Flexible in-cavity MRI receiving coil for ultra-high-resolution imaging of the pituitary gland.

OBJECTIVE: The objective of this study was the preclinical design and construction of a flexible intrasphenoid coil aiming for submillimeter resolution of the human pituitary gland. METHODS: Sphenoid sinus measurements determined coil design constraints for use in > 95% of adult patients. Temperature safety parameters were tested. The 2-cm-diameter coil prototype was positioned in the sphenoid sinus of cadaveric human heads utilizing the transnasal endoscopic approach that is used clinically. Signal-to-noise ratio (SNR) was estimated for the transnasal coil prototype compared with a standard clinical head coil. One cadaveric pituitary gland was explanted and histologically examined for correlation to the imaging findings. RESULTS: With the coil positioned directly atop the sella turcica at a 0° angle of the B0 static field, the craniocaudal distance (21.2 ± 0.8 mm) was the limiting constraint. Phantom experiments showed no detectable change in temperature at two sites over 15 minutes. The flexible coil was placed transnasally in cadaveric specimens using an endoscopic approach. The image quality was subjectively superior at higher spatial resolutions relative to that with the commercial 20-channel head coil. An average 17-fold increase in the SNR was achieved within the pituitary gland. Subtle findings visualized only with the transnasal coil had potential pathological correlation with immunohistochemical findings. CONCLUSIONS: A transnasal radiofrequency coil feasibly provides a 17-fold boost in the SNR at 3 T. The ability to safely improve the quality of pituitary imaging may be helpful in the identification and subsequent resection of small functional pituitary lesions.

White matter connectivity of subthalamic nucleus and globus pallidus interna targets for deep brain stimulation.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) have differential therapeutic effects for Parkinson's disease (PD) that drive patient selection. For example, GPi DBS is preferred for dystonic features and dyskinesia, whereas STN DBS has shown faster tremor control and medication reduction. Connectivity studies comparing these two targets, using patient-specific data, are still lacking. The objective was to find STN and GPi structural connectivity patterns in order to better understand differences in DBS-activated brain circuits between these two stimulation targets and to guide optimal contact selection. METHODS: The authors simulated DBS activation along the main axis of both the STN and GPi by using volume of activated tissue (VAT) modeling with known average stimulation parameters (2.8 V and 60 µsec for STN; 3.3 V and 90 µsec for GPi). The authors modeled VATs in the anterior, middle, and posterior STN and the anterior, midanterior, midposterior, and posterior GPi. The authors generated maps of the connections shared by the patients for each VAT by using probabilistic tractography of diffusion-weighted imaging data obtained in 46 PD patients who underwent DBS (26 with STN and 20 with GPi targeting), and differences between VATs for whole-brain and distal regions of interest (prefrontal cortex, supplementary motor area, primary motor cortex, primary sensory cortex, caudate, motor thalamus, and cerebellum) were generated from structural atlases. Differences between maps were quantified and compared. RESULTS: VATs across the STN and GPi had different structural connectivity patterns. The authors found significant connectivity differences between VATs for all regions of interest. Posterior and middle STN showed stronger connectivity to the primary motor cortex and supplementary motor area (SMA) (p < 0.001). Posterior STN had the strongest connectivity to the primary sensory cortex and motor thalamus (p < 0.001). Posterior GPi showed stronger connectivity to the primary motor cortex (p < 0.001). Connectivity to the SMA was similar for the posterior and midposterior GPi (p > 0.05), which was greater than that for the anterior GPi (p < 0.001). When both nuclei were compared, posterior and middle STN had stronger connectivity to the SMA, cerebellum, and motor thalamus than GPi (all p < 0.001). Posterior GPi and STN had similar connectivity to the primary sensory cortex. CONCLUSIONS: On patient-specific imaging, structural connectivity differences existed between GPi and STN DBS, as measured with standardized electrical field modeling of the DBS targets. These connectivity differences may correlate with the differential clinical benefits obtained by targeting each of the two nuclei with DBS for PD. Prospective work is needed to relate these differences to clinical outcomes and to inform targeting and programming.

