Cerebral vasospasm following tumor resection: Illustrative cases and review of the literature.

BACKGROUND: Cerebral vasospasm (CV) after tumor resection is a rare event, although it is associated with poorer postoperative outcomes and increased morbidity and mortality. Given the potential for neurologic injury secondary to CV, there is a need for further understanding of this phenomenon. Therefore, the purpose of this study is to investigate the risk factors of CV following intracranial tumor resection. METHODS: A literature review was conducted identifying 61 studies (40 individual case reports, 14 case series, and 7 cohort studies) reporting 179 individual cases. Additionally, two illustrative cases were presented. RESULTS: Post-tumor resection CV was reported more often in males (58.0 %) than females (42.0 %), with an average age of onset of 47.3 years in males compared to 40.4 years in females. Of those specified, CV most commonly occurred in posterior fossa tumors (51.8 %), followed by the sellar/suprasellar region (36.6 %). The most common pathologies were schwannoma (31.8 %), pituitary adenoma (27.8 %), meningioma (15.2 %), and craniopharyngioma (9.9 %). Vasospasm most commonly occurred diffusely in the anterior circulation (60.2 %), with MCA and ACA involvement indicated in 72.7 % and 64.8 % of all cases, respectively. Symptomatically, CV most commonly presented with altered mental status (73.9 %) or weakness (60.9 %), specifically hemiparesis (37.0 %) or altered consciousness (22.8 %). Most cases of vasospasm presented within the first week (58.4 %), with 97.7 % occurring within the first 2 weeks. A higher mortality rate was associated with onset before 3 days (n=6/13; 46.2 %). Mortality was reported in 17.3 % (n=18) of all cases and residual deficits were reported in 53.5 % (n=46) of those patients who survived. CONCLUSION: Most reports on CV involved posterior fossa tumors, the anterior circulation (most frequently the MCA), and tumors of varying histologies. Tumor location and vascular involvement may be related to distribution of spasm and symptomatology. Early onset of vasospasm may furthermore be related to poorer outcomes.

Applications of Functional Magnetic Resonance Imaging to the Study of Functional Connectivity and Activation in Neurological Disease: A Scoping Review of the Literature.

BACKGROUND: Functional magnetic resonance imaging (fMRI) has transformed our understanding of brain's functional architecture, providing critical insights into neurological diseases. This scoping review synthesizes the current landscape of fMRI applications across various neurological domains, elucidating the evolving role of both task-based and resting-state fMRI in different settings. METHODS: We conducted a comprehensive scoping review following the Preferred Reporting Items for Systematic Review and Meta-Analyses Extension for Scoping Reviews guidelines. Extensive searches in Medline/PubMed, Embase, and Web of Science were performed, focusing on studies published between 2003 and 2023 that utilized fMRI to explore functional connectivity and regional activation in adult patients with neurological conditions. Studies were selected based on predefined inclusion and exclusion criteria, with data extracted. RESULTS: We identified 211 studies, covering a broad spectrum of neurological disorders including mental health, movement disorders, epilepsy, neurodegeneration, traumatic brain injury, cerebrovascular accidents, vascular abnormalities, neurorehabilitation, neuro-critical care, and brain tumors. The majority of studies utilized resting-state fMRI, underscoring its prominence in identifying disease-specific connectivity patterns. Results highlight the potential of fMRI to reveal the underlying pathophysiological mechanisms of various neurological conditions, facilitate diagnostic processes, and potentially guide therapeutic interventions. CONCLUSIONS: fMRI serves as a powerful tool for elucidating complex neural dynamics and pathologies associated with neurological diseases. Despite the breadth of applications, further research is required to standardize fMRI protocols, improve interpretative methodologies, and enhance the translation of imaging findings to clinical practice. Advances in fMRI technology and analytics hold promise for improving the precision of neurological assessments and interventions.

Direct (D)-Wave Monitoring Enhancement With Subdural Electrode Placement: A Case Series.

