A Review of the Neurosurgical Management of Brain Metastases During Pregnancy.

OBJECTIVE: Patients with pregnancy-associated secondary brain tumors (PASBT) are challenging to manage. Because no guidelines for the management of such patients currently exist, we performed a systematic review of the literature using PRISMA guidelines with a discussion of management from a neurosurgeon's perspective. METHOD: Systematic review of the literature using PRISMA guidelines from 1999 to 2018. RESULTS: We identified 301 studies of which 16 publications (22 patients reporting 25 pregnancies, 20 deliveries, 5 early terminations) were suitable for final analysis. The most frequent primary cancers were breast (8/22, 36.36%), skin (6/22, 27.27%), and lung (5/22, 22.73%). Four patients (18.18%) had neurosurgical procedures during their pregnancies. Five patients (22.73%) received neurosurgical resection after their pregnancies. Nine patients (40.91%) received radiation therapy and seven patients (31.82%) received chemotherapy during pregnancy while seven patients (31.82%) received chemotherapy and radiation after pregnancy. There was 1 fetal death (5%) out of 20 healthy deliveries. Five pregnancies (20%) were terminated in the first trimester due to a need for urgent neurosurgical intervention. CONCLUSION: Management of PASBT remains a challenging issue. Maternal and fetal risks associated with surgical resection and teratogenicity due to adjuvant therapy should be discussed in the context of a multidisciplinary team. Timing of surgery and the use of systemic chemoradiation depends on the gestational age (GA) of the fetus, extent, and control of the mother's primary and metastatic disease. Guidelines need to be established to help neuro-oncology teams safely and effectively manage this group of patients.

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.

Surgical Management of Meningiomas Involving the Torcula, Transverse Sinus, and Jugular Bulb: A Technical Note and Review of the Literature.

Meningiomas that invade the confluens sinuum are rare and require extensive preoperative planning. Here, we describe the surgical and radio-oncological management of an aggressive large occipital meningioma invading the superior sagittal sinus, torcula, right and left transverse sinus down to the level of the jugular bulb in a 21-year-old female patient. Details of the surgical approach are presented to highlight the planned staged resection of this tumor at the level of the torcula to initially debulk the lesion while preserving venous outflow through the patent's sinus. Once the tumor fully occluded the confluens, a second-stage en bloc resection ensued. Postsurgical adjuvant radiation therapy was delivered via fractionated external beam therapy which has provided local control of the tumor since. This case is being discussed in the context of the pertinent literature to demonstrate the highly complex interdisciplinary and staged management of partially intravascular meningiomas involving the major venous sinuses.

Efficacy and Safety of Primary Stereotactic Radiosurgery in Patients With Intraventricular Meningiomas.

Purpose: Primary stereotactic radiosurgery for intraventricular meningiomas remains controversial owing to the potential for life-threatening peritumoral edema and lack of long-term follow-up data. We review the literature and present the largest series to assess efficacy and safety of primary stereotactic radiosurgery. Methods and Materials: A systematic review of the literature for primary stereotactic radiosurgery for intraventricular meningiomas was conducted. The retrospective series presented here comprised 33 patients who received primary stereotactic radiosurgery between 1999 and 2015 for a radiologically detected intraventricular meningioma. Demographic, diagnostic, and therapeutic data were extracted from medical records, imaging, and treatment-planning systems. Both standalone and pooled analysis were performed. Results: The mean patient age was 53 years, and 24 patients (73%) were female. The median Karnofsky performance status pretreatment was 80 (range, 60-100). The majority of lesions were located in the lateral ventricles (n = 32; 97%). The mean tumor volume was 8.7 cm3 (range, 0.6-44.55 cm3). The mean delivered dose was 1390.9 cGy. Complete imaging follow-up data were available for 21 patients (64%). Of those, 14 (67%) showed partial or marginal response, 7 (33%) had stable disease, and no patient progressed per Response Assessment in Neuro-Oncology criteria. On last follow-up, 32 patients (97%) had significant improvement in performance status and a decrease in pretreatment symptoms. No high-grade Common Terminology Criteria for Adverse Events (version 5.0) toxicity was observed with the dose range employed. Conclusions: Primary stereotactic radiosurgery for intraventricular meningiomas shows excellent treatment efficacy and low toxicity in patients with a long follow-up period. The best therapeutic algorithm remains to be established leveraging further clinical investigation.