Cochlear Implantation in Adults With Single-Sided Deafness: A Systematic Review and Meta-analysis.

OBJECTIVE: To determine the clinical outcomes of adult patients with single-sided deafness (SSD) undergoing ipsilateral cochlear implantation. DATA SOURCE: An electronic search of Medline and Embase articles. REVIEW METHODS: A systematic review was performed with a search strategy developed by a licensed librarian to identify studies of adult patients with SSD who underwent ipsilateral cochlear implantation. Articles were managed in Covidence and evaluated by 2 independent reviewers. Risk of bias was assessed and data were extracted, including patient demographics, etiology of deafness, duration of deafness, and postoperative change in speech recognition, tinnitus, sound localization, and quality of life (QoL). A meta-analysis was performed, and pooled mean differences were calculated for each outcome of interest via random effects models by each outcome, as well as subgroup analyses by the individual clinical score used. RESULTS: Of 2309 studies identified, 185 full texts were evaluated, and 50 were ultimately included involving 674 patients. Speech perception scores in quiet and noise, tinnitus control, sound localization, and QoL all significantly improved after implantation. Pooled outcomes demonstrated score improvements in speech perception (standardized mean difference [SMD], 2.8 [95% CI, 2.16-3.43]), QoL (SMD, 0.68 [95% CI, 0.45-0.91]), sound localization (SMD, -1.13 [95% CI, -1.68 to -0.57]), and tinnitus score reduction (SMD, -1.32 [95% CI, -1.85 to -0.80]). CONCLUSIONS: Cochlear implantation in adults with SSD results in significant improvements in speech perception, tinnitus control, sound localization, and QoL.

The Knosp Criteria Revisited: 3-Dimensional Volumetric Analysis as a Predictive Tool for Extent of Resection in Complex Endoscopic Pituitary Surgery.

BACKGROUND: The Knosp criteria have been the historical standard for predicting cavernous sinus invasion, and therefore extent of surgical resection, of pituitary macroadenomas. Few studies have sought to reappraise the utility of this tool after recent advances in visualization and modeling of tumors in complex endoscopic surgery. OBJECTIVE: To evaluate our proposed alternative method, using 3-dimensional (3D) volumetric imaging, and whether it can better predict extent of resection in nonfunctional pituitary adenomas. METHODS: Patients who underwent endoscopic transsphenoidal resection of pituitary macroadenomas at our institution were reviewed. Information was collected on neurological, endocrine, and visual function. Volumetric segmentation was performed using 3D Slicer software. Relationship of tumor volume, clinical features, and Knosp grade on extent of resection was examined. RESULTS: One hundred forty patients were identified who had transsphenoidal resection of nonfunctional pituitary adenomas. Macroadenomas had a median volume of 6 cm 3 (IQR 3.4-8.7), and 17% had a unilateral Knosp grade of at least 3B. On multiple logistic regression, only smaller log-transformed preoperative tumor volume was independently associated with increased odds of gross total resection (GTR; odds ratio: 0.27, 95% CI: 0.07-0.89, P < .05) when controlling for tumor proliferative status, age, and sex (area under the curve 0.67). The Knosp criteria did not independently predict GTR in this cohort ( P > .05, area under the curve 0.46). CONCLUSION: Increasing use of volumetric 3D imaging may better anticipate extent of resection compared with the Knosp grade metric and may have a greater positive predictive value for GTR. More research is needed to validate these findings and implement them using automated methods.

Extra-Axial Fluid Collections After Decompressive Craniectomy: Management, Outcomes, and Treatment Algorithm.