PURPOSE: Direct-wave (D-wave) neuromonitoring is a direct measure of corticospinal tract integrity that detects potential injury during spinal cord surgery. Epidural placement of electrodes used for D-wave measurements can result in high electrical impedances resulting in substantial signal noise that can compromise signal interpretation. Subdural electrode placement may offer a solution. METHODS: Medical records for consecutive patients with epidural and subdural D-wave monitoring were reviewed. Demographic and clinical information including preoperative and postoperative motor strength were recorded. Neuromonitoring charts were reviewed to characterize impedances and signal amplitudes of D-waves recorded epidurally (before durotomy) and subdurally (following durotomy). Nonparametric statistics were used to compare epidural and subdural D-waves. RESULTS: Ten patients (50% women, median age 50.5 years) were analyzed, of which five patients (50%) were functionally independent (modified McCormick grade ≤ II) preoperatively. D-waves were successfully acquired by subdural electrodes in eight cases and by epidural electrodes in three cases. Subdural electrode placement was associated with lower impedance values ( P = 0.011) and a higher baseline D-wave amplitude ( P = 0.007) relative to epidural placement. No association was observed between D-wave obtainability and functional status, and no adverse events relating to subdural electrode placement were encountered. CONCLUSIONS: Subdural electrode placement allows successful D-wave acquisition with accurate monitoring, clearer waveforms, and a more optimal signal-to-noise ratio relative to epidural placement. For spinal surgeries where access to the subdural compartment is technically safe and feasible, surgeons should consider subdural placement when monitoring D-waves to optimize clinical interpretation.

Ethical Incorporation of Artificial Intelligence into Neurosurgery: A Generative Pretrained Transformer Chatbot-Based, Human-Modified Approach.

INTRODUCTION: Artificial intelligence (AI) has become increasingly used in neurosurgery. Generative pretrained transformers (GPTs) have been of particular interest. However, ethical concerns regarding the incorporation of AI into the field remain underexplored. We delineate key ethical considerations using a novel GPT-based, human-modified approach, synthesize the most common considerations, and present an ethical framework for the involvement of AI in neurosurgery. METHODS: GPT-4, ChatGPT, Bing Chat/Copilot, You, Perplexity.ai, and Google Bard were queried with the prompt "How can artificial intelligence be ethically incorporated into neurosurgery?". Then, a layered GPT-based thematic analysis was performed. The authors synthesized the results into considerations for the ethical incorporation of AI into neurosurgery. Separate Pareto analyses with 20% threshold and 10% threshold were conducted to determine salient themes. The authors refined these salient themes. RESULTS: Twelve key ethical considerations focusing on stakeholders, clinical implementation, and governance were identified. Refinement of the Pareto analysis of the top 20% most salient themes in the aggregated GPT outputs yielded 10 key considerations. Additionally, from the top 10% most salient themes, 5 considerations were retrieved. An ethical framework for the use of AI in neurosurgery was developed. CONCLUSIONS: It is critical to address the ethical considerations associated with the use of AI in neurosurgery. The framework described in this manuscript may facilitate the integration of AI into neurosurgery, benefitting both patients and neurosurgeons alike. We urge neurosurgeons to use AI only for validated purposes and caution against automatic adoption of its outputs without neurosurgeon interpretation.

Influence of Preoperative Motor Score and Patient Comorbidities on Transcranial Motor-Evoked Potential Acquisition in Intracranial Surgery: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: Intraoperative neurophysiological monitoring plays a pivotal role in modern neurosurgery, aiding in real-time assessment of eloquent neural structures to mitigate iatrogenic neural injury. This study represents the largest retrospective series to date in monitoring corticospinal tract integrity during intracranial surgery with transcranial motor-evoked potentials (TCMEPs), focusing on the influence of demographic factors, comorbidities, and preoperative motor deficits on the reliability of intraoperative neurophysiological monitoring. While the impact of patient-specific factors affecting TCMEP monitoring in spine surgery is well-documented, similar insights for intracranial surgery are lacking. METHODS: A total of 420 craniotomy patients were retrospectively analyzed from electronic medical records from December 2017 to February 2023, excluding patients without preoperative Medical Research Council scores or medical histories. Using intrinsic hand muscles as a robust data set, 840 hand TCMEPs acquired during intracranial surgery were assessed. Demographic and clinical factors, including preoperative motor scores, were analyzed to identify associations with TCMEP acquisition and amplitude. Nonparametric statistics and multivariate regression analysis were employed. RESULTS: TCMEPs were successfully acquired in 734 (87.7%) patient hands, even in the presence of preoperative motor deficits in 13.9% of total patient hands. Preoperative motor scores did not predict the ability to acquire baseline TCMEPs ( P = .6). Notably, older age ( P < .001) and hypertension ( P = .01) were independent predictors of lower TCMEP acquisition rates. Preoperative motor scores significantly influenced TCMEP amplitudes, with higher scores correlating with higher amplitudes (1771 [SD = 1550] eve vs 882 [SD = 856] µV, P < .0001). Older age ( P < .001) and chronic kidney disease ( P = .04) were also associated with reduced TCMEP amplitudes. CONCLUSION: Our investigation into TCMEPs during intracranial surgery demonstrated a notably high acquisition rate in hand muscles, irrespective of preoperative motor deficits. Preoperative motor scores reliably correlated with TCMEP amplitudes in a linear fashion while advanced age and renal disease emerged as independent predictors of lower TCMEP amplitudes.

