Preservation Of Neurocognitive Function Research Articles

Safety and Feasibility of Hippocampal Sparing Cranial Radiation in Pediatric and Adolescent Acute Lymphoblastic Leukemia Patients: A Prospective Study.

Introduction Acute lymphoblastic leukemia (ALL) constitutes a significant portion of pediatric malignancies, with central nervous system (CNS) relapse posing a considerable threat to patient outcomes. While cranial radiation therapy (CRT)has been utilized to mitigate CNS relapse, it is associated with neurocognitive (NC) side effects. This study explores the feasibility and safety of using volumetric arc therapy (VMAT) with hippocampal sparing (HS) during cranial radiation therapy for ALL patients, aiming to reduce these side effects. Methodology This prospective observational study included pediatric and young adult patients with ALL who werein remission. HS was achieved using VMAT, and NC assessments were performed at baseline, six months, one year, and, to a limited extent, four years posttreatment. Results VMAT enabled precise hippocampal-sparing CRT with minimal dose to the hippocampus. Dosimetric analysis revealed that patients receiving 18 Gy had mean doses to planning target volume (PTV) and bilateral hippocampus of 18.9 and 9 Gy, respectively. Those receiving 12 Gy had corresponding doses of 13.3 and 7 Gy, respectively. Conformity and homogeneity indices were 0.9 and 0.1, and no brain relapses were observed among the patients in this study. NC assessments demonstrated no decline in intelligence quotient (IQ) scores over time, while only a subset of patients could be assessed at the four-year mark; telephone interviews suggested no significant cognitive decline. Conclusions This study highlights the potential of VMAT with HS as a promising approach to CRT for ALL patients in reducing the risk of NC side effects. The absence of brain relapses and preservation of NC function are encouraging findings, though larger studies are necessary to establish conclusive evidence.

Neuroprotection in radiotherapy of brain metastases: A pattern-of-care analysis in Germany, Austria and Switzerland by the German Society for radiation Oncology − working group Neuro-Radio-Oncology (DEGRO AG-NRO)

Background and purposeMany patients with solid tumors develop brain metastases (BM). With more patients surviving long-term, preservation of neurocognitive function gains importance. In recent years, several methods to delay cognitive deterioration have been tested in clinical trials. However, knowledge on the extent to which these neuroprotective strategies have been implemented in clinical practice is missing. Materials and methodsWe performed an online survey regarding treatment patterns of BM in German-speaking countries, focused on the use of neuroprotective approaches. The survey was distributed among radiation oncologists (ROs) registered within the database of the German Society for Radiation Oncology (DEGRO). ResultsPhysicians of 78 centers participated in the survey. Whole brain radiotherapy (WBRT) is still preferred by 70 % of ROs over stereotactic radiotherapy (SRT) in patients with 6–10 BM. For 4–5 BM WBRT is preferred by 23 % of ROs. The fraction of ROs using hippocampal sparing (HS) in WBRT has increased to 89 %, although the technique is used on a regular basis only by a minority (26 %). The drug memantine is not widely prescribed (14% of ROs). A trend was observed for university hospitals to implement neuroprotective approaches more frequently. ConclusionThere is considerable heterogeneity regarding the treatment of BM in German-speaking countries and a general standard of care is lacking. Neuroprotective strategies are not yet standard approaches in daily clinical routine, although usage is increasing. Further clinical trials, as well as improvement of technical opportunities and reimbursement, might further shift the treatment landscape towards neuroprotective radiation treatments in the future.