Surgical Morbidity in Relation to the Surgical Approach for Olfactory Groove Meningiomas-A Pooled Analysis of 1016 Patients and Proposal of a New Reporting System.

Background: There is currently no consensus in the field regarding whether a frontal or lateral approach is superior for microsurgical resection of olfactory groove meningiomas (OGM). Due to the lack of uniformity in classifying lesions and inherent differences in reporting outcomes after varying operative approaches, the best practice for approaching these lesions is yet to be determined. Objective: This study aimed to assess various surgical approaches undertaken for OGMs, investigate procedural aspects influencing the extent of resection, and analyze the respective complication rate associated with each approach. We performed a comprehensive literature review of presenting signs and symptoms in OGM patients, their surgical management, and the reported surgical outcomes. To address the lack of uniform data reporting across studies and to take more recent translational studies into account, we developed a new classification system for OGMs that can remedy the existing deficiencies in comparability of reporting. Methods: We conducted a PRISMA-guided literature search for surgical reports on OGMs published in the MRI era using broad search terms such as 'olfactory groove meningioma' and 'surgery', which yielded 20,672 results. After title screening and removal of duplicates, we assessed 871 studies on the specific surgical management of olfactory groove meningiomas. Following the application of exclusion criteria and abstract screening, a set of 27 studies was chosen for the final analysis of a pooled cohort of these reported patient outcomes. Results: The final twenty-seven studies included in our in-depth analysis identified a total of 1016 individual patients who underwent open microsurgical resection of OGMs. The approaches used included: pterional/unilateral, bifrontal with variations, and anterior interhemispheric approaches. Across all studies, gross total resection (Simpson Grades I or II) was achieved in 91.4% of cases, and subtotal resection (Grades III and IV) was reported in 8.6% of cases. A cumulative twenty-seven percent of surgical OGM patients sustained some form of complications. Minor issues accounted for 22.2% (CSF leak, seizures, infection, transient cranial nerve palsies, hydrocephalus), whereas major issues comprised 4.7% (hemorrhage, ischemic infarct, malignant cerebral edema). We then examined the correlation between these complications and the surgical approach chosen. Among pooled cohort of 426 patients who underwent unilateral approaches, 14% experienced minor complications, and 2.1% experienced major complications. For the mixed cohort of 410 patients who underwent bifrontal approaches, 24.6% experienced minor complications, and 7% experienced major complications. Conclusions: Unilateral approaches appear to have lower complication rates for the resection of OGMs compared to bilateral approaches. However, the extent of resection is not uniformly reported, making it difficult to identify differences. The use of an improved preoperative classification and scoring system can help establish a more coherent system to select the most suitable approach and to uniformly report surgical outcomes, such as EOR and complication rates specific to a given OGM and its surgical approach.

Primary epidural lymphocyte-depleted Hodgkin's lymphoma of the thoracic spine - presentation of a rare disease variant.

BACKGROUND: Lymphocyte-depleted Hodgkin's lymphoma is the rarest form of classical Hodgkin's lymphoma, accounting for < 1% of all cases. Patients often have advanced-stage disease at the time of presentation with an aggressive clinical course. Even more uncommon is primary extranodal disease and rarely it will be presenting with spinal cord compression. CASE PRESENTATION: An 88-year-old Caucasian female presented with a history of upper back pain for several months and new onset bilateral leg numbness and weakness. MRI of the spine showed a dorsal epidural lesion with cord compression at T1-T4 with involvement of the paraspinal muscles. The patient received urgent surgical decompression, with final histopathology showing a lymphocyte-depleted Hodgkin's lymphoma. Systemic work-up did not show evidence of nodal disease. Following surgery, she received a course of radiotherapy with good outcome. CONCLUSION: To the best of our knowledge, this is the first reported case of primary lymphocyte-depleted Hodgkin lymphoma presenting as epidural spinal cord compression. Our report, in conjunction with a review of the literature, suggests that surgical intervention is clearly indicated in de novo disease followed by radiotherapy.

The effects of design and positioning of carbon fiber lumbar interbody cages and their subsidence in vertebral bodies.

