To examine the preliminary efficacy of Cognitive Retraining and Functional Treatment (CRAFT) combining remote computerized cognitive training (CCT) and occupation-based treatment in adults with cancer-related cognitive impairment (CRCI). Three-armed randomized controlled trial including 74 individuals with CRCI, randomized into 12 weeks of either CRAFT, CCT alone, or treatment-as-usual. Assessments evaluating participation in daily life, perceived cognition, cognitive performance, quality-of-life, and treatment satisfaction were administered at baseline, post-intervention, and 3-month follow-up. Significant time × group interactions in favor of the CRAFT and CCT groups were found for participation in daily life (F2,34 = 5.31, p = .01, eta = .238), perceived cognition (F2,34 = 4.897, p = .014, eta = .224), and cognitive performance on speed of processing test (F = 5.678, p = .009, eta = .289). The CRAFT group demonstrated significantly larger clinically meaningful gains on participation in daily life (chi-square = 6.91, p = .032) and significantly higher treatment satisfaction. All treatment gains were maintained at a 3-month follow-up (n = 32). CCT and CRAFT were found to have a positive impact on participation and cognitive outcomes among individuals with CRCI. The CRAFT showed an additional advantage in improving self-chosen occupation-based goals suggesting that a combination of cognitive training with occupation-based intervention has a positive synergistic effect resulting in “real world” health benefits. A combination of cognitive training with occupation-based intervention has a positive effect resulting in clinically meaningful improvements in participation in daily life, objective cognitive performance, and subjective cognitive impairment. Clinical trial registration: ClinicalTrials.gov NCT04210778, December 26, 2019, retrospectively registered.

Abstract Radiotherapy has an important role in the treatment of brain metastases (BrM) but carries risk of short and/or long-term toxicity, termed radiation-induced neurotoxicity (RIN). As the diagnosis of RIN is crucial for correct pa-tient management, there is an unmet need for reliable biomarkers for RIN. The aim of this proof-of concept study was to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as RIN biomarkers. Twenty-four patients with BrM were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. During follow-up nine RIN events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RIN correlated with de-crease in BncfDNA. Changes in BncfDNA were independent of tumor response. Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy, further research is needed to establish BncfDNA as a novel plasma-based biomarker for RIN.

Background: Circulating cell-free DNA (cfDNA) is a novel type of biomarker with a broad utility in diagnostic medicine, based on the release of DNA fragments from dying cells to the circulation. We developed an approach for identifying the tissue origins of cfDNA, using cell-type-specific DNA methylation patterns, based on a massive reference atlas of the genome-wide methylomes of multiple human tissues and cell types. Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. We demonstrated that brain cell death in CNS cancer can be detected by tissue-specific methylation patterns of circulating cfDNA. Methods: We developed a cocktail of brain-specific DNA methylation markers, and used it to assess the presence of brain-derived-cfDNA in the plasma of patients with brain metastasis. Results: We identified significantly elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA (p<0.0001) in patients with brain metastases (n=29) compared with cancer patients without brain metastasis (n=113). Conclusions: We show a new set of biomarkers to identify brain damage with high specificity and resolution. We detected brain (neurons, oligodendrocytes, astrocytes) cfDNA in the plasma of patients with brain metastasis. Cell-type-specific cfDNA methylation markers allow the identification of collateral tissue damage, reveals the presence of metastases, and potentially assist in early cancer detection.

