Leptomeningeal Metastases: New Opportunities in the Modern Era

Leptomeningeal metastases arise from cancer cell entry into the subarachnoid space, inflicting significant neurologic morbidity and mortality across a wide range of malignancies. The modern era of cancer therapeutics has seen an explosion of molecular-targeting agents and immune-mediated strategies for patients with breast, lung, and melanoma malignancies, with meaningful extracranial disease control and improvement in patient survival. However, the clinical efficacy of these agents in those with leptomeningeal metastases remains understudied, due to the relative rarity of this patient population, the investigational challenges associated with studying this dynamic disease state, and brisk disease pace. Nevertheless, retrospective studies, post hoc analyses, and small prospective trials in the last two decades provide a glimmer of hope for patients with leptomeningeal metastases, suggesting that several cancer-directed strategies are not only active in the intrathecal space but also improve survival against historical odds. The continued development of clinical trials devoted to patients with leptomeningeal metastases is critical to establish robust efficacy outcomes in this patient population, define drug pharmacokinetics in the intrathecal space, and uncover new avenues for treatment in the face of leptomeningeal therapeutic resistance.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01261-4.     

Targeted Treatment of Brain Metastases

Purpose of Review

Brain metastases are the most common intracranial tumors in adults. Historically, the median survival after the diagnosis of brain metastases has been dismal and medical therapies had a limited role in the management of these patients.

Recent Findings

The advent of targeted therapy has ushered in an era of increased hope for patients with brain metastases. The most common malignancies that result in brain metastases—melanoma, lung cancer, and breast cancer, often have actionable mutations, which make them good candidates for targeted systemic therapy. These brain metastases have been shown to have relevant and sometimes divergent genetic alterations, and there has been a resurgence of interest in targeted drug delivery to the brain by using standard or pulsatile dosing to achieve adequate concentration in the brain.

Summary

An increased understanding of oncogenic alterations, a surge in targeted drug development with good blood barrier penetration, and inclusion of patients with active brain metastases on clinical trials have led to improved outcomes for patients with brain metastases.

     

Monitoring the Brain After Cardiac Arrest: a New Era

Purpose of Review

Of the approximately 350,000 out-of-hospital, and 750,000 after in-hospital cardiac arrest (CA) events in the US annually approximately 5-9% and 20% respectively may achieve return of spontaneous circulation (ROSC) after attempted cardiopulmonary resuscitation (CPR). Up to 2/3 of these initial survivors may go on die in the subsequent 24-72 hours after ROSC due to a combination of (1) on-going cerebral injury, (2) myocardial dysfunction and (3) massive systemic inflammatory response. In order to successfully manage patients more effectively, monitoring methods are needed to aid clinicians in the detection and quantification of intra-cardiac arrest and post-resuscitation pathophysiological cerebral injury processes in the intensive care unit.

Recent Findings

Over the last few years many modalities have been used for cerebral monitoring during and after CA, these include quantitative pupillometry, transcranial doppler sonography, optic nerve sheath diameter measurements, microdialysis, tissue oxygenation monitoring, intra-cranial pressure monitoring, and electroencephalography. Current studies indicate that these modalities may be used for the purpose of neurological monitoring during cardiac arrest resuscitation as well as in the post-resuscitation period.

Summary

Multiple overlapping processes, including alterations in cerebral blood flow (CBF), raised intracerebralpressure, disorders of metabolism, imbalanced oxygen delivery and reperfusion injury contribute to cell death during the post-resuscitation period has led to the birth of post-resuscitation management strategies in the 21st century. This review provides a succinct overview of currently available bedside invasive and non-invasive neuro-monitoring methods after CA.

     

伽玛刀治疗脑转移瘤18例报告

报告经伽玛刀治疗的脑转移瘤18例。原发肿瘤中肺及乳房癌占72.5％。脑转移瘤中属单发有11例,多发有7例。肿瘤平均直径19.46mm,肿瘤照射野覆盖平均为56.3％,瘤周边剂量平均为21.5Gy。出院后12例随访9天～1年(平均6.9个月),其中8例存活(平均8.4个月),4例死亡。获CT随访7例,示肿瘤缩小7例,消失4例(3例为多发肿瘤)。认为伽玛刀治疗简便、安全,对控制肿瘤生长有明显作用,并就伽玛刀治疗的指征等进行了讨论。     

绒癌脑转移的神经外科治疗

目的探讨绒癌脑转移神经外科诊断、治疗原则及手术方法。方法回顾性分析1995年1月至2007年1月间在我院确诊为绒癌脑转移而行神经外科手术治疗的21例患者的临床资料，其中19例术后接受了联合方案化疗。结果21例绒癌脑转移患者中，术后症状完全缓解11例，部分缓解8例，死亡2例。其中14例随访1～10年，存活11例，死亡3例；失访5例。结论对于绒癌脑转移患者。早期诊断与及时有效的化疗是改善预后的关键，积极的神经外科手术是挽救患者生命，获得进一步化疗机会的重要方法。     

Clinical Analysis of Novalis Stereotactic Radiosurgery for Brain Metastases

Objective

The authors analyzed the effectiveness and therapeutic response of Novalis shaped beam radiosurgery for metastatic brain tumors, and the prognostic factors which influenced the outcome.