The effect of hippocampal sparing during prophylactic cranial irradiation on the preservation of neurocognitive functions in patients with small cell lung cancer: a preliminary study

The effect of hippocampal sparing during prophylactic cranial irradiation on the preservation of neurocognitive functions in patients with small cell lung cancer: a preliminary study

Comparison of Hippocampal Volume Change after Whole-Brain Radiotherapy with and without Hippocampal Avoidance: A Post-Hoc Analysis of a Phase II Randomized Trial

Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) preserves verbal memory compared to conformal WBRT in the previously reported randomized phase II clinical trial. In the present study, we analyzed the changes in hippocampus volume between groups at longitudinal follow-up time points. We hypothesize better preservation of hippocampus volumes with time in the HA-WBRT group. In this post-hoc analysis of a single institution, single-blind, randomized phase II trial, patients with brain metastases were randomized to receive either HA-WBRT or conformal WBRT with 30 Gy in 10 fractions. Patients received gadolinium contrast-enhanced MRI every three months or when clinically indicated after WBRT until progression. Only patients with at least one follow-up MRI were included. The MRI was used to assess baseline intracranial volume, hippocampal volume, the ratio of the total hippocampus to total intracranial volume (HT%), and the ratio of the left (HL%) or right (HR%) hippocampus to total intracranial volume. The volumes were automatically calculated by volBrain, an online MRI brain volumetry system. We used linear mixed models with fixed and random effects to compare the changes of repeated measures of the hippocampus volumes over time between the two groups. Among 70 randomized patients, 51 (25 in the HA-WBRT group and 26 in the WBRT group) were included in the present analysis. There were no significant differences between the two groups in the baseline demographics, HT%, HR%, and HL%. The median follow-up time was 13.9 months (range 2.1-31.8 months), and more than 60% of patients had at least one year of follow-up. Linear mixed model analyses showed a more significant decrease of HT% over time in the WBRT arm (regression coefficient β = -0.002, p = 0.001) compared to the HA-WBRT arm (regression coefficient, β = -0.001, p = 0.254), with a significant group by time interaction (F-value = 4.27, p = 0.050). The HL% was stable over time in the HA-WBRT arm (β = 0.0001, p = 0.769) while it decreased in the WBRT arm (β = -0.001, p = 0.003), with a significant group by time interaction (F-value = 6.51, p = 0.015). In contrast, the HR% decreased over time in both groups (HA-WBRT: regression coefficient β = -0.001, p = 0.006; WBRT: regression coefficient β = -0.001, p < 0.001) without significant group by time interaction (F-value = 0.20, p = 0.662). HA-WBRT better preserves total hippocampus volume with time compared to WBRT, with the main effect contributed by preserving the left hippocampus volume. Further research is warranted to establish the relationship between hippocampus volume perpetuation and cognitive function preservation. The future goal is to investigate whether left-side unilateral HA-WBRT provides similar neurocognitive function preservation compared to standard bilateral HA-WBRT.

Hippocampal avoidance whole brain radiotherapy in brain metastasis using volumetric modulated arc therapy: experience from a Regional Cancer Centre of Eastern India.

Whole-brain radiotherapy is associated with neurocognitive decline and decreased quality-of-life (QOL) among survivors of brain metastasis. Hippocampal-avoidance whole-brain radiotherapy (HA-WBRT) has shown advantage in delaying or preventing the neurocognitive decline while maintaining disease control. This study was done to assess the benefits and feasibility of HA-WBRT in patients with cerebral metastasis in terms of preservation of neurocognitive function and quality of life. 27 patients with brain metastasis treated by HA-WBRT and having the records of detailed neurocognitive-assessments were analysed from the database of our hospital. The patients were treated with HA-WBRT to a total dose of 30 Gy in 10 fractions with LINAC based IMRT using the VMAT technique. Cognitive function assessment was carried out using "Examination of the Cognitive Functions" scale provided by Bangur-Institute-of-Neurosciences, Kolkata, 2 weeks prior to radiotherapy and post-treatment two-monthly up to 6 months followed by every 3 months till the last follow up. QOL was assessed at the same interval using the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR). Follow-up was done till the date of death. Mean relative cognitive decline percentage decreased over subsequent follow-up visits and was 13% (SD ± 6%), 5% (SD ± 5%), 5% (SD ± 9%) and 2% (SD ± 12%) at 2 months, 6 months, 9 months and 12 months, respectively (p ≤ 0.05). Statistically significant improvement was seen in the mean social-wellbeing (SWB) parameter of QOL (8%. ± 13%, 12%. ± 16%, 7%. ± 20%, no change at 2 months, 4 months, 6 months and 9 months, respectively) (p ≤ 0.05). Mean relative decline in the Emotional-Well Being (EWB) parameter was significant only at 12 months and was 20% (SD ± 35%) (p = 0.04). Mean FACT-BR total Score showed a slight decrease till 9 months from baseline, and then showed a slight improvement up to 12 months. HA-WBRT is feasible with LINAC-based IMRT using the VMAT technique and beneficial to the patients in preserving neurocognitive function and quality of life without compromising disease control.