BACKGROUND:Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS:Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS:During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS:Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Abstract Purpose: To examine the applicability and efficacy of Cognitive Retraining and Functional Treatment (CRAFT) combining remote computerized cognitive training (CCT) and occupation-based treatment in adults with cancer-related cognitive impairment (CRCI). Methods: Three-armed randomized controlled trial including 74 individuals with CRCI, randomized into 12 weeks of either CRAFT, CCT alone, or treatment-as-usual. Assessments evaluating participation in daily life, perceived cognition, cognitive performance, quality-of-life, and treatment satisfaction were administered at baseline, post-intervention and 3-month follow up. Results: Significant time X group interactions in favor of the CRAFT and CCT groups were found for participation in daily life (F2,34=5.31, p=.01, eta=.238), perceived cognition (F2,34=4.897, p=.014, eta=.224) and cognitive performance on speed of processing test (F=5.678, p=.009, eta=.289). CRAFT group demonstrated significantly larger clinically meaningful gains on participation in daily life (Chi-square= 6.91, p=.032) and significantly higher treatment satisfaction. All treatment gains were maintained at a 3-month follow-up (n=32). Conclusions: CCT and CRAFT were found to have a positive impact on participation and cognitive outcomes among individuals with CRCI. The CRAFT showed an additional advantage in improving self-chosen occupation-based goals suggesting that a combination of cognitive training with occupation-based intervention has a positive synergistic effect resulting in ‘real world’ health benefits. Implications for Cancer Survivors: A combination of cognitive training with occupation-based intervention has a positive effect resulting in clinically meaningful improvements in participation in daily life, objective cognitive performance, and subjective cognitive impairment. Clinical Trial Registration: ClinicalTrials.gov NCT04210778, December 26, 2019, retrospectively registered.

Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death in organs affected by cancer can be detected by tissue-specific methylation patterns of circulating cell-free DNA (cfDNA). We detected elevated levels of hepatocyte-derived cfDNA in the plasma of patients with liver metastases originating from different primary tumors, compared with cancer patients without liver metastases. In addition, patients with localized pancreatic or colon cancer showed elevated hepatocyte cfDNA, suggesting liver damage inflicted by micrometastatic disease, by primary pancreatic tumor pressing the bile duct, or by a systemic response to the primary tumor. We also identified elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA in a subpopulation of patients with brain metastases compared with cancer patients without brain metastasis. Cell type–specific cfDNA methylation markers enable the identification of collateral tissue damage in cancer, revealing the presence of metastases in specific locations and potentially assisting in early cancer detection.

The optimal high-dose methotrexate (HDMTX)-based combination therapy for primary central nervous system lymphoma is unknown. We report our experience with rituximab, HDMTX, procarbazine and lomustine (R-MPL) given as first-line treatment in our center. Fifty-two patients between 2006 and 2019 were included. Eighteen patients proceeded to autologous transplant or two cycles of intermediate-dose cytarabine. The median age was 62 y (range 28-94) and the Eastern Cooperative Oncology Group performance status (ECOG-PS) was >= 2 in 62% (32/52). The overall/complete response rates were 79% (41/52) and 52% (27/52), respectively. The median progression-free/overall survival was 19 m/84m, respectively. Grade 3-4 adverse events included infections (17%) and kidney injury (13%). Ten patients (19%) discontinued therapy for toxicity. There were no treatment-related deaths. In summary, in a cohort enriched in frail patients, R-MPL achieved good responses and OS and was safe for all ages. The PFS was sub-optimal, possibly explained by a low proportion of consolidation. This regimen should be evaluated prospectively.

