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Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57−88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88−100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P< 0.0001, Fisher’s exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.

There is no uniform standard of care for the treatment of refractory or recurrent primary central nervous lymphoma (r/r PCNSL). Many different systemic treatment regimens have been studied, but available data are based on small prospective or retrospective reports. There have been no randomized controlled trials in r/r PCNSL to date. Here, we provide an overview of published systemic regimens for the treatment of r/r PCNSL, as well as therapies that are under investigation. In addition, based on available data, we propose strategies of how to approach choice of therapy for different groups of patients in this disease setting. Patients can be mainly divided into three groups: 1) patients suitable for a re-challenge with high-dose methotrexate (HD-MTX)-based regimens and that may or may not be candidates for consolidation with high-dose chemotherapy with autologous stem cell transplant, 2) patients refractory to HD-MTX or that had early relapse, but suitable for an aggressive treatment strategy with re-induction with non-MTX-based therapy, possibly followed by high-dose chemotherapy with autologous transplant, and 3) patients not suitable for re-treatment with HD-MTX and that are not candidates for aggressive therapy. As PCNSL is a rare disease and as there is urgent need for better outcomes in r/r PCNSL, clinical trial participation is encouraged, especially in elderly or frail patients who are not candidates for high-dose chemotherapy and transplant.

Wearable digital health technologies and mobile apps (personal digital health technologies [DHTs]) hold great promise for transforming health research and care. However, engagement in personal DHT research is poor. The objective of this paper is to describe how participant engagement techniques and different study designs affect participant adherence, retention, and overall engagement in research involving personal DHTs. Quantitative and qualitative analysis of engagement factors are reported across 6 unique personal DHT research studies that adopted aspects of a participant-centric design. Study populations included (1) frontline health care workers; (2) a conception, pregnant, and postpartum population; (3) individuals with Crohn disease; (4) individuals with pancreatic cancer; (5) individuals with central nervous system tumors; and (6) families with a Li-Fraumeni syndrome affected member. All included studies involved the use of a study smartphone app that collected both daily and intermittent passive and active tasks, as well as using multiple wearable devices including smartwatches, smart rings, and smart scales. All studies included a variety of participant-centric engagement strategies centered on working with participants as co-designers and regular check-in phone calls to provide support over study participation. Overall retention, probability of staying in the study, and median adherence to study activities are reported. The median proportion of participants retained in the study across the 6 studies was 77.2% (IQR 72.6%-88%). The probability of staying in the study stayed above 80% for all studies during the first month of study participation and stayed above 50% for the entire active study period across all studies. Median adherence to study activities varied by study population. Severely ill cancer populations and postpartum mothers showed the lowest adherence to personal DHT research tasks, largely the result of physical, mental, and situational barriers. Except for the cancer and postpartum populations, median adherences for the Oura smart ring, Garmin, and Apple smartwatches were over 80% and 90%, respectively. Median adherence to the scheduled check-in calls was high across all but one cohort (50%, IQR 20%-75%: low-engagement cohort). Median adherence to study-related activities in this low-engagement cohort was lower than in all other included studies. Participant-centric engagement strategies aid in participant retention and maintain good adherence in some populations. Primary barriers to engagement were participant burden (task fatigue and inconvenience), physical, mental, and situational barriers (unable to complete tasks), and low perceived benefit (lack of understanding of the value of personal DHTs). More population-specific tailoring of personal DHT designs is needed so that these new tools can be perceived as personally valuable to the end user.

BackgroundThe benefit of immune checkpoint inhibitors (ICIs) in patients with leptomeningeal metastases (LMM) is unknown.MethodsWe undertook a phase II trial of pembrolizumab in patients with LMM from solid tumors. Eligible patients had radiologic/cytologic LMM and Eastern Cooperative Oncology Group performance status 0–1. Pembrolizumab was administered intravenously at 200 mg q3W until disease progression/unacceptable toxicity. The primary endpoint was central nervous system (CNS) response after four cycles, defined radiologically/cytologically/clinically. Serial cerebrospinal fluid (CSF) was assessed for tumor-derived DNA (t-DNA) aneuploidy and cytokines.ResultsThirteen of a planned 16 patients were treated between April 2017 and December 2019. The study closed early for poor accrual. Median age was 57 years (range: 22–79). Sixty-two percent of patients had tumors not traditionally ICI-responsive (hormone-receptor (HR)-positive breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (non-small cell lung cancer (NSCLC)=23%, head and neck carcinoma=8%, cutaneous squamous carcinoma (CSC)=8%). CNS response was observed in 38% of patients at 12 weeks (95% CI 13.9% to 68.4%) by pre-defined criteria and LM-RANO, and 2 achieved durable complete responses (CSC=1, overall survival (OS) 3+ years; NSCLC=1, OS 9 months). Median CNS progression-free survival and OS was 2.9 months (95% CI 1.3 to NR) and 4.9 months (95% CI 3.7 to NR), respectively. Grade 3+ treatment-related adverse events occurred in 15% of patients. Sensitivity for LMM detection by t-DNA and cytopathology was 84.6% (95% CI 54.6% to 98.1%) and 53.9% (95% CI 25.1% to 80.8%), respectively. Pre-therapy and on-therapy CSF cytokine analysis demonstrated complete responders clustered together.ConclusionsPembrolizumab conferred a 38% CNS response rate in patients with LMM, a tolerable safety profile, and deep responses in selected patients with ICI-responsive tumors. CSF t-DNA may be sensitive for LMM detection, and immunologic subsets of CNS response warrant further study.Trial registration numberNCT03091478