Anterior-posterior diameter is a key driver of resectability and complications for pituitary adenomas with suprasellar extension in endoscopic transsphenoidal surgery.

BACKGROUND: As endoscopic transsphenoidal approaches are more routinely selected for progressively larger pituitary adenomas with parasellar extension, understanding potential anatomical factors that limit resection and contribute to complications is becoming increasingly important for tailoring a surgical approach. This study aimed to reevaluate existing predictive tools for resectability in pituitary adenomas specifically with suprasellar extension, and furthermore identify any additional measurable features that may be more useful in preoperative planning. METHODS: A single-center retrospective chart review of adult patients who underwent endoscopic transsphenoidal surgery for pituitary adenomas with suprasellar extension from 2015 to 2020 was performed. Preoperative MRIs were systematically assessed to assign a Knosp classification, a Zurich Pituitary Score (ZPS), and for dimensional measurements of the suprasellar aspect of the lesions. Univariate comparisons and multivariate regression models were employed to assess the influence of these factors on extent of resection and postoperative complications. RESULTS: Of the 96 patients with suprasellar pituitary adenomas who underwent endoscopic transsphenoidal surgery, 74 patients (77%) had a gross total resection (GTR). Neither Knosp grade nor ZPS score, even when dichotomized, demonstrated an association with GTR (Knosp 3A-4 versus Knosp 0-2, p = 0.069; ZPS III-IV versus ZPS I-II, p = 0.079). Multivariate regression analysis identified suprasellar anterior-posterior tumor diameter (SSAP) as the only significant predictor of extent of resection in this cohort (OR 0.951, 95% CI 0.905-1.000, p = 0.048*). A higher SSAP also had the strongest association with intraoperative CSF leaks (p = 0.0012*) and an increased overall rate of postoperative complications (p = 0.002*). Further analysis of the regression model for GTR suggested an optimal cut point value for SSAP of 23.7 mm, above which predictability for failing to achieve GTR carried a sensitivity of 89% and a specificity of 41%. CONCLUSIONS: This study is unique in its examination of endoscopic transsphenoidal surgical outcomes for pituitary adenomas with suprasellar extension. Our findings suggest that previously established grading systems based on lateral extension into the cavernous sinus lose their predictive value in lesions with suprasellar extension and, more specifically, with increasing suprasellar anterior-posterior diameter.

Sonodynamic Therapy and Sonosensitizers for Glioma Treatment: A Systematic Qualitative Review.

Sonodynamic therapy (SDT) has emerged as an encouraging noninvasive technique that uses ultrasound to activate targeted agents to induce antitumor effects for the treatment of glioma. With extensive variation in the types of sonosensitizers, protocols for sonication, and model systems, a comprehensive overview of existing preclinical data on the efficacy of SDT in glioma treatment is warranted. Here, we conduct a systematic review of preclinical and early clinical literature on implementing SDT to treat in vitro and in vivo models of glioma. Our findings suggest that coupling sonosensitizers such as 5-aminolevulinic acid, hematoporphyrin monomethyl ether, and sinoporphyrin sodium with focused ultrasound induces robust cytotoxic activity in tumor cells (in vitro and in vivo). These effects are likely mediated by the oxidative stress induced by reactive oxygen species production, apoptotic signaling cascades, and intracellular calcium overload. Future research is needed to better understand the biochemical and mechanistic properties of SDT, and ongoing trials may help elucidate the clinical feasibility of glioma treatment with optimized sonically activated treatments.