OBJECTIVE:The purpose of the current study was to examine the unique contribution of personal and medical factors, objective and subjective cognition, and self-efficacy to the explained variance of quality of life (QoL) among survivors with self-reported cancer related cognitive impairment (CRCI). METHOD:Seventy-three cancer survivors (non-central nervous system) with CRCI (mean age: 50.85 ± 10.82 years old, mean years post-treatment: 3 ± 2.7) participated in this cross-sectional study. QoL was assessed using the Functional Assessment of Cancer Therapy (FACT)-GP, while the cognitive function was assessed both objectively using tests of attentional control, speed of processing and sustained attention, and subjectively using the FACT-Cognition perceived cognitive impairments (FACTcog-PCI) subscale. Self-efficacy was assessed using the New General Self-Efficacy Scale (NGSE). RESULTS:A hierarchical multiple linear regression analysis revealed that sustained attention, perceived cognitive impairment and self-efficacy, accounted for 54% of the variance of QoL (R2 = 0.543, p < 0.000), each providing a unique contribution to the explained variance (15-20% each) after controlling for age and gender. CONCLUSIONS:Considering that these variables may be amenable to change, this model can serve as a conceptual framework for designing effective cognitive treatment options for CRCI. Clinical Trial Registration: ClinicalTrials.gov NCTImplication for rehabilitationCancer related cognitive impairment is characterized by difficulties in the speed of processing performance, severe perceived cognitive impairments, and relatively low general self-efficacy.Multi-dimensional assessments including subjective and objective cognition as well as self-efficacy should be administered to cancer survivors with cognitive complaints to understand the underlying mechanisms of their QoL.Integrative cognitive rehabilitation interventions that aim to improve QoL among people with cancer-related cognitive impairment should target sustained attention, perceived cognitive impairment, and self-efficacy.

Introduction The purpose of this study was to test the feasibility of a telehealth intervention combining computerised cognitive training and occupation-based treatment among adult cancer survivors experiencing cancer-related cognitive impairment. Method This was a single-arm study including six cancer survivors with cancer-related cognitive impairment. Participants completed the computerised retraining and functional treatment intervention consisting of 10 hours of computerised cognitive training (BrainHQ) and approximately 10 1:1 remote sessions with an occupational therapist using an occupation-based approach. Feasibility was measured in terms of recruitment, adherence, acceptability and potential effectiveness. Assessments were administered at baseline, post-intervention and at 3-month follow-up and included measures of occupational performance, objective cognitive functions, quality of life and mood questionnaires. Results From the nine participants enrolled in the study, six completed 8–13 weeks of computerised retraining and functional treatment intervention and reported high satisfaction levels. Positive and significant improvements were found in occupational performance, useful field of view and social quality of life (all P < 0.05). The positive gains were maintained at the 3-month follow-up. Conclusion A combined model of computerised cognitive training and occupation-based treatment delivered remotely to adults with cancer-related cognitive impairment was found feasible and may improve occupational performance, cognitive functions and quality of life.

Abstract BACKGROUND Brain radiotherapy is the main therapeutic modality for brain metastases (BM), but carries short and long term toxicities, termed radiation-induced neurotoxicity (RIN), and classified to acute, early-delayed and late-delayed RIN according to its time onset. Although diagnosis of RIN is crucial for patient management, there is an unmet need for sensitive biomarkers for RIN. Here we report on a novel non-invasive biomarker for detection and monitoring RIN. As radiotherapy is known to induce brain cells apoptosis as well as BBB disruption, we hypothesized that circulating cell free DNA fragments derived from dying brain cells will be elevated in the blood of patients with RIN. Using comparative methylome analysis we identified 13 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes, and astrocytes. We searched for these brain-derived cfDNA (bncfDNA) in plasma samples of patients following brain irradiation. METHODS We followed 24 patients treated by brain radiotherapy for BM by clinical and radiological examinations before, during and after treatment. In addition, we serially collected blood samples for DNA analysis, and correlated bncfDNA levels with clinical and radiological assessment. RESULTS Patient`s median age was 60 years. Most common primary tumor sites were breast (25%), lung (20.8%) and melanoma (12.5%). RIN was detected in 10 patients (62%). BncfDNA levels increased up to 292.4 fold in acute RIN, up to 138533.1 in early-delayed RIN, and up to 58.4 fold in late-delayed RIN. Resolution of RIN correlated with decrease in bncfDNA. Changes in bncfDNA levels were independent of tumor response and suggested to reflect both symptomatic and asymptomatic RIN. CONCLUSION Increase in bncfDNA levels characterizes RIN independent of tumor response. Thus, BncfDNA may serve as a novel biomarker for brain cells death incurred by radiotherapy. Further studies are required to explore the clinical utility of bncfDNA as a RIN biomarker.