BACKGROUND: Extra-axial fluid collections (EACs) frequently develop after decompressive craniectomy. Management of EACs remains poorly understood, and information on how to predict their clinical course is inadequate. We aimed to better characterize EACs, understand predictors of their resolution, and delineate the best treatment paradigm for patients. METHODS: We reviewed patients who developed EACs after undergoing decompressive craniectomy for treatment of refractory intracranial pressure elevations. We excluded patients who had an ischemic stroke, as EACs in these patients have a different clinical course. We performed univariate analysis and multiple linear regression to find variables associated with earlier resolution of EACs and stratified our analyses by EAC phenotype (complicated vs. uncomplicated). We conducted a systematic review to compare our findings with the literature. RESULTS: Of 96 included patients, 73% were male, and median age was 42.5 years. EACs resolved after a median of 60 days. Complicated EACs were common (62.5%) and required multiple drainage methods before cranioplasty. These were not associated with a protracted course or increased risk of death (P > 0.05). Early bone flap restoration with simultaneous drainage was independently associated with earlier resolution of EACs (ß = 0.56, P < 0.001). Systematic review confirmed lack of standardized direction with respect to EAC management. CONCLUSIONS: Our analyses reveal 2 clinically relevant phenotypes of EAC: complicated and uncomplicated. Our proposed treatment algorithm involves replacing the bone flap as soon as it is safe to do so and draining refractory EACs aggressively. Further studies to assess long-term clinical outcomes of EACs are warranted.

Acute Cerebrovascular Events With COVID-19 Infection.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) has been associated with an increased incidence of thrombotic events, including stroke. However, characteristics and outcomes of COVID-19 patients with stroke are not well known. METHODS: We conducted a retrospective observational study of risk factors, stroke characteristics, and short-term outcomes in a large health system in New York City. We included consecutively admitted patients with acute cerebrovascular events from March 1, 2020 through April 30, 2020. Data were stratified by COVID-19 status, and demographic variables, medical comorbidities, stroke characteristics, imaging results, and in-hospital outcomes were examined. Among COVID-19-positive patients, we also summarized laboratory test results. RESULTS: Of 277 patients with stroke, 105 (38.0%) were COVID-19-positive. Compared with COVID-19-negative patients, COVID-19-positive patients were more likely to have a cryptogenic (51.8% versus 22.3%, P<0.0001) stroke cause and were more likely to suffer ischemic stroke in the temporal (P=0.02), parietal (P=0.002), occipital (P=0.002), and cerebellar (P=0.028) regions. In COVID-19-positive patients, mean coagulation markers were slightly elevated (prothrombin time 15.4±3.6 seconds, partial thromboplastin time 38.6±24.5 seconds, and international normalized ratio 1.4±1.3). Outcomes were worse among COVID-19-positive patients, including longer length of stay (P<0.0001), greater percentage requiring intensive care unit care (P=0.017), and greater rate of neurological worsening during admission (P<0.0001); additionally, more COVID-19-positive patients suffered in-hospital death (33% versus 12.9%, P<0.0001). CONCLUSIONS: Baseline characteristics in patients with stroke were similar comparing those with and without COVID-19. However, COVID-19-positive patients were more likely to experience stroke in a lobar location, more commonly had a cryptogenic cause, and had worse outcomes.

The Experiences of Minors Seeking Asylum in the United States: A Modified Consensual Qualitative Research Analysis.

Minors fleeing violence in their countries of origin constitute a significant portion of asylum seekers in the United States. Medical and mental health professionals provide continuity care services and offer pro bono forensic evaluations for this population to document evidence of human rights abuses and torture. The present study included a retrospective, qualitative chart review of deidentified personal declarations and clinician medico-legal affidavits associated with 36 asylum seekers under 21 years of age. Data were analyzed through a modified consensual qualified research (CQR-M) approach to identify patterns in these individuals' reports of persecution and assess health outcomes. Among the cases studied, violence by organized criminal groups (47.2%), family-based violence (44.4%), and gender-based violence (44.4%) were the most commonly cited reasons minors sought asylum. Evaluators documented a wide range of psychological sequelae: 80.5% of minors presented with clinically significant symptoms associated with trauma- and stressor-related disorders, depression, and/or anxiety at the time of their applications for asylum. Of note, almost three-quarters of the minors reported current enrollment in school and two-thirds reported factors related to adaptive functioning. Despite reported exposure to premigratory and migratory trauma, postmigratory stressors, and psychological sequelae related to their experiences of violence, these young asylum seekers exhibited signs of resilience and a range of health-promoting strengths.

A Multifaceted, Student-Led Approach to Improving the Opioid Prescribing Practices of Hospital Medicine Clinicians.