Direct-cortical visual evoked potential monitoring during brain tumor resection.

BACKGROUND: Visual evoked potential (VEP) recording is traditionally regarded as an unreliable evoked potential monitoring technique, precluding widespread use in intracranial neurosurgery. However, VEPs can serve as a useful intraoperative adjunct for real-time detection of mechanical damage to optic apparatuses. The low obtainability and prognostic utility of VEPs are associated with transcranial recording, which typically provides non-focal information and poor signal-to-noise ratio. Direct cortical VEP (DC-VEP) recordings may offer a solution. METHODS: We evaluated the obtainability of DC-VEPs as well as their prognostic utility in predicting postoperative visual function deterioration in a series of brain tumor patients undergoing craniotomies for tumor resection. Patient records were retrospectively reviewed for all consecutive patients undergoing brain tumor resections with DC-VEP monitoring. Pre- and postoperative visual fields were characterized from patient charts and associated with the presence of intraoperative monitoring alerts to determine the sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of DC-VEPs in detecting postoperative visual field deficits. RESULTS: Twenty-two patients (9 male, 13 female) were included, with a median age of 60 years. DC-VEPs were reliably detected in 19 of 23 included surgeries (82.6%). The reported sensitivity, specificity, PPV, and NPV in detecting postoperative visual field deficits was 60%, 92.9%, 75%, and 86.7%, respectively. There was a statistically significant association between monitoring alerts and the presence of visual field deterioration by Fischer's exact test (p = 0.0374). CONCLUSIONS: DC-VEPs can be reliably obtained and are useful for detecting mechanical injury to optic areas and tracts during tumor resection.

Hippocampal avoidance in whole brain radiotherapy and prophylactic cranial irradiation: a systematic review and meta-analysis.

PURPOSE: We systematically reviewed the current landscape of hippocampal-avoidance radiotherapy, focusing specifically on rates of hippocampal tumor recurrence and changes in neurocognitive function. METHODS: PubMed was queried for studies involving hippocampal-avoidance radiation therapy and results were screened using PRISMA guidelines. Results were analyzed for median overall survival, progression-free survival, hippocampal relapse rates, and neurocognitive function testing. RESULTS: Of 3709 search results, 19 articles were included and a total of 1611 patients analyzed. Of these studies, 7 were randomized controlled trials, 4 prospective cohort studies, and 8 retrospective cohort studies. All studies evaluated hippocampal-avoidance whole brain radiation treatment (WBRT) and/or prophylactic cranial irradiation (PCI) in patients with brain metastases. Hippocampal relapse rates were low (overall effect size = 0.04; 95% confidence interval [0.03, 0.05]) and there was no significant difference in risk of relapse between the five studies that compared HA-WBRT/HA-PCI and WBRT/PCI groups (risk difference = 0.01; 95% confidence interval [- 0.02, 0.03]; p = 0.63). 11 out of 19 studies included neurocognitive function testing. Significant differences were reported in overall cognitive function and memory and verbal learning 3-24 months post-RT. Differences in executive function were reported by one study, Brown et al., at 4 months. No studies reported differences in verbal fluency, visual learning, concentration, processing speed, and psychomotor speed at any timepoint. CONCLUSION: Current studies in HA-WBRT/HA-PCI showed low hippocampal relapse or metastasis rates. Significant differences in neurocognitive testing were most prominent in overall cognitive function, memory, and verbal learning. Studies were hampered by loss to follow-up.

Sonolucent cranioplasty: Is therapeutic FUS the next frontier?

Focused ultrasound (FUS) has emerged as a promising area of research in neuro-oncology. Preclinical and clinical investigation has demonstrated the utility of FUS in therapeutic applications including blood brain barrier disruption for therapeutic delivery, and high intensity FUS for tumor ablation. However, FUS as it exists today is relatively invasive as implantable devices are necessary to achieve adequate intracranial penetration. Sonolucent implants, composed of materials permeable to acoustic waves, have been used for cranioplasty and intracranial imaging with ultrasound. Given the overlap in ultrasound parameters with those used for intracranial imaging, and the demonstrated efficacy of sonolucent cranial implants, we believe that therapeutic FUS through sonolucent implants represents a promising avenue of future research. The potential applications of FUS and sonolucent cranial implants may confer the demonstrated therapeutic benefits of existing FUS applications, without the drawbacks and complications of invasive implantable devices. Here we briefly summarize existing evidence regarding sonolucent implants and describe applications for therapeutic FUS.