Date Presented 04/7/21 This study describes the feasibility of a combined telehealth intervention of computerized cognitive training together with occupation-based treatment for patients with cancer-related cognitive impairment (CRCI). The intervention was found feasible, and positive outcomes on occupational performance, cognitive functions, quality of life, and mood were revealed. This treatment can possibly add to the therapeutic landscape of CRCI, which currently impairs the life of millions worldwide. Primary Author and Speaker: Yafit Gilboa Contributing Authors: Anita Tollen, Marie Holmefur

BACKGROUND:Lymphoma of the nervous system is rare and usually involves the brain, spinal cord, or peripheral nerves. Hence, it has varied clinical presentations, and correct diagnosis is often challenging. Incorrect diagnosis delays the appropriate treatment and affects prognosis. We report 5 patients with delayed diagnosis of lymphoma involving the central and/or peripheral nervous system, initially evaluated for other neurological diagnoses. We also discuss the challenge of diagnosis and appropriate testing.METHODS:Retrospective review of 2011-2019 records of patients with confirmed nervous system lymphoma diagnosed in a tertiary care medical center.RESULTS:We present 5 adult patients initially evaluated for inflammatory myelopathy, inflammatory lumbosacral plexopathy, atypical parkinsonism, and demyelinating disease of the CNS. Final diagnosis of the nervous system lymphoma was delayed by 4 to 18 months and was based on tissue biopsy in 4, and on CSF and bone marrow examination in 1 patient.CONCLUSIONS:Lymphoma may imitate various central and peripheral nervous system disorders. We suggest several red flags that indicate the need to consider lymphoma, including subacute but progressive symptomatic evolution, painful neurological deficit, unclear clinical diagnosis, and transient steroid responsiveness. Correct diagnosis often requires a combination of diagnostic tests, while pathology testing is crucial for early diagnosis and is strongly recommended in the appropriate clinical setting.

Background: Venous thromboembolism (VTE) is a frequent, potentially lethal complication in individuals with cancer. Patients with brain tumors are at particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B cell lymphoma, involving the craniospinal axis. The incidence of VTE in patients with PCNSL was reported as very high, occurring mostly in the early period of therapy. Objectives: We aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (LMWH) throughout the treatment of PCNSL. Patients: All patients >18 years of age diagnosed and treated for PCNSL at our institution in 2005–2017 were included. Results: There were 44 patients; mean age at diagnosis was 61.5 years. Three patients (6.8%) had a personal history of thrombosis, 11 (25%) had a history of diabetes or smoking, and 32 (72%) had an Eastern Cooperative Oncology Group performance status of 0–1 at diagnosis. During treatment with LMWH, no VTE events were recorded; 2 (4.5%) patients experienced a minor bleeding event and 1 (2.3%) a major bleeding event. Conclusions: Among our 44 patients with PCNSL treated with prophylactic LMWH, no VTE events were recorded, and only 1 (asymptomatic) intracranial bleed was recorded. Within the limitations of a retrospective nonrandomized study, our findings suggest that VTE prophylaxis may be beneficial for individuals with PCNSL.

Purpose: Heat intolerance (HI) is determined in the Israel Defense Force according to a heat tolerance test (HTT) before returning to duty after an exertional heat stroke (EHS) event. Recently, increased numbers of female combatants resulted in an increased number of EHS cases among women and a higher percentage of heat intolerance (HI) individuals. We aimed to evaluate the differences between tolerance to heat among women performing an HTT in relation to their menstrual cycle phase. Method: Thirty-three female participants were sorted into two groups: HI and heat tolerant (HT) according to two HTTs performed during both the luteal and follicular phases of the menstrual cycle or while consuming and during a break from consuming contraceptives. Results: HT women had an 18% higher maximal oxygen uptake (p < .005, 95% CI [2.6,9.8]) and 1.2% lower skin temperature in the HTT at the during and follicular phases (p < .01, 95% CI [0.12,0.77]) and 1.7% lower at the off and luteal phases (p < .001, 95% CI [0.34,0.92]). The mean sweat rate was 14% lower among the HI group only at the HTT at the during and follicular phases (p < .05, 95% CI (3,88)]). Conclusion: We found that HT can be predicted using aerobic capacity and core body temperature. Moreover, during the luteal phase, women presented altered thermoregulation that decreased the probability of being HT. This emphasizes the importance of considering the HT/HI criteria in the HTT for women, according to their aerobic ability and menstrual-cycle phase.