BACKGROUND: The development of guidelines for opioid prescribing, including those from the Society of Hospital Medicine and the Centers for Disease Control and Prevention, has been associated with changes in prescription patterns. However, many providers remain unaware of best practices surrounding appropriate opioid prescribing. METHODS: The research team implemented a multimodal quality improvement intervention, led by first-year medical students, designed to increase clinician adherence to current prescribing guidelines for patients discharged on opioids. This intervention included an awareness campaign, educational sessions for providers, and weekly performance feedback. RESULTS: A total of 4,993 discharges were identified in the baseline period and 4,811 discharges in the intervention period. During the baseline period, 12.3% of all patients discharged were discharged with opioid prescriptions vs. 11.4% during the intervention period (p = 0.165). Of these, approximately 60% were new opioid prescriptions during both periods (p = 0.991). The study's efforts were associated with a decrease in the percentage of patients discharged with opioid prescriptions longer than seven days (45.2% preintervention to 39.5% postintervention, p < 0.042); an increase in the percentage of patients with follow-up appointments within seven days of discharge (38.6% to 65.9%, p = 0.001); and an increase in documentation of prescription history obtained from the state Prescription Monitoring Program registry (32.5% to 39.7%, p = 0.042). CONCLUSION: This intervention provided a successful framework to engage learners in improving opioid prescribing practices. The results are promising, but the experiences highlight the significant effort and resources needed to change prescriber practices, potentially limiting sustainability.

Randomized controlled trials comparing surgery to non-operative management in neurosurgery: a systematic review.

BACKGROUND: A randomized controlled trial (RCT) remains the pinnacle of clinical research design. However, RCTs in neurosurgery, especially those comparing surgery to non-operative treatment, are rare and their relevance and applicability have been questioned. This study set out to assess trial design and quality and identify their influence on outcomes in recent neurosurgical trials that compare surgery to non-operative treatment. METHODS: From 2000 to 2017, PubMed and Embase databases and four trial registries were searched. RCTs were evaluated for study design, funding, adjustments to reported outcome measures, accrual of patients, and academic impact. RESULTS: Eighty-two neurosurgical RCTs were identified, 40 in spine disorders, 19 neurovascular and neurotrauma, 11 functional neurosurgery, ten peripheral nerve, and two pituitary surgery. Eighty-four RCTs were registered, of which some are ongoing. Trial registration rate differed per subspecialty. Funding was mostly from non-industry institutions (58.5%), but 25.6% of RCTs did not report funding sources. 36.4% of RCTs did not report a difference between surgical and non-operative treatment, 3.7% favored non-operative management. Primary and secondary outcome measures were changed in 13.2% and 34.2% of RCTs respectively and varied by subspecialty. 41.9% of RCTs subtracted ≥ 10% of the anticipated accrual and 12.9% of RCTs added ≥ 10%. 7.3% of registered RCTs were terminated, mostly due to too slow recruitment. Subspecialty, registration, funding, masking, population size, and changing outcome measures were not significantly associated with a reported benefit of surgery. High Jadad scores (≥ 4) were negatively associated with a demonstration of surgical benefit (P < 0.05). CONCLUSIONS: Neurosurgical RCTs comparing surgical to non-operative treatment often find a benefit for surgical treatment. Changes to outcome measurements and anticipated accrual are common and funding sources are not always reported.

Non-electrographic Seizures Due to Subdural Hematoma: A Case Series and Review of the Literature.

Seizures due to subdural hematoma (SDH) are a common finding, typically diagnosed using electroencephalography (EEG). At times, aggressive management of seizures is necessary to improve neurologic recovery and outcomes. Here, we present three patients who had undergone emergent SDH evacuation and showed postoperative focal deficits without accompanying electrographic epileptiform activity. After infarction and recurrent hemorrhage were ruled out, seizures were suspected despite a negative EEG. Patients were treated aggressively with AEDs and eventually showed clinical improvement. Long-term monitoring with EEG revealed electrographic seizures in a delayed fashion. EEG recordings are an important tool for seizure detection, but should be used as an adjunct to, rather than a replacement for, the clinical examination in the acute setting. At times, aggressive treatment of suspected postoperative seizures is warranted despite lack of corresponding electrographic activity and can improve clinical outcomes.