Methods

We performed a retrospective analysis of 106 patients who underwent 159 treatments for 640 metastatic brain lesions between January 2000 and April 2008. The pathologies of the primary tumor were mainly lung (45.3%), breast (18.2%) and GI tract (13.2%). We classified the patients using Radiation Therapy Oncology Group Recursive Partitioning Analysis (RPA) and then analyzed the survival and prognostic factors according to the Kaplan Meier method and univariate analysis.

Results

The overall median actuarial survival rate was 7.3 months from the time of first radiosurgery treatment while 1 and 2 year actuarial survival estimates were 31% and 14.4%, respectively. Median actuarial survival rates for RPA classes I, II, and III were 31.3 months, 7.5 months and 1.7 months, respectively. Patients'' life spans, higher Karnofsky performance scores and age correlated closely with RPA classes. However, sex and the number of lesions were not found to be significantly associated with length of survival.

Conclusion

This result suggests that Novalis radiosurgery can be a good treatment option for treatment of the patients with brain metastases.     

Efficacy and Safety of Fractionated Stereotactic Radiosurgery for Large Brain Metastases

Objective

To investigate the efficacy and safety of fractionated stereotactic radiosurgery for large brain metastases (BMs).

Methods

Between June 2011 and December 2013, a total of 38 large BMs >3.0 cm in 37 patients were treated with fractionated Cyberknife radiosurgery. These patients comprised 16 men (43.2%) and 21 women, with a median age of 60 years (range, 38-75 years). BMs originated from the lung (n=19, 51.4%), the gastrointestinal tract (n=10, 27.0%), the breast (n=5, 13.5%), and other tissues (n=3, 8.1%). The median tumor volume was 17.6 cc (range, 9.4-49.6 cc). For Cyberknife treatment, a median peripheral dose of 35 Gy (range, 30-41 Gy) was delivered in 3 to 5 fractions.

Results

With a median follow-up of 10 months (range, 1-37 months), the crude local tumor control (LTC) rate was 86.8% and the estimated LTC rates at 12 and 24 months were 87.0% and 65.2%, respectively. The median overall survival (OS) and progression-free survival (PFS) rates were 16 and 11 months, respectively. The estimated OS and PFS rates at 6, 12, and 18 months were 81.1% and 65.5%, 56.8% and 44.9%, and 40.7% and 25.7%, respectively. Patient performance status and preoperative focal neurologic deficits improved in 20 of 35 (57.1%) and 12 of 17 patients (70.6%), respectively. Radiation necrosis with a toxicity grade of 2 or 3 occurred in 6 lesions (15.8%).

Conclusion

These results suggest a promising role of fractionated stereotactic radiosurgery in treating large BMs in terms of both efficacy and safety.     

The Molecular Landscape of Pediatric Brain Tumors in the Next-Generation Sequencing Era

Pediatric brain tumors are a leading cause of cancer-related death in children. In recent years, the application of next-generation sequencing and other high-throughput technologies to analysis of pediatric brain tumors has generated an abundance of molecular information. This has provided an unprecedented understanding of their biology and is refining tumor classification into clinically relevant subgroups. In this review, we provide an overview of our evolving molecular knowledge of the commonest pediatric brain tumors, pilocytic astrocytomas, ependymomas, medulloblastomas, and pediatric glioblastomas, as well as the biological and potential clinical implications of this new knowledge. Studies aimed at investigating intratumoral heterogeneity are also discussed.     

Update on the Management of Brain Metastasis

Brain metastases occur in almost one-third of adult patients with solid tumor malignancies and lead to considerable patient morbidity and mortality. The rising incidence of brain metastases has been ascribed to the development of better imaging and screening techniques and the formulation of better systemic therapies. Until recently, the multimodal management of brain metastases focused primarily on the utilization of neurosurgical techniques, with varying combinations of whole-brain radiation therapy and stereotactic radio-surgical procedures. Over the past 2 decades, in particular, the increment in knowledge pertaining to molecular genetics and the pathogenesis of brain metastases has led to significant developments in targeted therapies and immunotherapies. This review article highlights the recent updates in the management of brain metastases with an emphasis on novel systemic therapies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01312-w.     