Radiotherapy is a common treatment for brain metastases. However, it is commonly associated with central nervous system (CNS) toxicity. There are no biomarkers for early detection of radiotoxicity. Here we explore the utility of cell-free circulating DNA (cfDNA) for detection of brain cells death in the context of brain metastases. Using comparative methylome analysis we have previously identified 12 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes and astrocytes. These brain-specific methylation markers were identified in plasma of patients suffering from multiple sclerosis, as well as traumatic and ischemic brain damage. We hypothesize that brain-derived cell-free DNA (bncfDNA) can be identified in patients suffering from brain metastases receiving radiotherapy, and can potentially be used as a biomarker to help guide treatment. MATERIALS AND We recruit oncological patients treated by brain radiotherapy for brain metastases. We serially assess each patient before, during and after treatment by neurological examination and MRI studies. In each study visit a blood sample is collected for bncfDNA measurement. Preliminary results on samples from 22 patients show elevation of bncfDNA in patients suffering from brain metastases (average 8501 copies/ml; range 0-112336 copies/ml) compared with an extremely low background in healthy individuals (average 6 copies/ml; range 0–33 copies/ml); p < 0.0001). We observed elevation of cfDNA derived from neurons, oligodendrocytes and astrocytes. Next, we studied bncDNA levels following brain radiotherapy. Preliminary results from a patient suffering from an acute central facial paralysis during radiotherapy show clinical correlation of bncfDNA levels with neurological impairment related to acute radiotoxicity. Other patients are still followed-up with bncfDNA measurement during and after radiotherapy. BncfDNA reflects brain cells death incurred by metastases, as well as damage associated with radiotherapy, and may serve as circulating biomarker for neurotoxicity in patients suffering from brain metastases.

•Early hydrocephalus is common in L. monocytogenes meningitis.•Suspect hydrocephalus when neurological deterioration occurs few days after initial presentation, especially when treatment was not directed against L. monocytogenes.•Appropriate antimicrobial treatment and surgical ventriculostomy usually result in a favorable outcome.•Meningitis complicated by hydrocephalus should raise to possibility of L. monocytogenes.

Listeria monocytogenes is a gram-positive bacterium with a predilection to infect the central nervous system, often affecting immunocompromised or elderly patients. The most common manifestations are meningitis and rhomboencephalitis. We report two cases of Listeria meningitis complicated by acute hydrocephalus several days after presentation and we further review the literature of similar cases. We conclude that acute hydrocephalus is a significant, not often recognized, complication of Listeria meningitis, usually occurring several days from onset when coverage did not include anti-Listeria antimicrobials. In high risk patients, meningitis combined with acute hydrocephalus is suggestive of LM infection.

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days–19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

Spinal cord infarction is a rare but often devastating disorder caused by disruption in the vascular spinal supply. We report a patient with spinal cord infarction associated with lenalidomide therapy for primary amyloidosis, in the background of other predisposing factors. We describe the clinical case and discuss the possible explanation for this rare complication. As spinal cord infarction is not a known complication of lenalidomide therapy or amyloidosis, this description raises the potential of such a side effect in some certain conditions and discusses the role of the old and new anticoagulant agents in prevention of thromboembolic complications in high-risk patients.