Unveiling the axonal connectivity between the precuneus and temporal pole: Structural evidence from the cingulum pathways.

Neuroimaging studies have consistently demonstrated concurrent activation of the human precuneus and temporal pole (TP), both during resting-state conditions and various higher-order cognitive functions. However, the precise underlying structural connectivity between these brain regions remains uncertain despite significant advancements in neuroscience research. In this study, we investigated the connectivity of the precuneus and TP by employing parcellation-based fiber micro-dissections in human brains and fiber tractography techniques in a sample of 1065 human subjects and a sample of 41 rhesus macaques. Our results demonstrate the connectivity between the posterior precuneus area POS2 and the areas 35, 36, and TG of the TP via the fifth subcomponent of the cingulum (CB-V) also known as parahippocampal cingulum. This finding contributes to our understanding of the connections within the posteromedial cortices, facilitating a more comprehensive integration of anatomy and function in both normal and pathological brain processes. PRACTITIONER POINTS: Our investigation delves into the intricate architecture and connectivity patterns of subregions within the precuneus and temporal pole, filling a crucial gap in our knowledge. We revealed a direct axonal connection between the posterior precuneus (POS2) and specific areas (35, 35, and TG) of the temporal pole. The direct connections are part of the CB-V pathway and exhibit a significant association with the cingulum, SRF, forceps major, and ILF. Population-based human tractography and rhesus macaque fiber tractography showed consistent results that support micro-dissection outcomes.

Pituitary metastases: a case series and scoping review.

PURPOSE: To understand the natural history and optimal treatment strategy for pituitary gland metastasis. METHODS: We performed both a retrospective chart review of patients treated at our institution and a scoping review of the topic. RESULTS: The retrospective review identified seven patients with an average age of 59.6 years. Primary histologies included breast cancer (4), melanoma (1), renal cell carcinoma (1), and sarcoma (1). Two patients had anterior pituitary endocrine dysfunction, one of whom was the only patient with visual symptoms. All patients were treated with radiosurgery and two also underwent surgical resection. Overall survival ranged from 6.5 to 117 months. Literature review identified 166 patients from 71 studies. The most common primary cancer was lung (27.7%), followed by breast (18.7%) and renal (14.5%) cancer. 107 presented with endocrine dysfunction, including 41 cases of diabetes insipidus and 55 cases of hypopituitarism. 110 presented with visual compromise. 107 patients received radiotherapy, 96 underwent surgical resection and 44 received systemic chemotherapy/immunotherapy. Surgery was significantly associated with an increased likelihood of vision improvement and a decreased likelihood of endocrine normalization. Radiographic regression predicted visual improvement. Median overall survival was 9.9 months (range: 0.2-96). CONCLUSIONS: This scoping review showed that both radiosurgery and surgical resection have been frequently used to treat pituitary metastases with good response. Vision improvement is more likely to happen following surgical resection, likely at the expense of endocrine dysfunction. Despite treatment and radiographic response, patient survival remains less than a year.

Postoperative CT scans after resection of brain metastases: neurosurgical routine or added value?

BACKGROUND: Metastasis is the most common brain tumor in adults. It is the standard of care at most North American centers to obtain an early postoperative imaging after their resection. However, the necessity of this practice in the absence of a new postoperative deficit remains unclear. METHODS: We retrospectively reviewed our surgical cohort of patients who underwent resection of brain metastases from July 2018 to June 2019. We collected demographic data and reviewed results of routine postoperative CT scans and neurological morbidities to examine the diagnostic and therapeutic yield of an early postoperative scan. In addition, we performed a systematic review of the topic. RESULTS: Our review included 130 patients, all of whom underwent gross total resection of one or more brain metastases. On postoperative CT, none had unexpected findings such as cavity hematoma or new ischemia; no changes in management resulted from postoperative imaging. One patient required a higher dose of dexamethasone on postoperative day 4 for delayed hemiparesis and aphasia due to cerebral edema. Three additional patients underwent a wound washout for delayed infection during a subsequent admission. Our systematic review identified three additional studies; in a combined cohort of 450 patients (including our own), no patients had clinically actionable findings on routine postoperative CT. CONCLUSIONS: Following resection of brain metastases, a routine postoperative CT scan has low diagnostic yield and did not change patient management in any cases examined in this work.