Inhibition of Brain Oestrogen Receptors by RU 58668

The purpose of this study was to determine if injections of the 11ß-substituted steroidal antioestrogen, RU 58668, would block two measures of oestrogen receptor action in ovariectomized adult female rats. Using an in vitro nuclear exchange assay, it was found that RU 58668 reduced cell nuclear []> ³H]-oestradiol binding in brain tissue 24  h after it was injected. However, pituitary cell nuclear [³H]-oestradiol binding was significantly reduced just 2  h after the antioestrogen was injected. Our results demonstrate that RU 58668 can reach the brain following a subcutaneous injection, but that it needs more time to reach the brain than it does to reach the pituitary. Since the levels of hypothalamic and pituitary progestin receptors are known to be regulated by oestradiol, cytosolic [³H]-R5020 binding was used as an in vitro assay of endogenous oestrogen receptor action. RU 58668 blocked induction by oestradiol of cytosolic [³H]-R5020 binding in both the brain and pituitary 48  h after it was injected. In the absence of oestradiol, RU 58668 did not stimulate cell nuclear [³H]-oestradiol binding or cytosolic [³H]-R5020 binding in either brain or pituitary. In conclusion, injections of RU 58668 blocked two measures of oestrogen receptor action in the brain and pituitary without showing oestrogenic activity itself.     

New Horizons for the Next Era of Human Brain Imaging, Cognitive, and Behavioral Research: Pacific Rim Interactivity

Beginning in the 1990’s, substantial advances have been made in the ability to image the living human brain. Functional MRI, PET, and other modalities have been developed to provide a rich means for assessing brain function and structure across spatial and temporal dimensions. Such methods are now the preferred means to examine the brain in vivo, with several thousand articles now appearing in the literature each year. The next era of human brain imaging is upon us now as technological developments reach a level where data can be processed quickly and combined with other biological information to provide fundamentally new applications and insights. This new era will involve and require the collaborative participation of leading research groups from around the world to share information and expertise for understanding observed effects and synthesizing these into new knowledge. One particular community that is gaining in its prominence in the field is that of the Pacific Rim, whose collective research efforts present an important corpus of research effort into brain structure and function. The Pacific Rim represents an important community of researchers interested in the greater sharing of ideas. In this special issue of Brain Imaging and Behavior, we focus on emerging areas of research that utilize brain imaging methodology, and discuss how current developments are driving the expansion of functional imaging research. Moreover, we focus on the robust interaction of researchers from around the Pacific Rim whose collaborations are significantly shaping the future of brain imaging.     

脑转移瘤治疗方法的对比研究

目的比较手术结合全脑放疗、X-刀和X-刀结合全脑放疗治疗单发脑转移瘤的效果。方法回顾分析我院自1996年2月至2000年4月间经手术结合放射治疗的脑转移瘤84例、X-刀和X-刀结合全脑放疗治疗的脑转移瘤102例,从中选择符合条件的脑转移瘤患者86例,分成3组:手术结合全脑放疗组36例;X-刀组32例;X-刀结合全脑放疗组18例。从临床症状变化,生存时间,局部控制率,肿瘤脑远隔部位生长率,因中枢神经系统病变死亡率等方面比较三种方法的疗效。结果手术结合全脑放疗组、X-刀组和X-刀结合全脑放疗组的临床有效率分别为86.1%(31/36),87.5%(28/32)和88.9%(16/18);中位生存时间分别为54周,50周和51周;1年生存率分别为47.2%(17/36),43.8%(14/32)和44.4%(8/18)。1年肿瘤局部控制率分别为83.3%(30/36),78.1(25/32)和77.8%(14/18)。因中枢神经系统病变死亡率分别为26.7%(8/30),30%(6/20)和28.6%(4/14),三组之间无明显差异(P>0.05)。肿瘤脑远隔部位发生率分别为13.9%(5/36),37.5%(12/32)和11.1%(2/18),X-刀组明显高于其他两组(P<0.05)。结论对于单发脑转移瘤,单纯X-刀可以获得与手术结合全脑放疗和X-刀结合全脑放疗相同的生存时间、局部控制率;全脑放疗可降低肿瘤脑远隔部位生长率,但对生存时间和局部控制率无明显影响。     

Fluid Management in Acute Brain Injury

Purpose of the Review

The aims of fluid management in acute brain injury are to preserve or restore physiology and guarantee appropriate tissue perfusion, avoiding potential iatrogenic effects. We reviewed the literature, focusing on the clinical implications of the selected papers. Our purposes were to summarize the principles regulating the distribution of water between the intracellular, interstitial, and plasma compartments in the normal and the injured brain, and to clarify how these principles could guide fluid administration, with special reference to intracranial pressure control.

Recent Findings

Although a considerable amount of research has been published on this topic and in general on fluid management in acute illness, the quality of the evidence tends to vary. Intravascular volume management should aim for euvolemia. There is evidence of harm with aggressive administration of fluid aimed at achieving hypervolemia in cases of subarachnoid hemorrhage. Isotonic crystalloids should be the preferred agents for volume replacement, while colloids, glucose-containing hypotonic solutions, and other hypotonic solutions or albumin should be avoided. Osmotherapy seems to be effective in intracranial hypertension management; however, there is no clear evidence regarding the superiority of hypertonic saline over mannitol.

Summary

Fluid therapy plays an important role in the management of acute brain injury patients. However, fluids are a double-edged weapon because of the potential risk of hyper-hydration, hypo- or hyper-osmolar conditions, which may unfavorably affect the clinical course and the outcome.