Adjustable, Dynamic Subcortical Stimulation Technique for Brain Tumor Resection: A Case-Series.

BACKGROUND AND OBJECTIVES: Subcortical stimulation (SCS) is the gold standard neuromonitoring technique for intraoperative identification of descending white matter tracts. Dynamic SCS confers several advantages over more commonly used static devices; however, current commercially available devices for dynamic SCS have not been widely adopted. METHODS: We fashioned a dynamic SCS device using a stainless-steel suction and commonly available materials and assessed its efficacy in a series of 14 patients with brain tumors. The device was used to provide continuous SCS during tumor resection. Preoperative and postoperative motor function were characterized, and preoperative and postoperative imaging were analyzed to determine extent of tumor resection and proximity to motor-eloquent structures. Inferential statistics were used to correlate study parameters. RESULTS: Fourteen patients (12 male and 2 female, median age 52.5 years) were analyzed. The lowest intraoperative SCS intensities were 10 to 15 mA (3 surgeries), 5 to 10 mA (4 surgeries), and <5 mA (2 surgeries). SCS with this device did not elicit motor evoked potentials in 5 surgeries because of distance from the corticospinal tract (CST) and served as negative controls. Three patients (21.4%) experienced new postoperative motor deficits immediately after surgery that resolved by discharge. We observed no instances of mechanical CST injury resulting in permanent postoperative motor deficits using this technique and no correlation between lower SCS intensity and the presence of new motor impairments after surgery. No patient experienced an intraoperative seizure. CONCLUSION: The novel dynamic SCS device is easily adoptable and allows accurate intraoperative identification of the CST, facilitating safe resection of tumors near motor-eloquent structures.

Intraoperative awake language mapping correlates to preoperative connectomics imaging: An instructive case.

Connectomics enables the study of structural-functional relationships in the brain, and machine learning technologies have enabled connectome maps to be developed for individual brain tumor patients. We report our experience using connectomics to plan and guide an awake craniotomy for a tumor impinging on the language area. Preoperative connectomics imaging demonstrated proximity of the tumor to parcellations of the language area. Intraoperative awake language mapping was performed, revealing speech arrest and paraphasic errors at areas of the tumor boundary correlating to functional regions that explained these findings. This instructive case highlights the potential benefits of implementing connectomics into neurosurgical planning.

Neuromonitoring Guided Vessel Identification in Iatrogenic Arterial Injury During Meningioma Resection.

Neuromonitoring is commonly used in neurosurgery and allows intraoperative assessment of functional pathways in the brain during surgery. Monitoring alerts can guide surgical decision making in real-time allowing surgeons to mitigate or avoid potential iatrogenic injury and subsequent postoperative neurologic sequelae that may result from cerebral ischemia or malperfusion. Here we present a case of a patient undergoing a right pterional craniotomy for the resection of a tumor which crosses midline with multimodal intraoperative neuromonitoring including somatosensory evoked potentials, transcranial motor evoked potentials, and visual evoked potentials. During the final portion of tumor resection, arterial bleeding was noted of unknown origin shortly followed by loss of right lower extremity motor evoked potential recordings. Motor evoked potential recordings in the right upper, and left upper and lower extremities were stable, as well as all somatosensory evoked potentials and visual evoked potentials. This distinct pattern of right lower extremity motor-evoked potential loss suggested compromise of the contralateral anterior cerebral artery and guided the surgeons to a rapid intervention. The patient awoke from surgery with moderate postoperative weakness in the affected limb that resolved to preoperative status by postoperative day 2, and back to normal strength prior to three-month follow-up. In this case the neuromonitoring data suggested compromise to the contralateral anterior cerebral artery which guided the surgeons to investigate and identify the site of vascular injury. The present case reinforces the utility of neuromonitoring in emergent surgical situations to guide surgical decision making.

Short and long-term prognostic value of intraoperative motor evoked potentials in brain tumor patients: a case series of 121 brain tumor patients.