The Learning Curve and Inter-Observer Variability in Contouring the Hippocampus under the Hippocampal Sparing Guidelines of Radiation Therapy Oncology Group 0933.

Hippocampal-sparing brain radiotherapy (HS-BRT) in cancer patients results in preservation of neurocognitive function after brain RT which can contribute to patients’ quality of life (QoL). The crucial element in HS-BRT treatment planning is appropriate contouring of the hippocampus. Ten doctors delineated the left and right hippocampus (LH and RH, respectively) on 10 patients’ virtual axial images of brain CT fused with T1-enhanced MRI (1 mm) according to the RTOG 0933 atlas recommendations. Variations in the spatial localization of the structure were described in three directions: right–left (X), cranio-caudal (Y), and forward–backward (Z). Discrepancies concerned three-dimensional localization, shape, volume and size of the hippocampus. The largest differences were observed in the first three delineated cases which were characterized by larger hippocampal volumes than the remaining seven cases. The volumes of LH of more than half of hippocampus contours were marginally bigger than those of RH. Most differences in delineation of the hippocampus were observed in the area of the posterior horn of the lateral ventricle. Conversely, a large number of hippocampal contours overlapped near the brainstem and the anterior horn of the lateral ventricle. The most problematic area of hippocampal contouring is the posterior horn of the lateral ventricle. Training in the manual contouring of the hippocampus during HS-BRT treatment planning under the supervision of experienced radiation oncologists is necessary to achieve optimal outcomes. This would result in superior outcomes of HS-BRT treatment and improvement in QoL of patients compared to without HS-BRT procedure. Correct delineation of the hippocampus is problematic. This study demonstrates difficulties in HS-BRT treatment planning and highlights critical points during hippocampus delineation.

ML-18 High-dose chemotherapy supported by autologous stem cell transplant in relapsed and refractory primary CNS lymphoma

While whole brain radiation therapy (WBRT) has been performed as consolidation therapy in primary central nervous system lymphoma (PCNSL), high-dose chemotherapy supported by autologous stem cell transplant (HDC/ASCT) is widely investigated today as an alternative treatment strategy, given the high risk for radiation-induced neurotoxicity in WBRT. Various conditioning regimens have been investigated in phase II trials, which report non-inferiority of HDC/ASCT in efficacy and preservation of neurocognitive function in comparison with WBRT. Besides its promising efficacy, treatment-related deaths are reported in 11% in patients treated by a conditioning regimen using thiotepa, busulfan and cyclophosphamide (TBC), which raises a concern for safety. Among several conditioning regimens, analysis using registry data of Japan Society for Hematopoietic Cell Transplantation has revealed that the use of conditioning regimens containing thiotepa was a positive factor for longer PFS. According to the result of a phase I trial in Japan which investigated HDC/ASCT using thiotepa and busulfan (BuTT), thiotepa was approved by the pharmaceuticals and medical devices agency (PMDA) on March 2020. In comparison with the TBC regimen, cyclophosphamide is omitted, and the dose of thiotepa is lower (250 mg/m2, 3 days in TBC; 5 mg/kg, 2 days in BuTT) in BuTT, therefore BuTT could be less toxic in comparison with TBC, and no treatment-related deaths were observed in the phase I study in Japan. Further investigation on the efficacy and safety of BuTT in actual clinical practice is warranted. We have constituted a multi-disciplinary team in our institution in order to perform HDC/ASCT using BuTT in relapsed/refractory PCNSL. Treatment indications are as follows; 65 years old or younger, previously treated by rituximab, methotrexate, procarbazine and vincristine (R-MPV), good organ function and neurological status. Future directions along with preliminary treatment results will be discussed at the meeting.