Neurosurgical management of adult diffuse low grade gliomas in Canada: a multi-center survey.

Adult diffuse low-grade gliomas are slow growing, World Health Organization grade II lesions with insidious onset and ultimate anaplastic transformation. The timing of surgery remains controversial with polarized practices continuing to govern patient management. As a result, the management of these patients is variable. The goal of this questionnaire was to evaluate practice patterns in Canada. An online invitation for a questionnaire including diagnostic, preoperative, perioperative, and postoperative parameters and three cases with magnetic resonance imaging data with questions to various treatment options in these patients was sent to practicing neurosurgeons and trainees. Survey was sent to 356 email addresses with 87 (24.7%) responses collected. The range of years of practice was less than 10 years 36% (n = 23), 11-20 years 28% (n = 18), over 21 years 37% (n = 24). Twenty-two neurosurgery students of various years of training completed the survey. 94% (n = 47) of surgeons and trainees (n = 20) believe that we do not know the "right treatment". 90% of surgeons do not obtain formal preoperative neurocognitive assessments. 21% (n = 13) of surgeons and 23% of trainees (n = 5) perform a biopsy upon first presentation. A gross total resection was believed to increase progression free survival (surgeons: 75%, n = 46; trainees: 95%, n = 21) and to increase overall survival (surgeons: 64%, n = 39, trainees: 68%, n = 15). Intraoperative MRI was only used by 8% of surgeons. Awake craniotomy was the procedure of choice for eloquent tumors by 80% (n = 48) of surgeons and 100% of trainees. Of those surgeons who perform awake craniotomy 93% perform cortical stimulation and 38% performed subcortical stimulation. Using the aid of three hypothetical cases with progressive complexities in tumor eloquence there was a trend for younger surgeons to operate earlier, and use awake craniotomy to obtain greater extent of resection with the aid of cortical stimulation when compared to senior surgeons who still more often preferred a "wait-and-see" approach. Despite the limitations of an online survey study, it has offered insights into the variability in surgeon practice patterns in Canada and the need for a consensus on the workup and surgical management of this disease.

LITTing up Gliomas-Is the Future Bright?

Background: Laser interstitial thermal therapy (LITT) represents an attractive therapeutic strategy for several intracranial pathologies; however, there is a paucity of literature regarding its efficacy for the treatment of gliomas. Methods: MEDLINE, EMBASE, Scopus, and Web of Science were searched from inception until March 19, 2021. Studies specifically relating to the use of LITT in treatment of glioma were eligible for inclusion. A meta-analysis of means was performed to assess the progression-free survival (PFS) and overall survival (OS) following LITT and descriptive statistics relating to patients undergoing LITT were collated and a meta-analysis of proportions was also performed to assess the rate of complications. Results: In total, 17 studies were included for the meta-analysis, comprising 401 patients with 408 gliomas of which 88 of 306 (28.8%) were grade 1 or 2 and 218 of 306 (71.2%) were grade 3 or 4. Of these, 256 of 408 (62.8%) were primary presentation and 152 of 408 (37.2%) were recurrent. The pooled mean OS was 13.58 months (95% confidence interval [CI] 9.77-17.39) and the PFS was 4.96 months (95% CI 4.19-5.72). The OS and PFS of recurrent glioblastoma were 12.4 months (95% CI 9.61-16.18) and 4.84 months (95% CI 0.23-9.45), respectively. Complications occurred in 114 of 411 (24%; 95% CI 14-41), of which 44 (11%) were transient deficits. Conclusions: There is an increasing body of evidence demonstrating the use of LITT in the surgical management of deep-seated gliomas in patients of poor performance status. However, further studies are required to interrogate the clinical effectiveness of LITT in the setting of gliomas as well as assessing the survival benefit versus standard treatment alone.

