse astrocytomas and anaplastic astrocytomas.
Conclusions
The present study demonstrates a significant association between tumor EOR and survival in patients with GII/III gliomas. The EOR cut-off value for 5-year PFS was ≥ 85.3%. It is noteworthy that supratotal or gross total resection significantly correlated with better PFS in
IDH
-mutant type of WHO grade II and III astrocytic tumors. In light of our finding that EOR did not correlate with PFS in patients with aggressive
IDH
-wild type of diffuse astrocytomas and anaplastic astrocytomas, we suggest treatments that are more intensive will be needed for the control of these tumors.
Purpose: Given its high spatial resolution and vasculature selectivity, the cone-beam computed tomography (CT) angiography (CBCTA) image acquired by selective 3D rotational angiography (3DRA) is the ...most suitable 3D image for the target definition of stereotactic radiosurgery (SRS) for intracranial arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Furthermore, the relatively low temporal resolution of 3DRA-based CBCTA can be complemented by the stereotactic co-registration of orthogonally paired 2D dynamic digital subtraction angiography (2D-DSA). The integration of 2D-DSA, which is usually limited to one or a few frames for each projection, into CBCTA and/or planning CT can be achieved only by catheter-directed angiography on the day of SRS via a dedicated image localizer under rigid frame fixation to the skull, which imposes substantial burdens on patients. This study aimed to demonstrate a novel, convenient, and significantly less invasive method for the frameless co-registration of biplane 2D-DSA whole frames and CBCTA on commercially available dedicated software, namely, Brainlab® Elements (Brainlab AG, Munich, Germany), and present its prerequisite for successful image fusion.Technical Report: Elements have afforded the following functionality: A 3D vasculature image is automatically extracted as a floating image from any 3D image series containing vascular details and then subsequently co-registered manually and automatically to a selected frame pair of 2D-DSA with a six-degree-of-freedom rigid registration. As a preclinical feasibility study, two anonymous image datasets from patients harboring cerebral AVM and transverse-sigmoid (TS) DAVF were used to verify the accuracy and practicality of Elements for the frameless co-registration of 2D/3D vascular images, particularly on the assumption of clinical workflow for the target delineation of SRS planning. The use of ordinary unsubtracted CBCTA resulted in the insufficient extraction of abutting vessels or vessels that are in close proximity to bony structures, particularly in the case of TS-DAVF, where the fistulous pouch and the affected venous sinuses were adjacent to the cranial bone. By contrast, the amount and selectivity of vasculatures and the accuracy of subsequent image fusion were significantly improved from the subtracted CBCTA. The integration of CBCTA into dynamic 2D-DSA allowed the simultaneous review of both image information by sharing any concerning point and 2D or 3D structures under a common 3D coordinate.Conclusions: Elements enable the clinically useful frameless co-registration of biplane 2D-DSA whole frames into CBCTA, for which the routine acquisition of both subtracted and unsubtracted CBCTA axial images for ordinary diagnostic purposes is an indispensable prerequisite for successful image fusion and further widespread application. This frameless integration of the 2D/3D angiogram would dramatically enhance both the frame-based and frameless SRS workflow and circumstances by allowing users to forward SRS planning well in advance before SRS, along with the omission of invasive angiography on the day of SRS, and would broaden the implementation of frameless SRS. Furthermore, the comprehensive alternating interactive review of the 2D/3D integrated angiogram leads to a more in-depth quasi-4D understanding of the affected angioarchitectures compared with the separate viewing of each image.
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