PURPOSE: Iatrogenic neurologic deficits adversely affect patient outcomes following brain tumor resection. Motor evoked potential (MEP) monitoring allows surgeons to assess the integrity of motor-eloquent areas in real-time during tumor resection to lessen the risk of iatrogenic insult. We retrospectively associate intraoperative transcranial and direct cortical MEPs (TC-MEPs, DC-MEPs) to early and late post-operative motor function to prognosticate short- and long-term motor recovery in brain tumor patients undergoing surgical resection in peri-eloquent regions. METHODS: We reviewed 121 brain tumor patients undergoing craniotomies with DC-MEP and/or TC-MEP monitoring. Motor function scores were recorded at multiple time-points up to 1 year postoperatively. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated at each time point. RESULTS: The sensitivity, specificity, PPV, and NPV of TC-MEP in the immediate postoperative period was 17.5%, 100%, 100%, and 69.4%, respectively. For DC-MEP monitoring, the respective values were 25.0%, 100%, 100%, and 68.8%. By discharge, sensitivity had increased for both TC-MEP and DC MEPs to 43.8%, and 50.0% respectively. Subset analysis on patients without tumor recurrence/progression at long term follow-up (n = 62 pts, 51.2%) found that all patients with stable monitoring maintained or improved from preoperative status. One patient with transient intraoperative TC-MEP loss and permanent DC-MEP loss suffered a permanent deficit. CONCLUSION: Brain tumor patients who undergo surgery with intact MEP monitoring and experience new postoperative deficits likely suffer transient deficits that will improve over the postoperative course in the absence of disease progression.

Utility of 5-ALA for fluorescence-guided resection of brain metastases: a systematic review.

PURPOSE: 5-aminolevulinic acid (5-ALA) has demonstrated its utility as an intraoperative imaging adjunct during fluorescence guided resection of malignant gliomas. However, literature regarding 5-ALA-guided resection for brain metastases is limited. We conducted a systematic review to evaluate the efficacy of 5-ALA fluorescence for resection of metastatic brain tumors. METHODS: PubMed was queried for studies involving 5-ALA and brain metastases, and results were screened following PRISMA guidelines. Articles related to 5-ALA and brain metastasis were further assessed based on inclusion and exclusion criteria and results were analyzed for 5-ALA fluorescence rates stratified by tumor primary sites and histological subtypes. RESULTS: Of 421 identified search results, 10 studies were included and a total of 631 patients analyzed. Of these studies, 60% were retrospective in design. The reported rates of 5-ALA fluorescence in included brain metastases ranged from 27.6 to 86.9%, with variability across and within tumor types. No studies concluded improved operative outcomes or survival outcomes related to 5-ALA use. CONCLUSIONS: Current studies regarding 5-ALA fluorescence in brain metastases are limited and do not confirm efficacy for improving extent of resection or post-operative survival. Fluorescence is variable across and within tumor types. Further studies are necessary to evaluate whether specific tumors may benefit from 5-ALA FGS or if changes in delivery protocols or fluorescence quantification may affect intraoperative utility.

Analysis of factors leading to early termination in glioblastoma-related clinical trials.

PURPOSE: Terminated clinical trials are an inefficient use of financial, patient, and administrative resources. We reviewed ClinicalTrials.gov for completed and terminated clinical trials for glioblastoma multiforme (GBM) and compared reported characteristics of completed and terminated trials to identify factors associated with early trial termination. METHODS: ClinicalTrials.gov was queried to identify all completed and terminated GBM-related clinical trials. Trial characteristics were examined and the reason for trial termination was determined. Univariate analysis by Pearson's chi-square and a multivariate logistic regression were performed to identify independent predictors of early trial termination. RESULTS: We identified 886 completed and terminated GBM-related trials between 2003 and 2020. Of these, 175 (19.8%) were terminated prior to completion. The most common reason for termination was participant accrual difficulties, accounting for 63 (36.0%) terminated trials. Trial termination was associated with trials that reported a primary purpose of diagnosis relative to treatment (OR = 2.952, p = 0.001). CONCLUSION: Early termination of clinical trials investigating interventions for the treatment of GBM is associated with diagnostic trials relative to therapeutic trials. Patient accrual difficulties are the most commonly identified reason for early trial termination. Predictors of trial termination should be considered when designing GBM-related clinical trials to minimize the odds of early trial termination.