Oversight and Ethical Regulation of Conflicts of Interest in Neurosurgery in the United States.

BACKGROUND: Developmental incentives are fundamental to surgical progress, yet financial and professional incentives inherently create conflicts of interest (COI). Understanding how to manage COI held by neurosurgeons, industry, hospitals, and journal editors, without thwarting progress and innovation is critical. OBJECTIVE: To present an overview of COI associated with innovation in neurosurgery, and review ways to manage these in an ethically sound manner. METHODS: A review of the literature was performed to assess conflicts of interest that affect neurosurgical innovation, and review ways to manage COI of various parties while adhering to ethical standards. RESULTS: COI are inherent to collaboration and innovation, and are therefore an unavoidable component of neurosurgery. The lack of a clear distinction between clinical practice and innovation, ability to use devices off-label, and unstandardized disclosure requirements create inconsistencies in the way that conflicts of interest are handled. Additionally, lack of requirements to compare innovation to the standard of care and inherent bias that affects study design and interpretation can have profound effects on the medical literature. Conflicts of interest can have both direct and downstream effects on neurosurgical practice, and it is possible to manage them while improving the quality of research and innovation. CONCLUSION: Conflicts of interest are inherent to surgical innovation, and can be handled in an ethically sound manner. Neurosurgeons, device companies, hospitals, and medical journals can take steps to proactively confront bias and ensure patient autonomy and safety. These steps can preserve public trust and ultimately improve evidence-based neurosurgical practice.

Outcomes of intraparenchymal hemorrhage after direct oral anticoagulant or vitamin K antagonist therapy: A systematic review and meta-analysis.

Direct Oral Anticoagulants (DOAC) are increasingly used as an alternative to vitamin-K antagonists (VKA) for anticoagulation and have shown lower rates of intracranial hemorrhage; however, there is disagreement in the literature over the outcomes of the intraparenchymal hemorrhages (IPH) associated with DOACs, and clinical concern regarding the lack of standardized reversal strategies for DOACs. Thus, the aim of this meta-analysis was to compare mortality, hematoma volume, and risk of hematoma expansion in patients who developed an IPH on DOACs versus VKA. A systematic review of the literature was conducted in accordance with the PRISMA guidelines. Studies were selected that reported on mortality, hematoma expansion, and hematoma volume in DOAC-associated IPH. Pooled risk ratios (RR) were calculated for mortality and hematoma expansion and pooled mean difference (MD) was calculated for hematoma volume (ml) using random-effect models. 15 studies reporting on 1238 patients were included in the systematic review. Eleven of these compared DOAC-IPH to VKA-IPH and were pooled quantitatively. DOAC-IPH was not associated with increased mortality risk (RR: 0.95, 95%-CI: 0.72 -1.27) or increased hematoma expansion risk (RR: 0.92; 95%-CI: 0.75-1.12) compared to VKA-IPH. The hematoma volume of DOAC- IPH was statistically significantly smaller than VKA-IPH (MD: -12.14 ml; 95%-CI: -15.38; -8.89). In conclusion, DOAC-IPH was not associated with increased mortality or hematoma expansion compared to VKA-IPH and may be associated with a smaller hematoma volume.

Endocrine function and gland volume after endoscopic transsphenoidal surgery for nonfunctional pituitary macroadenomas.