This is a prospective, rigorous inquiry into the systemic immune effects of standard adjuvant chemoradiotherapy, for WHO grade 4, glioblastoma. The purpose is to identify peripheral immunologic effects never yet reported in key immune populations, including myeloid-derived suppressor cells, which are critical to the immune suppressive environment of glioblastoma. We hypothesize that harmful immune-supportive white blood cells, myeloid derived suppressor cells, expand in response to conventionally fractionated radiotherapy with concurrent temozolomide, essentially promoting systemic immunity similar what is seen in chronic diseases like diabetes and heart disease. 16 patients were enrolled in a single-institution, observational, immune surveillance study where peripheral blood was collected and interrogated by flow cytometry and RNAseq. Tumor tissue from baseline assessment was analyzed with spatial proteomics to link peripheral blood findings to baseline tissue characteristics. We identified an increase in myeloid-derived suppressor cells during the final week of a six-week treatment of chemoradiotherapy in peripheral blood of patients that were not alive at two years after diagnosis compared to those who were living. This was also associated with a decrease in CD8 T lymphocytes that produced IFNγ, the potent anti-tumor cytokine. These data suggest that, as in chronic inflammatory disease, systemic immunity is impaired following delivery of adjuvant chemoradiotherapy. Finally, baseline investigation of myeloid cells within tumor tissue did not differ between survival groups, indicating immune surveillance of peripheral blood during adjuvant therapy may be a critical missing link to educate our understanding of the immune effects of standard of care therapy for glioblastoma.

In recent times, a greater emphasis has been placed on framing patient clinical assessments and QOL as both endpoints and prognostic factors for neuro-oncological care. However, there is currently a lack of consensus on the most effective metrics and instruments for use in patients with primary brain tumors. Due to the heterogeneity in clinical characteristics, histological classification, anatomical location, and available treatment modalities for glioma, quantifying patient clinical condition and QOL within this unique population is particularly challenging. In this paper, we comprehensively review the available literature on the use of clinical assessment tools in glioma patients, highlighting the strengths and limitations of prominent instruments. We demonstrate that clinical outcome assessment (COA) instruments provide valuable and complementary insights into the physical, psychological, and spiritual well-being of glioma patients.

The monoclonal antibody rituximab improves clinical outcome in the treatment of CD20-positive lymphomatous neoplasms, and it is an established drug for treatment of these cancers. Successful mRNA COVID-19 (SARS-CoV-2) vaccination is extremely important for lymphoma patients because they tend to be elderly with comorbidities which leaves them at increased risk of poor outcomes once infected by Coronavirus. Anti-CD20 therapies such as rituximab, deplete B-cell populations and can affect vaccine efficacy. Therefore, a knowledge of the effect of COVID-19 vaccination in this group is critical. We followed a cohort of 28 patients with CD20-positive lymphomatous malignancies treated with rituximab that started prior to their course of COVID-19 vaccination, including boosters. We assayed for vaccine “take” in the humoral (IgG and IgA) and cellular compartment. Here, we show that short-term and long-term development of IgG and IgA antibodies directed toward COVID-19 spike protein are reduced in these patients compared to healthy controls. Conversely, the robustness and breath of underlying T-cell response is equal to healthy controls. This response is not limited to specific parts of the spike protein but spans the spike region, including response to the conserved Receptor Binding Domain (RBD). Our data informs on rational vaccine design and bodes well for future vaccination strategies that require strong induction of T-cell responses in these patients.