Preservation of neurocognitive function in the treatment of brain metastases.

Neurocognitive function (NCF) deficits are common in patients with brain metastases, occurring in up to 90% of cases. NCF deficits may be caused by tumor-related factors and/or treatment for the metastasis, including surgery, radiation therapy, chemotherapy, and immunotherapy. In recent years, strategies to prevent negative impact of treatments and ameliorate cognitive deficits for patients with brain tumors have gained momentum. In this review, we report on research that has established the efficacy of preventative and rehabilitative therapies for NCF deficits in patients with brain metastases. Surgical strategies include the use of laser interstitial thermal therapy and intraoperative mapping. Radiotherapy approaches include focal treatments such as stereotactic radiosurgery and tailored approaches such as hippocampal avoidant whole-brain radiotherapy (WBRT). Pharmacologic options include use of the neuroprotectant memantine to reduce cognitive decline induced by WBRT and incorporation of medications traditionally used for attention and memory problems. Integration of neuropsychology into the care of patients with brain metastases helps characterize cognitive patterns, educate patients and families regarding their management, and guide rehabilitative therapies. These and other strategies will become even more important for long-term survivors of brain metastases as treatment options improve.

Research Progress in the Treatment of Brain Metastases from Non-small Cell Lung Cancer

肺癌是全世界癌症相关死亡的首要原因，肺癌最常见的病理类型是非小细胞肺癌（non-small cell lung cancer, NSCLC），NSCLC引起的脑转移发病率一直呈上升趋势。脑转移严重影响患者的认知功能、生存时间及生活质量，预后极差，自然病程约1个月-3个月。经过治疗后中位生存时间也仅有3个月-6个月，1年生存率为14%，2年生存率仅为7.6%。脑转移的部位、数量、大小与其症状及生存期相关，有中枢神经系统症状的患者预后更差。脑转移瘤治疗的目标是优化总体生存率和生活质量，并优先保留神经认知功能。目前，NSCLC脑转移的主要治疗方式包括放疗、手术、化疗、分子靶向、免疫治疗。临床上要根据患者的异质性（临床特点、病理类型、组织分型等），对患者最佳的治疗方式进行多学科的评估。本文旨在对当前治疗方法的研究进展进行综述。

Anesthesia for neurosurgery (Part II)

The central nervous system (CNS) deserves special consideration in the perioperative setting for several reasons for an anesthetist. An understanding of neuroanatomy is essential because neuro anesthesia continues to develop and evolution of neurosurgical practice is accompanied by new challenges for the anesthetist. Basic knowledge and expertise of the neuro-anesthetist can directly influence patient outcome. With the recent advancement in functional and minimally invasive procedures, there is an increased emphasis on the provision of optimal operative conditions, preservation of neurocognitive function, minimizing interference with electrophysiological monitoring, and a rapid, high-quality recovery. So, during neuro anesthesia, anesthesiologist needs to know physiology of CNS including cerebral metabolism and cerebral blood flow. Neuro anesthesia can be challenging, because sometimes apparently contradictory demands must be managed, for example, achieving optimal conditions for neurophysiological monitoring while maintaining sufficient anesthetic depth, or maintaining oxygen delivery to neuronal tissue and simultaneously preventing high blood pressures that might induce local bleeding. One of the peculiarities of neuro anesthesia has always been that as much importance is attached to wakening the patient as sending them to sleep. We have included the anesthesia for neurosurgery in two parts. In the first part, we had discussed cerebral anatomy, physiology and intracranial pressure, in the second part we have included anesthesia considerations for surgery for brain tumor, aneurysmal surgery, temporal lobe surgery, trans sphenoidal surgery and traumatic brain injury. Keywords: Anesthesia, Neurosurgery.