OBJECTIVELoss of pituitary function due to nonfunctional pituitary adenoma (NFPA) may be due to compression of the pituitary gland. It has been proposed that the size of the gland and relative perioperative gland expansion may relate to recovery of pituitary function, but the extent of this is unclear. This study aims to assess temporal changes in hormonal function after transsphenoidal resection of NFPA and the relationship between gland reexpansion and endocrine recovery.METHODSPatients who underwent endoscopic transsphenoidal surgery by a single surgeon for resection of a nonfunctional macroadenoma were selected for inclusion. Patients with prior pituitary surgery or radiosurgery were excluded. Patient characteristics and endocrine function were extracted by chart review. Volumetric segmentation of the pre- and postoperative (≥ 6 months) pituitary gland was performed using preoperative and long-term postoperative MR images. The relationship between endocrine function over time and clinical attributes, including gland volume, were examined.RESULTSOne hundred sixty eligible patients were identified, of whom 47.5% were female; 56.9% of patients had anterior pituitary hormone deficits preoperatively. The median tumor diameter and gland volume preoperatively were 22.5 mm (interquartile range [IQR] 18.0-28.8 mm) and 0.18 cm3 (IQR 0.13-0.28 cm3), respectively. In 55% of patients, endocrine function normalized or improved in their affected axes by median last clinical follow-up of 24.4 months (IQR 3.2-51.2 months). Older age, male sex, and larger tumor size were associated with likelihood of endocrine recovery. Median time to recovery of any axis was 12.2 months (IQR 2.5-23.9 months); hypothyroidism was the slowest axis to recover. Although the gland significantly reexpanded from preoperatively (0.18 cm3, IQR 0.13-0.28 cm3) to postoperatively (0.33 cm3, IQR 0.23-0.48 cm3; p < 0.001), there was no consistent association with improved endocrine function.CONCLUSIONSRecovery of endocrine function can occur several months and even years after surgery, with more than 50% of patients showing improved or normalized function. Tumor size, and not gland volume, was associated with preserved or recovered endocrine function.

Timing of surgery in traumatic brachial plexus injury: a systematic review.

OBJECTIVE: Ideal timeframes for operating on traumatic stretch and blunt brachial plexus injuries remain a topic of debate. Whereas on the one hand spontaneous recovery might occur, on the other hand, long delays are believed to result in poorer functional outcomes. The goal of this review is to assess the optimal timeframe for surgical intervention for traumatic brachial plexus injuries. METHODS: A systematic search was performed in January 2017 in PubMed and Embase databases according to the PRISMA guidelines. Search terms related to "brachial plexus injury" and "timing" were used. Obstetric plexus palsies were excluded. Qualitative synthesis was performed on all studies. Timing of operation and motor outcome were collected from individual patient data. Patients were categorized into 5 delay groups (0-3, 3-6, 6-9, 9-12, and > 12 months). Median delays were calculated for Medical Research Council (MRC) muscle grade ≥ 3 and ≥ 4 recoveries. RESULTS: Forty-three studies were included after full-text screening. Most articles showed significantly better motor outcome with delays to surgery less than 6 months, with some studies specifying even shorter delays. Pain and quality of life scores were also significantly better with shorter delays. Nerve reconstructions performed after long time intervals, even more than 12 months, can still be useful. All papers reporting individual-level patient data described a combined total of 569 patients; 65.5% of all patients underwent operations within 6 months and 27.4% within 3 months. The highest percentage of ≥ MRC grade 3 (89.7%) was observed in the group operated on within 3 months. These percentages decreased with longer delays, with only 35.7% ≥ MRC grade 3 with delays > 12 months. A median delay of 4 months (IQR 3-6 months) was observed for a recovery of ≥ MRC grade 3, compared with a median delay of 7 months (IQR 5-11 months) for ≤ MRC grade 3 recovery. CONCLUSIONS: The results of this systematic review show that in stretch and blunt injury of the brachial plexus, the optimal time to surgery is shorter than 6 months. In general, a 3-month delay appears to be appropriate because while recovery is better in those operated on earlier, this must be considered given the potential for spontaneous recovery.

Quality of reporting and assessment of patient-reported health-related quality of life in patients with brain metastases: a systematic review.