Multiplicity does not significantly affect outcomes in brain metastasis patients treated with surgery.

Background: Brain metastasis quantity may be a negative prognostic factor for patients requiring resection of at least one lesion. Methods: We retrospectively reviewed patients who underwent surgical resection of brain metastases from July 2018 to June 2019 at our institution, and examined outcomes including overall survival (OS), progression free survival (PFS), and rates of local failure (LF). Patients were grouped according to the number of metastases at the time of surgery (single vs multiple). Results: We identified 130 patients who underwent surgical resection as the initial treatment modality. At the time of surgery, 87 patients had only one lesion (control) and 43 had multiple (>1). Two-year OS for the entire cohort was 46%, with equal rates in both the multiple metastases group and the control group (P = .335). 2-year PFS was 27%; 21% in the multiple metastases group and 31% in the control group (P = .766). The rate of LF at 2 years was 32%, with equal rates in both the multiple lesion group and control group (P = .889). On univariate analysis, multiplicity was not significantly correlated to OS (HR = 0.80, 95% CI: 0.51-1.26, P = .336), PFS (HR = 1.06, 95% CI: 0.71-1.59, P = .766) or LF (HR = 1.06, 95% CI: 0.57-1.97, P = .840). Multivariate analysis revealed preoperative tumor volume of the resected lesion to be the single correlate for OS (P = .0032) and PFS (P = .0081). Conclusions: Having more than one metastasis does not negatively impact outcomes in patients treated with surgery. In carefully selected patients, especially those with large tumors, surgery should be considered regardless of the total number of lesions.

Laser interstitial thermal therapy for the treatment of insular lesions: A systematic review.

Background: The surgical treatment of insular lesions has been historically associated with high morbidity. Laser interstitial thermal therapy (LITT) has been increasingly used in the treatment of insular lesions, commonly neoplastic or epileptogenic. Stereotaxis is used to guide laser probes to the insula where real-time magnetic resonance thermometry defines lesion creation. There is an absence of previously published reviews on insular LITT, despite a rapid uptake in use, making further study imperative. Methods: Here we present a systematic review of the PubMed and Scopus databases, examining the reported clinical indications, outcomes, and adverse effects of insular LITT. Results: A review of the literature revealed 10 retrospective studies reporting on 53 patients (43 pediatric and 10 adults) that were treated with insular LITT. 87% of cases were for the treatment of epilepsy, with 89% of patients achieving seizure outcomes of Engle I-III following treatment. The other 13% of cases reported on insular tumors and radiological improvement was seen in all cases following treatment. All but one study reported adverse events following LITT with a rate of 37%. The most common adverse events were transient hemiparesis (29%) and transient aphasia (6%). One patient experienced an intracerebral hemorrhage, which required a decompressive hemicraniectomy, with subsequent full recovery. Conclusion: This systematic review highlights the suitability of LITT for the treatment of both insular seizure foci and insular tumors. Despite the growing use of this technique, prospective studies remain absent in the literature. Future work should directly evaluate the efficacy of LITT with randomized and controlled trials.

A Network-Based Approach to Glioma Surgery: Insights from Functional Neurosurgery.

The evaluation and manipulation of structural and functional networks, which has been integral to advancing functional neurosurgery, is beginning to transcend classical subspecialty boundaries. Notably, its application in neuro-oncologic surgery has stimulated an exciting paradigm shift from the traditional localizationist approach, which is lacking in nuance and optimization. This manuscript reviews the existing literature and explores how structural and functional connectivity analyses have been leveraged to revolutionize and individualize pre-operative tumor evaluation and surgical planning. We describe how this novel approach may improve cognitive and neurologic preservation after surgery and attenuate tumor spread. Furthermore, we demonstrate how connectivity analysis combined with neuromodulation techniques can be employed to induce post-operative neuroplasticity and personalize neurorehabilitation. While the landscape of functional neuro-oncology is still evolving and requires further study to encourage more widespread adoption, this functional approach can transform the practice of neuro-oncologic surgery and improve the care and outcomes of patients with intra-axial tumors.