Anesthesia for Neurosurgery (Part I)

The central nervous system (CNS) deserves special consideration in the perioperative setting for several reasons for an anesthetist. An understanding of neuroanatomy is essential because neuro anesthesia continues to develop and evolution of neurosurgical practice is accompanied by new challenges for the anesthetist. Basic knowledge and expertise of the neuro-anesthetist can directly influence patient outcome. With the recent advancement in functional and minimally invasive procedures, there is an increased emphasis on the provision of optimal operative conditions, preservation of neurocognitive function, minimizing interference with electrophysiological monitoring, and a rapid, high-quality recovery. So, during neuro anesthesia, anesthesiologist needs to know physiology of CNS including cerebral metabolism and cerebral blood flow. Neuro anesthesia can be challenging, because sometimes apparently contradictory demands must be managed, for example, achieving optimal conditions for neurophysiological monitoring while maintaining sufficient anesthetic depth, or maintaining oxygen delivery to neuronal tissue and simultaneously preventing high blood pressures that might induce local bleeding. One of the peculiarities of neuro anesthesia has always been that as much importance is attached to wakening the patient as sending them to sleep.

Awake surgery for right frontal lobe glioma can preserve visuospatial cognition and spatial working memory.

Awake surgery is the standard treatment to preserve motor and language functions. This longitudinal study aimed to evaluate the resection rate and preservation of neurocognitive functions in patients with right frontal lobe glioma who underwent awake surgery. Thirty-three patients (mean age, 48.0 years) with right frontal lobe glioma who underwent awake surgery at our hospital between 2013 and 2019 were included. Fourteen, thirteen, and six cases had WHO classification grades of II, III, and IV, respectively. We evaluated visuospatial cognition (VSC) and spatial working memory (SWM) before and three months after surgery. Relevant brain areas for VSC and SWM were intraoperatively mapped, whenever the task was successfully accomplished. Therefore, patients were divided into an intraoperative evaluation group and a non-evaluation group for each function, and the resection rate and functional outcomes were compared. The removal rate in the evaluation group for VSC and SWM were similar to that in the non-evaluation group. Chronic impairment rate of VSC was significantly lower in the evaluation than in the non-evaluation group (5.6% vs. 33.3%, p = 0.034). No patient showed postoperative SWM impairment in the evaluation group as opposed to the non-evaluation group (16.7%, p = 0.049). The probability of resection of the deeper posterior part of the middle frontal gyrus, the relevant area of VSC, was higher in the non-evaluation group than in the evaluation group. We statistically verified that awake surgery for right frontal lobe glioma results in successful preservation of VSC and SWM with satisfying resection rates.

Timeline Of Hippocampal Atrophy Following Whole-Brain Radiation Therapy With And Without Hippocampus Avoidance

In the past decade, the overall survival rates of patients with cerebral metastases have significantly improved. Quality of life and, more specifically, the preservation of neurocognitive functions have thus gained increasing importance. Cognitive decline has been specifically correlated with hippocampal atrophy. The aim of this study was to depict and compare the time course of hippocampal atrophy following conventional whole-brain radiation therapy (WBRT) and hippocampus avoidance WBRT (HA-WBRT). 168 patients with cerebral metastases of solid tumors without meningeal spread, who had received WBRT or HA-WBRT between December 2003 and December 2016 were identified. Forty-six HA-WBRT and 92 WBRT patients were included, who underwent at least one three-dimensional (3D) contrast-enhanced T1-weighted magnetic resonance imaging sequence (Gd-T1MRI) before and after irradiation. HA-WBRT patients were treated analogously to the ongoing HIPPORAD-trial (DRKS00004598) protocol: HA-WBRT (30 Gy in 12 fractions, D98% to hippocampus ≤9 Gy, D2% ≤ 17 Gy) with simultaneous integrated boost (51/42 Gy in 12 fractions) on metastases/resection cavities. WBRT was mainly performed with 35 Gy in 14 fractions (43.9%) and 30 Gy in 10 fractions (30.8%). The bilateral hippocampal volume was segmented and quantified using the Computational Anatomy Toolbox (CAT12), based on 3D Gd-T1MRI sequences within 24 months before and 48 months after therapy. Surgical resections, pre- and post-irradiations were taken into account. The statistical analysis of the non-linear time course of hippocampal atrophy was performed with R (Version 3.4.4) using a Generalized Additive Mixed Model (GAMM), with “time” and “irradiation group” (WBRT versus HA-WBRT) as variables of interest and by modelling patients and scanners as random effects. Variability arising from interindividual differences such as age, sex and total brain volume was statistically controlled for. A total of 922 Gd-T1MRI sequences were analyzed. By evaluating the time course of hippocampal atrophy in the interval between 24 months before and 48 months after radiation therapy, the results revealed a significant hippocampal volume decrease across time after both WBRT and HA-WBRT (p < 10-16). However, the atrophy across time was significantly lower in the HA-WBRT group compared to the WBRT group as indicated by a significant interaction of irradiation group by time (p < .006). HA-WBRT is a therapeutic option for patients with multiple brain metastases, which can effectively and durably minimize the extent of irradiation-induced hippocampal atrophy compared to conventional WBRT. Considering this effect, HA-WBRT with simultaneous integrated boost has the potential to prevent neurocognitive adverse effects, which will be further evaluated in the multicentric phase II HIPPORAD-trial.

Hippocampal-sparing radiotherapy and neurocognitive impairment: A systematic literature review.

Whole-brain radiation therapy (WBRT) is an effective therapeutic modality in patients with brain metastases. However, nearly 90% of patients undergoing WBRT suffer from a neurocognitive function (NCF) impairment at diagnosis, and up to two-thirds will experience a further decline within 2-6 months after WBRT. Focal-dose reduction on bilateral hippocampus is thought to improve NCF preservation. The aim was to present a systematic review of clinical results on NCF after hippocampal-sparing (HS) WBRT. A systematic review of published literature was performed on PubMed and the Cochrane Library. Only prospective clinical trials reporting NCF outcome in patients treated with HS-WBRT have been analyzed. A total of 165 patients from three studies were included. These studies are characterized by small sample size and different methods in terms of WBRT technique but with similar planning analysis and NCF assessment tests. No significant changes in NCF (i.e., verbal and nonverbal learning memory, executive functions, and psychomotor speed) between baseline and 4-month follow-up after RT and only a mean relative decline in delayed recall at 4 months (7% compared to 30% of historical control) were observed. Considering preliminary results on NCF preservation, further studies seem justified in patients undergoing brain irradiation for brain metastases or referred for prophylactic cranial irradiation to evaluate long-term effects on NCF and quality of life.

Optimized stereoelectroencephalography-guided radiofrequency thermocoagulation in the treatment of patients with focal epilepsy.

Epilepsy is a severe health disorder affecting people of all ages with high prevalence worldwide. The introduction of new antiepileptic drugs has yielded notable effects in recent decades, yet there are still approximately 30% of patients with seizures refractory to medical therapy. Open surgical resection is widely accepted as a highly effective approach for the treatment of drug-resistant focal epilepsy if the epileptogenic zone can be precisely delineated. However, concerns about the impact of open surgery on brain function have driven considerable interest in less invasive techniques. Clinically, stereoelectroencephalography (SEEG) offers a unique means of exploring the pathophysiologic process and accurately mapping the epileptogenic network in presurgical evaluations for patients with epilepsy because of insufficient information from other noninvasive investigations. Moreover, SEEG-guided radiofrequency thermocoagulation (SEEG-guided RF-TC), which ablates lesions directly through the recording electrodes according to electroclinical evidence, has emerged as a promising, minimally invasive modality with notable preservation of neurocognitive functions. This critical review summarizes the technical details of the parameters and the selection of patients for SEEG-guided RF-TC based on the literature as well as our experiences. With respect to the parameters, the power and duration of RF-TC are discussed. In particular, an optimized SEEG-guided RF-TC modality that integrates more contacts from multiple different electrodes to create a confluent lesioning field is proposed for a more curative effect in comparison to the current protocol of palliative treatment in which RF-TC selectively disrupts critical hubs in the epileptic network through contiguous contacts within the range of a single electrode. Currently, SEEG-guided RF-TC is indicated for a variety of small, deeply seeded and well-demarcated epileptogenic foci, such as deep heterotopic nodules and hypothalamic hamartoma. The efficacy of treating patients with focal cortical dysplasias in the eloquent cortex and with mesial temporal lobe epilepsy associated with hippocampal sclerosis needs to be further determined. Given the small number of patients reported, randomized controlled trials are necessary to compare the efficacy of SEEG-guided RF-TC with conventional methods in the future.

Significant Preservation of Neurocognitive Function (NCF) and Patient-Reported Symptoms with Hippocampal Avoidance (HA) during Whole-Brain Radiotherapy (WBRT) for Brain Metastases: Final Results of Nrg Oncology CC001

NRG Oncology CC001, a phase III trial of WBRT plus memantine (WBRT+M) with or without HA, sought to evaluate the neuro-protective effects of avoiding the hippocampus using intensity-modulated radiotherapy. Patients (pts) with brain metastasis were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+M (30Gy in 10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module. Cumulative incidence estimated time to NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module and analyzed using mixed effects models and t-tests. From 7/2016 to 3/2018, 518 pts were randomized. Median age was 61.5 years. Median follow-up for alive patients was 7.9 mos. HA-WBRT+M was associated with lower risk of NCF failure (adjusted HR=0.74, 95% confidence interval (CI): 0.58-0.95, p=0.02). The difference was first seen at 4 months (62.7% HA-WBRT+M vs. 54.5% WBRT+M) and was attributable to improvements in executive function at 4 mos (p=0.01) and encoding (p=0.049) and consolidation (p=0.02) at 6 mos. Age≤61 predicted lower risk of NCF failure (HR=0.60, 95%CI: 0.46-0.79, p=0.0002); non-significant test for interaction indicated independent effects of HA and age on NCF. Patient-reported fatigue (p=0.036), difficulty speaking (p=0.049) and problems remembering things (p=0.013) at 6 mos favored the HA-WBRT+M arm. Imputation models accounting for missing data confirmed NCF results and also favored the HA-WBRT+M arm for patient-reported cognition (p=0.011) and symptom interference (p=0.008) at 6 mos. Toxicity, overall survival, and intracranial progression were not significantly different between the treatment arms. Hippocampal avoidance during WBRT better preserves neurocognitive function and patient-reported symptoms, while achieving similar intracranial control and survival, and should be considered standard of care for patients eligible to receive WBRT and anticipated to live 4 months or longer. Data analyses for longer-term (12-mo) follow-up are planned for June 2019 and will be presented for the first time at the meeting. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.

Neurorestoration of Sustained Attention in a Model of HIV-1 Associated Neurocognitive Disorders

Due to the sustained prevalence of human immunodeficiency virus (HIV)-1 associated neurocognitive disorders (HAND) in the post-combination antiretroviral therapy (cART) era, as well as the increased prevalence of older HIV-1 seropositive individuals, there is a critical need to develop adjunctive therapeutics targeted at preserving and/or restoring neurocognitive function. To address this knowledge gap, the present study examined the utility of S-Equol (SE), a phytoestrogen produced by gut microbiota, as an innovative therapeutic strategy. A signal detection operant task with varying signal durations (1,000, 500, 100 ms) was utilized to assess sustained attention in HIV-1 transgenic (Tg) and control animals. During the signal detection pretest assessment, HIV-1 Tg animals displayed profound deficits in stimulus-response learning and sustained attention relative to control animals. Subsequently, between 6 and 8 months of age, HIV-1 Tg and control animals were treated with a daily oral dose of either placebo or SE (0.05, 0.1, 0.2 mg) and a posttest assessment was conducted in the signal detection operant task with varying signal durations. In HIV-1 Tg animals, a linear decrease in the number of misses at 100 ms was observed as SE dose increased, suggesting a dose response with the most effective dose at 0.2 mg SE, approximating controls. Comparison of the number of misses across signal durations at the pretest and posttest revealed a preservation of neurocognitive function in HIV-1 Tg animals treated with 0.2 mg SE; an effect that was in sharp contrast to the neurocognitive decline observed in HIV-1 Tg animals treated with placebo. The results support the utility of 0.2 mg SE as a potential efficacious neuroprotective and/or neurorestorative therapeutic for sustained attention, in the absence of any adverse peripheral effects, in the HIV-1 Tg rat. Thus, the present study highlights the critical need for further in vivo studies to elucidate the full potential and generalizability of phytoestrogen treatment for HAND.

Multiinstitutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases from non-small cell lung cancer (JLGK0901 study-NSCLC).

OBJECTIVEPrevious Japanese Leksell Gamma Knife Society studies (JLGK0901) demonstrated the noninferiority of stereotactic radiosurgery (SRS) alone as the initial treatment for patients with 5-10 brain metastases (BMs) compared with those with 2-4 BMs in terms of overall survival and most secondary endpoints. The authors studied the aforementioned treatment outcomes in a subset of patients with BMs from non-small cell lung cancer (NSCLC).METHODSPatients with initially diagnosed BMs treated with SRS alone were enrolled in this prospective observational study. Major inclusion criteria were the existence of up to 10 tumors with a maximum diameter of less than 3 cm each, a cumulative tumor volume of less than 15 cm3, and no leptomeningeal dissemination in patients with a Karnofsky Performance Scale score of 70% or better.RESULTSAmong 1194 eligible patients, 784 with NSCLC were categorized into 3 groups: group A (1 tumor, n = 299), group B (2-4 tumors, n = 342), and group C (5-10 tumors, n = 143). The median survival times were 13.9 months in group A, 12.3 months in group B, and 12.8 months in group C. The survival curves of groups B and C were very similar (hazard ratio [HR] 1.037; 95% CI 0.842-1.277; p < 0.0001, noninferiority test). The crude and cumulative incidence rates of neurological death, deterioration of neurological function, newly appearing lesions, and leptomeningeal dissemination did not differ significantly between groups B and C. SRS-induced complications occurred in 145 (12.1%) patients during the median post-SRS period of 9.3 months (IQR 4.1-17.4 months), including 46, 54, 29, 11, and 5 patients with a Common Terminology Criteria for Adverse Events v3.0 grade 1, 2, 3, 4, or 5 complication, respectively. The cumulative incidence rates of adverse effects in groups A, B, and C 60 months after SRS were 13.5%, 10.0%, and 12.6%, respectively (group B vs C: HR 1.344; 95% CI 0.768-2.352; p = 0.299). The 60-month post-SRS rates of neurocognitive function preservation were 85.7% or higher, and no significant differences among the 3 groups were found.CONCLUSIONSIn this subset analysis of patients with NSCLC, the noninferiority of SRS alone for the treatment of 5-10 versus 2-4 BMs was confirmed again in terms of overall survival and secondary endpoints. In particular, the incidence of neither post-SRS complications nor neurocognitive function preservation differed significantly between groups B and C. These findings further strengthen the already-reported noninferiority hypothesis of SRS alone for the treatment of patients with 5-10 BMs.

Preservation of Neurocognitive Function (NCF) with Conformal Avoidance of the Hippocampus during Whole-Brain Radiotherapy (HA-WBRT) for Brain Metastases: Preliminary Results of Phase III Trial NRG Oncology CC001

Preservation of Neurocognitive Function (NCF) with Conformal Avoidance of the Hippocampus during Whole-Brain Radiotherapy (HA-WBRT) for Brain Metastases: Preliminary Results of Phase III Trial NRG Oncology CC001

Alpha-Mannosidosis: Therapeutic Strategies.

Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis. In this review, the genetic of alpha-mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I–II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-mannosidosis.