Brain metastases (BMs) have become increasingly prevalent and present unique considerations for patients, including neurocognitive sequelae and advanced disease burden. Therefore, assessing health-related quality of life (HRQoL) via patient-reported outcome measures (PROMs) is an important element of managing these patients. A systematic review of the literature was conducted with the aims of (1) assessing how PROMS used in BM patients were validated, (2) assessing PROM content, and (3) evaluating quality of PROM-results reporting. PROM validation and quality of reporting were assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) grading criteria and International Society of Quality of Life (ISOQOL)-recommended PROM-reporting standards, respectively. Forty-seven studies reporting on 5178 patients with a range of primacy cancer types were included. Eight different PROMs were applied, ranging from general to brain-specific questionnaires. Weaknesses in the validation of these PROMs were assessed by the COSMIN criteria. Many of these PROMs were not developed for BM patients and contained little information on cognitive symptoms. The overall quality of PROM reporting was insufficient based on the ISOQOL scale. Given the unique clinical considerations in BM patients, our results indicate the need for a standardized, validated questionnaire to assess HRQoL in this population. Additionally, there is room for quality improvement with regard to reporting of PROM-related results.

Stereotactic radiosurgery versus whole-brain radiotherapy after intracranial metastasis resection: a systematic review and meta-analysis.

BACKGROUND: In patients with one to three brain metastases who undergo resection, options for post-operative treatments include whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) of the resection cavity. In this meta-analysis, we sought to compare the efficacy of each post-operative radiation modality with respect to tumor recurrence and survival. METHODS: Pubmed, Embase and Cochrane databases were searched through June 2016 for cohort studies reporting outcomes of SRS or WBRT after metastasis resection. Pooled effect estimates were calculated using fixed-effect and random-effect models for local recurrence, distant recurrence, and overall survival. RESULTS: Eight retrospective cohort studies with 646 patients (238 with SRS versus 408 with WBRT) were included in the analysis. Comparing SRS to WBRT, the overall crude risk ratio using the fixed-effect model was 0.59 for local recurrence (95%-CI: 0.32-1.09, I2: 3.35%, P-heterogeneity = 0.36, 3 studies), 1.09 for distant recurrence (95%-CI: 0.74-1.60, I2: 50.5%, P-heterogeneity = 0.13; 3 studies), and 2.99 for leptomeningeal disease (95% CI 1.55-5.76; I2: 14.4% p-heterogeneity: 0.28; 2 studies). For the same comparison, the risk ratio for median overall survival was 0.47 (95% CI: 0.41-0.54; I2: 79.1%, P-heterogeneity < 0.01; 4 studies) in a fixed-effect model, but was no longer significant (0.63; 95%-CI: 0.40-1.00) in a random-effect model. SRS was associated with a lower risk of leukoencephalopathy (RR: 0.15, 95% CI: 0.07-0.33, 1 study), yet with a higher risk of radiation-necrosis (RR: 19.4, 95% CI: 1.21-310, 1 study). CONCLUSION: Based on retrospective cohort studies, the results of this study suggest that SRS of the resection cavity may offer comparable survival and similar local and distant control as adjuvant WBRT, yet may be associated with a higher risk for developing leptomeningeal disease. Future research on SRS should focus on achieving a better understanding of the various factors that may favor SRS over WBRT.

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis.

Arsenic exposure increases risk for cancers and is teratogenic in animal models. Here we demonstrate that small ubiquitin-like modifier (SUMO)- and folate-dependent nuclear de novo thymidylate (dTMP) biosynthesis is a sensitive target of arsenic trioxide (As2O3), leading to uracil misincorporation into DNA and genome instability. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and serine hydroxymethyltransferase (SHMT) generate 5,10-methylenetetrahydrofolate for de novo dTMP biosynthesis and translocate to the nucleus during S-phase, where they form a multienzyme complex with thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR), as well as the components of the DNA replication machinery. As2O3 exposure increased MTHFD1 SUMOylation in cultured cells and in in vitro SUMOylation reactions, and increased MTHFD1 ubiquitination and MTHFD1 and SHMT1 degradation. As2O3 inhibited de novo dTMP biosynthesis in a dose-dependent manner, increased uracil levels in nuclear DNA, and increased genome instability. These results demonstrate that MTHFD1 and SHMT1, which are key enzymes providing one-carbon units for dTMP biosynthesis in the form of 5,10-methylenetetrahydrofolate, are direct targets of As2O3-induced proteolytic degradation, providing a mechanism for arsenic in the etiology of cancer and developmental anomalies.