Complications in 622 cases of frame-based stereotactic biopsy, a decreasing procedure.

BACKGROUND: Frame-based stereotactic brain biopsy has played an important role in the management of patients with suspected neoplastic intracranial lesions over the last three decades. We reviewed the surgical experience of one surgeon to determine the nature and frequency of complications associated with this procedure. METHODS: Records were reviewed for 858 patients undergoing frame-based stereotactic procedures from January 1986 to May 2006. Data on each case were prospectively collected by the senior author. Procedures for Ommaya reservoir placement, brachytherapy, stereotactic craniotomy flap localization, shunt placement, or treatment of previously-diagnosed intracranial cystic lesions were excluded, leaving 614 patients in whom a total of 622 procedures were performed for purely diagnostic purposes. Complication rates and their association with clinical variables were sought. RESULTS: Morbidity and mortality rates were 6.9% (43/622) and 1.3% (8/622), respectively. The risk of symptomatic hemorrhage (intracerebral hemorrhage [ICH], subarachnoid hemorrhage [SAH], intraventricular hemorrhage [IVH]) was 4.8%. The risks of transient or permanent neurological deficits were 2.9% (18/622) and 1.5% (9/622), respectively. Biopsy of deep-seated lesions was associated with increased overall complication rate, while biopsy of Glioblastoma Multiforme (GBM) was associated with perioperative mortality. CONCLUSIONS: Overall, complication rates were comparable with those in previous reports. The subgroup of patients with deep-seated lesions or a histologic diagnosis of GBM may possess an elevated risk of overall complications or mortality, respectively, compared to other patients undergoing frame-based stereotactic brain biopsy.

Epigenetic regulation of glial fibrillary acidic protein by DNA methylation in human malignant gliomas.

Glial fibrillary acidic protein (GFAP) is an intermediate filament expressed in glial cells that stabilizes and maintains the cytoskeleton of normal astrocytes. In glial tumors, GFAP expression is frequently lost with increasing grade of malignancy, suggesting that GFAP is important for maintaining glial cell morphology or regulating astrocytoma cell growth. Most permanent human glioma cell lines are GFAP negative by immunocytochemistry. Given that the GFAP gene is not mutated in human glioma specimens or glioma cell lines, we considered epigenetic mechanisms, such as promoter methylation, as a cause of silencing of GFAP in these tumors. In this study, we treated known GFAP-negative glioma cell lines with 5-aza-2'-deoxycytidine to examine GFAP promoter hypermethylation. Additionally, we performed bisulfite sequencing on primary glioma samples and glioma cell lines and showed an inverse relationship between GFAP promoter methylation status and GFAP expression. Using a gene reporter assay with the GFAP promoter cloned upstream of a luciferase gene, we showed that methylation of the GFAP promoter downregulates the expression of the luciferase gene. Our results suggest that epigenetic silencing of the GFAP gene through DNA methylation of its promoter region may be one mechanism by which GFAP is downregulated in human gliomas and glioma cell lines.

Inhibition of the MET Receptor Tyrosine Kinase as a Novel Therapeutic Strategy in Medulloblastoma.