Background NF1 inactivation is associated with sensitivity to MEK inhibitor targeted therapy in low-grade and some high-grade gliomas. NF1 loss may also be a harbinger of exploitable vulnerabilities in IDH-wildtype glioblastoma (GBM). Accurate and consistent detection of NF1 loss, however, is fraught given the large gene size, challenges with complete coverage and variant calling upon sequencing, and mechanisms of mRNA and protein regulation that result in early degradation in the absence of genomic alterations. Here, we seek to perform a composite analysis for NF1 loss accounting for genomic alterations and protein expression via immunohistochemistry. We also characterize the landscape of NF1 alterations in GBM. Methods We assembled a single-institution, retrospective cohort of 542 IDH-wildtype GBM with somatic next generation sequencing to investigate the frequency and nature of detected NF1 alterations. We selected 69 GBMs from which to build a tissue microarray (TMA) of 44 NF1 -wildtype and 25 NF1 -mutant cases. We performed NF1 immunohistochemistry using two different NF1 antibodies (NFC, Sigma-Aldrich; and iNF-07E, iNFixion Bioscience) and correlated results with clinical, genomic, and other immunohistochemical features. Results In our retrospective cohort, we identified 88 IDH-wildtype GBM with NF1 alterations (16%). NF1 alterations were mutually exclusive with EGFR and MDM2 alterations ( p -adj < 0.001, 0.05, respectively), but co-occurred with PIK3R1 alterations (Log 2 (OR) = − 1.6, p-adj = 0.03). Of the 63 scorable sporadic GBMs in the TMA, 14 harbored NF1 inactivating alterations and of those, 12 (86%) demonstrated minimal NF1 immunoreactivity by NFC antibody, compared to 8 (57%) by iNF-07E antibody. Among the 42 scorable NF1 -wildtype GBM in the TMA, NF1 immunostaining was minimal in 18 (43%) by NFC antibody compared to 4 (10%) by iNF-07E antibody, potentially reflecting false positives or differential protein regulation. Minimal immunoreactivity by NFC antibody was associated with decreased median overall survival (8.5 vs. 16.4 months, p  = 0.011). Cox proportional hazards model correcting for prognostic variables in this subset revealed HR 3.23 (95% CI 1.29–8.06, p  = 0.01) associated with decreased NF1 expression by IHC. Conclusion NF1 immunostaining may serve as a sensitive surrogate marker of NF1 genomic inactivation and a valuable extension to next-generation sequencing for defining NF1 status. Minimal NF1 immunoreactivity is a poor prognostic marker, even in IDH-wildtype glioblastoma without apparent NF1 genomic alterations, but the underlying molecular mechanism requires further investigation.

MR perfusion imaging is important in the clinical evaluation of primary brain tumors, particularly in differentiating between true progression and treatment-induced change. The utility of velocity-selective ASL (VSASL) compared to the more commonly utilized DSC perfusion technique was assessed in routine clinical surveillance MR exams of 28 patients with high-grade gliomas at 1.5T. Using RANO criteria, patients were assigned to two groups, one with detectable residual/recurrent tumor (“RT”, n = 9), and the other with no detectable residual/recurrent tumor (“NRT”, n = 19). An ROI was drawn to encompass the largest dimension of the lesion with measures normalized against normal gray matter to yield rCBF and tSNR from VSASL, as well as rCBF and leakage-corrected relative CBV (lc-rCBV) from DSC. VSASL (rCBF and tSNR) and DSC (rCBF and lc-rCBV) metrics were significantly higher in the RT group than the NRT group allowing adequate discrimination (p < 0.05, Mann–Whitney test). Lin’s concordance analyses showed moderate to excellent concordance between the two methods, with a stronger, moderate correlation between VSASL rCBF and DSC lc-rCBV (r = 0.57, p = 0.002; Pearson’s correlation). These results suggest that VSASL is clinically feasible at 1.5T and has the potential to offer a noninvasive alternative to DSC perfusion in monitoring high-grade gliomas following therapy.

Recent advancements in understanding the biology of glioblastomas (GBM) and increasing adoption of genomic sequencing in oncology practice have led to the discovery of several targetable mutations in these cancers. Among them, the BRAF V600E mutation can be found in approximately 3% of GBM. Despite the aggressive nature of GBM, metastatic disease is rarely observed. While there are growing data utilizing BRAF-targeting strategies in patients with GBM, data examining their efficacy in cases of metastatic GBM are lacking. We present the case of a 46-year-old female with GBM, isocitrate dehydrogenase (IDH)-wildtype and O 6 -methylguanine-DNA methyltransferase promoter (MGMT) unmethylated, BRAF V600E-mutant, and MYC amplified with extra-central nervous system spread to the spine and lung. Four months after completion of treatment with standard chemoradiation and temozolomide, the patient developed severe back pain, leading to the eventual discovery of her metastatic disease. Based on the presence of the BRAF V600E mutation, the patient was treated with and achieved an intracranial and systemic response to combination BRAF-MEK targeted inhibition for 9 months before evidence of progression.