Prospective Analysis of Radiation-Induced Contrast Enhancement and Health-Related Quality of Life After Proton Therapy for Central Nervous System and Skull Base Tumors.

PURPOSE: Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). METHODS AND MATERIALS: Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. RESULTS: The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. CONCLUSIONS: The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.

BBB opening by low pulsed electric fields, depicted by delayed-contrast MRI, enables efficient delivery of therapeutic doxorubicin doses into mice brains.

BACKGROUND: Pharmacological treatment of CNS diseases is limited due to the presence of the blood-brain barrier (BBB). Recent years showed significant advancement in the field of CNS drug delivery enablers, with technologies such as MR-guided focused ultrasound reaching clinical trials. This have inspired researchers in the field to invent novel brain barriers opening (BBo) technologies that are required to be simple, fast, safe and efficient. One such technology, recently developed by us, is BDF (Barrier Disrupting Fields), based on low pulsed electric fields (L-PEFs) for opening the BBB in a controlled, safe, reversible and non-invasive manner. Here, we conducted an in vivo study to show that BDF is a feasible technology for delivering Doxorubicin (Doxo) into mice brain. Means for depicting BBBo levels were developed and applied for monitoring the treatment and predicting response. Overall, the goals of the presented study were to demonstrate the feasibility for delivering therapeutic Doxo doses into naïve and tumor-bearing mice brains and applying delayed-contrast MRI (DCM) for monitoring the levels of BBBo. METHODS: L-PEFs were applied using plate electrodes placed on the intact skull of naïve mice. L-PEFs/Sham mice were scanned immediately after the procedure by DCM ("MRI experiment"), or injected with Doxo and Trypan blue followed by delayed (4 h) perfusion and brain extraction ("Doxo experiment"). Doxo concentrations were measured in brain samples using confocal microscopy and compared to IC50 of Doxo in glioma cell lines in vitro. In order to map BBBo extent throughout the brain, pixel by pixel MR image analysis was performed using the DCM data. Finally, the efficacy of L-PEFs in combination with Doxo was tested in nude mice bearing intracranial human glioma tumors. RESULTS: Significant amount of Doxo was found in cortical regions of all L-PEFs-treated mice brains (0.50 ± 0.06 µg Doxo/gr brain) while in Sham brains, Doxo concentrations were below or on the verge of detection limit (0.03 ± 0.02 µg Doxo/gr brain). This concentration was x97 higher than IC50 of Doxo calculated in gl261 mouse glioma cells and x8 higher than IC50 of Doxo calculated in U87 human glioma cells. DCM analysis revealed significant BBBo levels in the cortical regions of L-PEFs-treated mice; the average volume of BBBo in the L-PEFs-treated mice was x29 higher than in the Sham group. The calculated BBBo levels dropped exponentially as a function of BBBo threshold, similarly to the electric fields distribution in the brain. Finally, combining non-invasive L-PEFs with Doxo significantly decreased brain tumors growth rates in nude mice. CONCLUSIONS: Our results demonstrate significant BBBo levels induced by extra-cranial L-PEFs, enabling efficient delivery of therapeutic Doxo doses into the brain and reducing tumor growth. As BBBo was undetectable by standard contrast-enhanced MRI, DCM was applied to generate maps depicting the BBBo levels throughout the brain. These findings suggest that BDF is a promising technology for efficient drug delivery into the brain with important implications for future treatment of brain cancer and additional CNS diseases.

Differential chronic social stress models in male and female mice.

Chronic stress creates an allostatic overload that may lead to mood disorders such as anxiety and depression. Modern causes of chronic stress in humans are mostly social in nature, relating to work and relationship stress. Research into neural and molecular mechanisms of vulnerability and resilience following chronic social stress (CSS) is ongoing and uses animal models to discover efficient prevention strategies and treatments. To date, most CSS studies have neglected the female sex and used male-focused aggression-based animal models such as chronic social defeat stress (CSDS). Accumulating evidence on sex differences suggests differences in the stress response, the prevalence of stress-related illness and in response to treatment, indicating that researchers should expand CSS investigation to include female-focused protocols alongside the popular CSDS protocols. Here, we describe a novel female mouse model of CSS and a parallel modified male mouse model of CSDS in C57BL/6 mice. These new models enable the investigation of vulnerability, coping and downstream effectors mediating short-term and long-term consequences of CSS in both sexes. Our data demonstrate differential effects on male and female mice during, soon after, and many weeks after CSS. Female mice are more prone to body weight loss during CSS and hyperactive anxious behaviour following CSS. Both sexes show reduced social interaction, but only stressed male mice show long-term changes in emotional memory and neuroendocrine function. We further discuss future avenues of research using these models to investigate mechanisms pertaining to sensitivity to CSS and treatment response profiles, in a sex-appropriate manner.

Neuro-ophthalmologic outcomes of standard versus hypo-fractionated stereotactic radiotherapy of AVPM.