Medulloblastoma is the most common pediatric posterior fossa malignancy, with a 5-year overall survival of only 60% and many survivors experiencing treatment-related morbidity secondary to current therapeutic regimens. With an improved understanding of the molecular basis for this disease, the opportunity to develop novel treatments with more tolerable toxicity profiles that target key molecular pathways, now exists. Recently, the hepatocyte growth factor (HGF)/MET signaling pathway has been implicated in medulloblastoma pathogenesis. Several therapeutic strategies targeting this pathway exist, including small molecule inhibitor therapy against the MET receptor tyrosine kinase. We examined the in vitro efficacy of targeting the MET receptor using the highly specific small molecule inhibitor PHA665752 as a novel treatment strategy in medulloblastoma. MET inhibition using PHA665752 was effective at reducing the proliferative capacity of the D283, ONS76, and MED8A medulloblastoma cell lines as assessed by MTS assay. Furthermore, PHA665752 treatment reduced D283 and ONS76 cell motility and impaired the growth of D283 cells in soft agar. Pretreatment of D283, ONS76, and MED8A cells with PHA665752 blocked exogenous recombinant human HGF-induced up-regulation of the downstream RAS/mitogen-activated protein kinase signaling pathway in D283, ONS76 and MED8A cell lines. Similarly, PHA665752 prevented HGF-induced phosphatidylinositol 3-kinase/AKT signaling in ONS76 and MED8A cells. These results highlight the efficacy of targeting the MET receptor tyrosine kinase therapeutically in medulloblastoma and provide support for further preclinical testing of small molecule inhibitors targeting the MET receptor in medulloblastoma.

Genetic and epigenetic inactivation of Kruppel-like factor 4 in medulloblastoma.

Although medulloblastoma is the most common pediatric malignant brain tumor, its molecular underpinnings are largely unknown. We have identified rare, recurrent homozygous deletions of Kruppel-like Factor 4 (KLF4) in medulloblastoma using high-resolution single nucleotide polymorphism arrays, digital karyotyping, and genomic real-time polymerase chain reaction (PCR). Furthermore, we show that there is loss of physiological KLF4 expression in more than 40% of primary medulloblastomas both at the RNA and protein levels. Medulloblastoma cell lines drastically increase the expression of KLF4 in response to the demethylating agent 5-azacytidine and demonstrate dense methylation of the promoter CpG island by bisulfite sequencing. Methylation-specific PCR targeting the KLF4 promoter demonstrates CpG methylation in approximately 16% of primary medulloblastomas. Reexpression of KLF4 in the D283 medulloblastoma cell line results in significant growth suppression both in vitro and in vivo. We conclude that KLF4 is inactivated by either genetic or epigenetic mechanisms in a large subset of medulloblastomas and that it likely functions as a tumor suppressor gene in the pathogenesis of medulloblastoma.

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

An epigenetic genome-wide screen identifies SPINT2 as a novel tumor suppressor gene in pediatric medulloblastoma.

Medulloblastoma (MB) is a malignant cerebellar tumor that occurs primarily in children. The hepatocyte growth factor (HGF)/MET pathway has an established role in both normal cerebellar development as well as the development and progression of human brain tumors, including MB. To identify novel tumor suppressor genes involved in MB pathogenesis, we performed an epigenome-wide screen in MB cell lines, using 5-aza-2'deoxycytidine to identify genes aberrantly silenced by promoter hypermethylation. Using this technique, we identified an inhibitor of HGF/MET signaling, serine protease inhibitor kunitz-type 2 (SPINT2/HAI-2), as a putative tumor suppressor silenced by promoter methylation in MB. In addition, based on single nucleotide polymorphism array analysis in primary MB samples, we identified hemizygous deletions targeting the SPINT2 locus in addition to gains on chromosome 7 encompassing the HGF and MET loci. SPINT2 gene expression was down-regulated and MET expression was up-regulated in 73.2% and 45.5% of tumors, respectively, by quantitative real-time PCR. SPINT2 promoter methylation was detected in 34.3% of primary MBs examined by methylation-specific PCR. SPINT2 reexpression in MB cell lines reduced proliferative capacity, anchorage independent growth, cell motility in vitro, and increased overall survival times in vivo in a xenograft model (P<0.0001). Taken together, these data support the role of SPINT2 as a putative tumor suppressor gene in MB, and further implicate dysregulation of the HGF/MET signaling pathway in the pathogenesis of MB.