STUDY DESIGN: A biomechanical study using human cadaveric lumbar spines. OBJECTIVES: To determine the strength and stiffness of 3 carbon fiber cage designs in axial compression. To assess the effects of bone mineral density (BMD) on vertebral endplate failure with respect to the different cage patterns. SUMMARY OF BACKGROUND DATA: Unilateral transforaminal approaches are gaining popularity compared with posterolateral lumbar interbody fusion. With differences in the inherent strengths of each quadrant of the endplate, the effect of different cage designs and their location on the endplate may affect subsidence and fusion success. METHODS: BMD measurements were obtained from 30 human spinal segments from L3 to L5. Discectomies were performed and cages were placed on the cephalad endplate of each vertebra in 3 configurations: 2 small posterolateral rectangular cages; 1 small anterior banana cage; and 1 small central rectangular cage. Each segment was tested under compression until endplate failure was recorded. Two-way analysis of variance was used to test for the effects of cage design on cage subsidence and endplate failure. Analysis of covariance was conducted to test for the effects of age, BMD, and vertebral levels on the failure load and stiffness for each cage design. RESULTS: Cage design was not significant in affecting failure force across the endplate. There were insignificant differences comparing stiffness in compression for the 3 different cage placements patterns. Low BMD adversely affected failure force and construct stiffness across all 3 cage patterns. CONCLUSIONS: Cage design and position do not significantly affect failure of the construct or stiffness in compression across the endplate. BMD significantly affects both failure forces and stiffness but is not dependent on the positioning or design of the cage.

The Emerging Applications of Nanotechnology in Neuroimaging: A Comprehensive Review.

Neuroimaging modalities such as computer tomography and magnetic resonance imaging have greatly improved in their ability to achieve higher spatial resolution of neurovascular and soft tissue neuroanatomy, allowing for increased accuracy in the diagnosis of neurological conditions. However, the use of conventional contrast agents that have short tissue retention time and associated renal toxicities, or expensive radioisotope tracers that are not widely available, continue to limit the sensitivity of these imaging modalities. Nanoparticles can potentially address these shortcomings by enhancing tissue retention and improving signal intensity in the brain and neural axis. In this review, we discuss the use of different types of nanotechnology to improve the detection, diagnosis, and treatment of a wide range of neurological diseases.

Phage Particles of Controlled Length and Genome for In Vivo Targeted Glioblastoma Imaging and Therapeutic Delivery.

M13 bacteriophage (phage) are versatile, genetically tunable nanocarriers that have been recently adapted for use as diagnostic and therapeutic platforms. Applying p3 capsid chlorotoxin fusion with the "inho" circular single-stranded DNA (cssDNA) gene packaging system, we produced miniature chlorotoxin inho (CTX-inho) phage particles with a minimum length of 50 nm that can target intracranial orthotopic patient-derived GBM22 glioblastoma tumors in the brains of mice. Systemically administered indocyanine green conjugated CTX-inho phage accumulated in brain tumors, facilitating shortwave infrared detection. Furthermore, we show that our inho phage can carry cssDNA that are transcriptionally active when delivered to GBM22 glioma cells in vitro. The ability to modulate the capsid display, surface loading, phage length, and cssDNA gene content makes the recombinant M13 phage particle an ideal delivery platform.

A comprehensive literature review and meta-analysis of the prevalence of pan-cancer BRCA mutations, homologous recombination repair gene mutations, and homologous recombination deficiencies.