BACKGROUND: Most anterior visual pathway meningiomas (AVPM) are benign and slow-growing, but these tumors may affect visual functions, including visual acuity (VA) and visual field (VF). Due to location, most are treated non-surgically by fractionated stereotactic radiotherapy (FSRT), aiming to prevent tumor progression and visual functions deterioration. Unfortunately, FSRT in itself may affect visual functions. The current preferred treatment regimen (in terms of safety and effectiveness) is undetermined. While most cases are treated with conventional fractionation (cFSRT)-50.4-54 Gy in 28-30 fractions of 1.8-2 Gy, advances in technology have allowed shortening of total treatment length to hypofractionation (hSRT)-25-27 Gy in 3-5 fractions of 5-9 Gy. Our aim was to evaluate the association of radiotherapy regimen for treating AVPM (cFSRT vs. hSRT) with visual function outcomes (VA, VF) at the last neuro-ophthalmologic evaluation. METHODS: We conducted a retrospective cohort study of AVPM cases treated at Sheba Medical Center during 2004-2015. We compared cFSRT and hSRT regimens regarding visual function (VA, VF) outcomes at the last neuro-ophthalmologic evaluation. VA was determined by the logarithm of the minimum angle of resolution (LogMAR). VF was determined by the mean deviation (MD). A clinically relevant change in VA was defined as 0.2 LogMAR. RESULTS: 48 patients (13 receiving hSRT, 35 receiving cFSRT) were included, with a median follow-up of 55 months. No significant difference was evident regarding LogMAR or MD of involved eyes at the last evaluation. Six (17%) patients in the cFSRT group experienced clinically relevant VA deterioration in the involved eye, compared with six (46%) in hSRT (p = 0.06). CONCLUSION: Our findings, using comprehensive and meticulous investigation of visual outcomes, suggest that hSRT may be associated with higher risk for VA and VF deterioration in AVPM especially in ONSM. We recommend the use of cFSRT for ONSM.

A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma.

BACKGROUND: Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that the metabolic stress induced by a KD combined with metformin would enhance radiation's efficacy. We sought to assess the tolerability and feasibility of this approach. METHODS: A single-institution phase I clinical trial. Radiotherapy was either 60 or 35 Gy over 6 or 2 weeks, for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a Modified Atkins Diet (ModAD) supplemented with medium chain triglycerides (MCT). There were three cohorts: Dietary intervention alone, and dietary intervention combined with low-dose or high-dose metformin; all patients received radiotherapy. Factors associated with blood ketone levels were investigated using a mixed-model analysis. RESULTS: A total of 13 patients were accrued, median age 61 years, of whom six had newly diagnosed and seven with recurrent disease. All completed radiation therapy; five patients stopped the metabolic intervention early. Metformin 850 mg three-times daily was poorly tolerated. There were no serious adverse events. Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0. 02) and low insulin levels (p = 0.002). Median progression free survival was ten and four months for newly diagnosed and recurrent disease, respectively. CONCLUSIONS: The intervention was well tolerated. Higher serum ketone levels were associated with both dietary intake and metformin use. The recommended phase II dose is eight weeks of a ModAD combined with 850 mg metformin twice daily.

The Implication of Combat Stress and PTSD Trajectories in Metabolic Syndrome and Elevated C-Reactive Protein Levels: A Longitudinal Study.

OBJECTIVE: This study sheds light on the importance of long-term follow-up of trauma survivors, posttraumatic stress disorder (PTSD) trajectories, and early detection of health risk factors in trauma survivors. The present study prospectively assessed the following over 23 years: (1) the association of psychological and physiologic stress during captivity with elevated C-reactive protein (CRP) levels and metabolic syndrome (MetS), which includes hypertension; elevated levels of insulin, triglycerides, and fasting glucose; decreased levels of high-density lipoprotein cholesterol; and obesity and (2) the implication of PTSD trajectories in elevated CRP levels and MetS. METHODS: Measurements were taken in 1991, 2003, 2008, and 2015. Participants were 116 Israeli combat veterans of the 1973 Yom Kippur War (of these, 101 were former prisoners of war [ex-POWs] and 15 were comparable controls). The medical assessments relevant for this study were body mass index, fasting blood glucose levels, and diabetes, blood pressure or a diagnosis of hypertension, high-density lipoprotein cholesterol and triglyceride levels, and medication intake. In addition, the PTSD Inventory was used to assess PTSD symptoms and trajectories over time according to DSM-IV-TR PTSD criteria. RESULTS: Captivity-in particular, the captivity stressors of weight loss, physical suffering, psychological suffering, and humiliation-was implicated in both elevated CRP levels and MetS, significantly so with elevated CRP levels (P = .01, R² = 0.33). Captivity-induced PTSD, in particular chronic and delayed PTSD trajectories, was associated with elevated CRP levels and MetS, significantly so for MetS (P = .05). CONCLUSIONS: Monitoring inflammation using markers like CRP level in trauma survivors can be beneficial, particularly if PTSD is chronic or delayed. Clinicians treating trauma survivors should raise awareness of the importance of such measures in light of long-term health vulnerabilities.

The episodic engram transformed: Time reduces retrieval-related brain activity but correlates it with memory accuracy.

We took snapshots of human brain activity with fMRI during retrieval of realistic episodic memory over several months. Three groups of participants were scanned during a memory test either hours, weeks, or months after viewing a documentary movie. High recognition accuracy after hours decreased after weeks and remained at similar levels after months. In contrast, BOLD activity in a retrieval-related set of brain areas during correctly remembered events was similar after hours and weeks but significantly declined after months. Despite this reduction, BOLD activity in retrieval-related regions was positively correlated with recognition accuracy only after months. Hippocampal engagement during retrieval remained similar over time during recall but decreased in recognition. Our results are in line with the hypothesis that hippocampus subserves retrieval of real-life episodic memory long after encoding, its engagement being dependent on retrieval demands. Furthermore, our findings suggest that over time episodic engrams are transformed into a parsimonious form capable of supporting accurate retrieval of the crux of events, arguably a critical goal of memory, with only minimal network activation.

Signatures of Memory: Brain Coactivations during Retrieval Distinguish Correct from Incorrect Recollection.

Are specific distributed coactivations in the brain during memory retrieval a signature of retrieval outcome? Here we show that this is indeed the case. Widespread brain networks were reported to be involved in the retrieval of long-term episodic memories. Although functional coactivation among particular regions occurs during episodic memory retrieval, it is unknown to what extent it contributes to the accuracy and confidence of recollection. In this study we set out to explore this question. Participants saw a narrative documentary movie. A week later they underwent an fMRI scan during which they either accepted or rejected factual or fictitious verbal statements concerning the movie. Correct vs. incorrect responses to factual statements were more common and were provided with higher confidence than those made to fictitious statements. Whereas activity in the retrieval network correlated mostly with confidence, coactivations primarily correlated with memory accuracy. Specifically, coactivations of left medial temporal lobe regions with temporal and parietal cortices were greater during correct responses to factual statements, but did not differ between responses to fictitious statements. We propose that network coactivations play a role in recovering memory traces that are relevant to online retrieval cues, culminating in distinct retrieval outcomes.

Subjective vs. documented reality: a case study of long-term real-life autobiographical memory.

A young woman was filmed during 2 d of her ordinary life. A few months and then again a few years later she was tested for the memory of her experiences in those days while undergoing fMRI scanning. As time passed, she came to accept more false details as true. After months, activity of a network considered to subserve autobiographical memory was correlated with memory confidence rather than with accuracy. After years, mainly regions of the temporal pole displayed this pattern. These results might reflect a slow process of increased reliance on schemata at the expense of accuracy.

Enhanced intersubject correlations during movie viewing correlate with successful episodic encoding.

While much has been learned regarding the neural substrates supporting episodic encoding using highly controlled experimental protocols, relatively little is known regarding the neural bases of episodic encoding of real-world events. In an effort to examine this issue, we measured fMRI activity while observers viewed a novel TV sitcom. Three weeks later, subsequent memory (SM) for the narrative content of movie events was assessed. We analyzed the encoding data for intersubject correlations (ISC) based on subjects' subsequent memory (ISC-SM) performance to identify brain regions whose BOLD response is significantly more correlated across subjects during portions of the movie that are successfully as compared to unsuccessfully encoded. These regions include the parahippocampal gyrus, superior temporal gyrus, anterior temporal poles, and the temporal-parietal junction. Further analyses reveal (1) that these correlated regions can display distinct activation profiles and (2) that the results seen with the ISC-SM analysis are complementary to more traditional linear models and allow analysis of complex time course data. Thus, the ISC-SM analysis extends traditional subsequent memory findings to a rich, dynamic and more ecologically valid situation.

They saw a movie: long-term memory for an extended audiovisual narrative.

We measured long-term memory for a narrative film. During the study session, participants watched a 27-min movie episode, without instructions to remember it. During the test session, administered at a delay ranging from 3 h to 9 mo after the study session, long-term memory for the movie was probed using a computerized questionnaire that assessed cued recall, recognition, and metamemory of movie events sampled approximately 20 sec apart. The performance of each group of participants was measured at a single time point only. The participants remembered many events in the movie even months after watching it. Analysis of performance, using multiple measures, indicates differences between recent (weeks) and remote (months) memory. While high-confidence recognition performance was a reliable index of memory throughout the measured time span, cued recall accuracy was higher for relatively recent information. Analysis of different content elements in the movie revealed differential memory performance profiles according to time since encoding. We also used the data to propose lower limits on the capacity of long-term memory. This experimental paradigm is useful not only for the analysis of behavioral performance that results from encoding episodes in a continuous real-life-like situation, but is also suitable for studying brain substrates and processes of real-life memory using functional brain imaging.