There is significant improvement in the outcomes following treatment with PARP inhibitors among patients with certain tumors that have BRCA mutations (BRCAm), homologous recombination repair (HRR) gene mutations, or homologous recombination deficiency (HRD) positivity. We performed a literature review and meta-analysis to evaluate the prevalence of BRCA1/2m, HRR gene mutations, and HRD positivity across multiple cancers. There were 265 publications on BRCA1/2 mutation prevalence, 189 on HRR gene mutation prevalence, and 7 on HRD positivity prevalence. The prevalences of germline BRCA1m and BRCA2m were 7.8% and 5.7% for breast cancer, 13.5% and 6.6% for ovarian cancer, 0.5% and 3.5% for prostate cancer, and 1.1% and 4.1% for pancreatic cancer, respectively. The prevalences of somatic BRCA1m and BRCA2m were 3.4% and 2.7% for breast cancer, 4.7% and 2.9% for ovarian cancer, 5.7% and 3.2% for prostate cancer, and 1.2% and 2.9% for pancreatic cancer, respectively. We identified 189 studies with over 418,649 samples across 25 tumor types that examined mutations in one or more HRR genes other than BRCA1/2. The prevalence of mutations among HRR genes remained low (less than 1%), with ATM (5.2%), CHEK2 (1.6%), and PALB2 (0.9%) exhibiting the highest prevalence. Seven studies evaluated HRD positivity in breast, ovarian, and prostate cancer patients. The prevalence of HRD positivity was 56% overall (95% CI = 48%-64%). The understanding of biomarker prevalence across tumor types and standardization of biomarker assays could have important clinical implications.

Current Treatment Approaches and Global Consensus Guidelines for Brain Metastases in Melanoma.

Background: Up to 60% of melanoma patients develop melanoma brain metastases (MBM), which traditionally have a poor diagnosis. Current treatment strategies include immunotherapies (IO), targeted therapies (TT), and stereotactic radiosurgery (SRS), but there is considerable heterogeneity across worldwide consensus guidelines. Objective: To summarize current treatments and compare worldwide guidelines for the treatment of MBM. Methods: Review of global consensus treatment guidelines for MBM patients. Results: Substantial evidence supported that concurrent IO or TT plus SRS improves progression-free survival (PFS) and overall survival (OS). Guidelines are inconsistent with regards to recommendations for surgical resection of MBM, since surgical resection of symptomatic lesions alleviates neurological symptoms but does not improve OS. Whole-brain radiation therapy is not recommended by all guidelines due to negative effects on neurocognition but can be offered in rare palliative scenarios. Conclusion: Worldwide consensus guidelines consistently recommend up-front combination IO or TT with or without SRS for the treatment of MBM.

A Systematic Review and Meta-Analysis on the Prognostic Value of BRCA Mutations, Homologous Recombination Gene Mutations, and Homologous Recombination Deficiencies in Cancer.

Patients with BRCA1/2 mutations (BRCAm), loss-of-function mutations in other homologous recombination repair (HRRm) genes, or tumors that are homologous recombination deficiency positivity (HRD+) demonstrate a robust response to PARPi therapy. We conducted a systematic literature review and meta-analysis to evaluate the prognostic value of BRCAm, HRRm, and HRD+ on overall survival (OS) among those treated by chemotherapy or targeted therapy other than PARPi across tumor types. A total of 135 eligible studies were included. Breast cancer (BC) patients with BRCA1/2m had a similar overall survival (OS) to those with wild-type BRCA1/2 (BRCA1/2 wt) across 18 studies. Ovarian cancer (OC) patients with BRCA1/2m had a significantly longer OS than those with BRCA1/2 wt across 24 studies reporting BRCA1m and BRCA2m, with an HR of 0.7 (0.6-0.8). Less OS data were reported for other tumors: 6 studies for BRCA2m compared with BRCA2 wt in prostate cancer with an HR of 1.9 (1.1-3.2) and 2 studies for BRCA1/2m compared with BRCA1/2 wt in pancreatic cancer with an HR of 1.5 (0.8-3.1). Only 4 studies reported HRD+ by either BRCA m or genomic instability score (GIS) ≥ 42 and OS by HRD status. The HR was 0.67 (0.43-1.02) for OS with HRD+ vs. HRD-. A total of 15 studies reported the association between HRRm and OS of cancers in which one or more HRR genes were examined. The HR was 1.0 (0.7-1.4) comparing patients with HRRm to those with HRR wild-type across tumors. Our findings are useful in improving the precision and efficacy of treatment selection in clinical oncology.

Inducing DNA damage through R-loops to kill cancer cells.

R-loops are intermediate structures of transcription that can accumulate when transcriptional elongation is blocked by inhibiting BRD4. In normal cells, R-loop persistence suppresses firing of adjacent replication origins. This control is lost in a subset of cancer cells, where BRD4 inhibition results in R-loop accumulation, leading to transcription-replication collisions and DNA double-strand breaks during S-phase, followed by cell death. This finding sheds new light on the mechanisms by which BRD4 inhibitors function as cancer therapies, and indicates that targeting other cellular events to cause R-loop accumulation may be useful for cancer treatment.

BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage.

Proper chromatin function and maintenance of genomic stability depends on spatiotemporal coordination between the transcription and replication machinery. Loss of this coordination can lead to DNA damage from increased transcription-replication collision events. We report that deregulated transcription following BRD4 loss in cancer cells leads to the accumulation of RNA:DNA hybrids (R-loops) and collisions with the replication machinery causing replication stress and DNA damage. Whole genome BRD4 and γH2AX ChIP-Seq with R-loop IP qPCR reveals that BRD4 inhibition leads to accumulation of R-loops and DNA damage at a subset of known BDR4, JMJD6, and CHD4 co-regulated genes. Interference with BRD4 function causes transcriptional downregulation of the DNA damage response protein TopBP1, resulting in failure to activate the ATR-Chk1 pathway despite increased replication stress, leading to apoptotic cell death in S-phase and mitotic catastrophe. These findings demonstrate that inhibition of BRD4 induces transcription-replication conflicts, DNA damage, and cell death in oncogenic cells.

Indications, feasibility, safety, and efficacy of CyberKnife radiotherapy for the treatment of olfactory groove meningiomas: a single institutional retrospective series.

PURPOSE: To assess the safety and efficacy of CyberKnife® radiotherapy (CKRT) for the treatment of olfactory groove meningiomas (OGMs). METHODS: A retrospective review was performed of 13 patients with OGM treated with CKRT from September 2005 to May 2018 at our institution. Nine patients were treated primarily with CKRT, 3 for residual disease following resection, and 1 for disease recurrence. RESULTS: Five patients were treated with stereotactic radiosurgery (SRS), 6 with hypofractionated stereotactic radiotherapy (HSRT), and 2 with fractionated stereotactic radiotherapy (FSRT). The median tumor volume was 8.12 cm3. The median prescribed dose was 14.8 Gy for SRS, 27.3 Gy for HSRT, and 50.2 Gy for FSRT. The median maximal dose delivered was 32.27 Gy. Median post treatment follow-up was 48 months. Twelve of 13 patients yielded a 100% regional control rate with a median tumor volume reduction of 31.7%. Six of the 12 patients had reduced tumor volumes while the other 6 had no changes. The thirteenth patient had significant radiation-induced edema requiring surgical decompression. Twelve patients were alive and neurologically stable at the time of the review. One patient died from pneumonia unrelated to his CKRT treatment. CONCLUSIONS: CKRT appears to be safe and effective for the treatment of OGMs.

Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints.

In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. Delivery of siRNA-peptide nanoplexes co-targeting MK2 and XPA to pre-existing p53-deficient tumors in a highly aggressive, immunocompetent mouse model of lung adenocarcinoma improves long-term survival and cisplatin response beyond those of the synthetic lethal p53 mutant/MK2 combination alone. These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment.

Cervical spine instability following cervical laminectomies for Chiari II malformation: a retrospective cohort study.

OBJECTIVE: The treatment of symptomatic Chiari II malformations typically involves multilevel cervical laminectomies in very young children. These patients are at significant risk of cervical instability. The purpose of this study was to determine the incidence and significance of cervical instability after multilevel cervical laminectomies in a cohort of patients decompressed for Chiari II malformation. METHODS: Postoperative dynamic lateral cervical spine radiographs were obtained on pediatric patients who had multilevel cervical laminectomies for symptomatic Chiari II malformations. Postoperative cervical spine instability was determined radiographically using published criteria. Clinical instability and need for cervical fusion were also assessed. RESULTS: Nine patients met inclusion criteria for the study. Five of the nine patients (56%) showed evidence of radiographic instability of their cervical spines following surgery for their Chiari II malformations, according to the criteria used. No patient showed evidence of clinical instability or required cervical fusion. CONCLUSION: Radiographic evidence of cervical spine instability following multilevel cervical laminectomies for Chiari II is common but may be of minimal clinical significance. The reason for the lack of clinical instability in what might be considered high-risk patients is not understood.

Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.

Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles.

Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5- to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors.