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Brain metastasis still encompass very grim prognosis and therefore understanding the underlying mechanisms is an urgent need toward developing better therapeutic strategies. We uncover the intricate interactions between recruited innate immune cells and resident astrocytes in the brain metastatic niche that facilitate metastasis of melanoma and breast cancer. We show that granulocyte-derived lipocalin-2 (LCN2) induces inflammatory activation of astrocytes, leading to myeloid cell recruitment to the brain. LCN2 is central to inducing neuroinflammation as its genetic targeting or bone-marrow transplantation from LCN2-/- mice was sufficient to attenuate neuroinflammation and inhibit brain metastasis. Moreover, high LCN2 levels in patient blood and brain metastases in multiple cancer types were strongly associated with disease progression and poor survival. Our findings uncover a previously unknown mechanism, establishing a central role for the reciprocal interactions between granulocytes and astrocytes in promoting brain metastasis and implicate LCN2 as a prognostic marker and potential therapeutic target.

Glioblastoma (GBM) typically presents as a single lesion. Multicentric GBM are defined as well separated lesions on MRI (enhancing and non-enhancing). Multicentric GBM with non-enhancing lesions (MNE-GBM) are rarely described in literature. We aimed at describing the radiologic characteristics, treatment, and clinical course of those patients. The institutional neuropathological database was searched for GBM patients diagnosed between 1/1/2015 and 31/05/2018. All pre-operative MRI brain scans were reviewed to identify patients with MNE-GBM. Electronic medical records and follow-up MRI scans were reviewed to assess progression-free survival (PFS) and overall survival (OS). Out of 149 adult patients with newly diagnosed GBM, 12 met the inclusion criteria of MNE-GBM, all of them presented at least one enhancing lesion. Median follow-up for the MNE-GBM patients was 16.1 months. At last follow-up, all patients had recurrence (median PFS 7.6 months) and eleven patients had deceased. Median OS was 16.2 months (95% CI, 4.1–27.5). Eleven patients received radiotherapy concomitant with temozolomide as initial treatment. Radiation field included all the disease foci (enhancing and non-enhancing lesions) in 8 patients, five of them progressed within the non-enhancing lesion. Three patients did not receive radiation for the entire non-enhancing lesions, and two of them progressed within the non-irradiated areas. In conclusion, MNE-GBM is not rare, and has high risk of aggressive progression within the separate non-enhancing lesion.

Direct oral anticoagulants (DOACs) are increasingly prescribed in treatment of cancer-associated thrombosis, but limited data exist regarding safety of DOACs in patients with brain metastases. We aimed to determine the incidence of intracranial hemorrhage (ICH) in patients with brain metastases receiving DOACs or low-molecular-weight heparin (LMWH) for venous thromboembolism or atrial fibrillation. An international 2-center retrospective cohort study was designed. Follow-up started on the first day of concomitant anticoagulation and brain tumor diagnosis. At least 2 brain imaging studies were mandated. The primary outcome was the cumulative incidence of any spontaneous ICH at 12-month follow-up with death as a competing risk. Major ICH was defined as spontaneous, ≥10 mL in volume, symptomatic, or requiring surgical intervention. Imaging studies were centrally reviewed by a neuroradiologist blinded for anticoagulant type. PANWARDS (platelets, albumin, no congestive heart failure, warfarin, age, race, diastolic blood pressure, stroke) score for prediction of ICH was calculated. We included 96 patients with brain metastases (41 DOAC, 55 LMWH). The 12-month cumulative incidence of major ICH was 5.1% in DOAC-treated patients and 11.1% in those treated with LMWH (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.09-2.21). When anticoagulation was analyzed as a time-varying covariate, the risk of any ICH did not differ between DOAC- and LMWH-treated patients (HR, 0.98; 95% CI, 0.28-3.40). PANWARDS score was not associated with ICH risk. This international 2-center study suggests comparable safety of LMWH and DOACs in patients with brain metastases.

BACKGROUND Although the association of attention deficit hyperactivity disorder (ADHD) with psychiatric disorders is well known, its association with somatic diseases is unclear. Only few studies have investigated the gastrointestinal (GI) morbidity in adult patients with ADHD. AIM To measure gastrointestinal comorbidity and its burden on healthcare in young adults with ADHD. METHODS The cohort included subjects aged 17-35 years recruited to the Israel Defense Forces in 2007-2013, 33380 with ADHD and 355652 without (controls). The groups were compared for functional and inflammatory conditions of the gastrointestinal tract and clinic and specialist visits for gastrointestinal symptoms/disease during service (to 2016). Findings were analyzed by generalized linear models adjusted for background variables. RESULTS Compared to controls, the ADHD group had more diagnoses of functional gastrointestinal disorders (referred to as FGID), namely, dyspepsia [odds ratio (OR): 1.48, 95% confidence interval (CI): 1.40-1.57, P < 0.001], chronic constipation (OR: 1.64, 95%CI: 1.48-1.81, P < 0.001), and irritable bowel syndrome (OR: 1.67, 95%CI: 1.56-1.80, P < 0.001) but not of organic disorders (inflammatory bowel disease, celiac disease). They had more frequent primary care visits for gastrointestinal symptoms [rate ratio (RR): 1.25, 95%CI: 1.24-1.26, P < 0.001] and referrals to gastrointestinal specialists (RR: 1.96, 95%CI: 1.88-2.03, P < 0.001) and more episodes of recurrent gastrointestinal symptoms (RR: 1.29, 95%CI: 1.21-1.38, P < 0.001). Methylphenidate use increased the risk of dyspepsia (OR: 1.49, 95%CI: 1.28-1.73, P < 0.001) and constipation (OR: 1.42, 95%CI: 1.09-1.84, P = 0.009). CONCLUSION ADHD in young adults is associated with an excess of FGID and increased use of related health services. Research is needed to determine if an integrative approach treating both conditions will benefit these patients and cut costs.

The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006–2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan–Meier survival curves with log-rank test were used for statistical analyses. Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

Background Meningiomas are the most common primary central nervous system tumors. Potential risk factors include obesity, height, history of allergy/atopy, and autoimmune diseases, but findings are conflicting. This study sought to assess the role of the different risk factors in the development of meningioma in adolescents/young adults. Methods The cohort included 2,035,915 Jewish men and women who had undergone compulsory physical examination between 1967 and 2011, at age 16 to 19 years, prior to and independent of actual military enlistment. To determine the incidence of meningioma, the military database was matched with the Israel National Cancer Registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, and history of allergic or autoimmune disease. Results A total of 480 subjects (328 females) were diagnosed with meningioma during a follow-up of 40,304,078 person-years. Median age at diagnosis was 42.1 ± 9.4 years (range 17.4–62.6). On univariate analysis, female sex (p Conclusions This large population study showed that sex and adolescent height in males (> 1.85 m) were associated with an increased risk of meningioma in adulthood.

Background: Breast cancer is the second most common cause of central nervous system (CNS) metastasis, leading to a significant decrease in survival rate. High risk groups for CNS involvement include younger age, human epidermal growth factor 2 (HER2) over-expression, estrogen receptor (ER) and progesterone receptor (PR) negativity, high histologic grade, and presence of systemic metastases. Young age at diagnosis of breast cancer is associated with more aggressive biological behavior and worse prognosis than in the elderly. However, data are limited regarding CNS involvement in this group of patients. Although it could be expected that younger patients would also have a poor prognosis after the diagnosis of CNS metastases, earlier studies have demonstrated conflicting results, some with favorable outcomes for this unique group. In this study we aimed to explore the differences in the patterns and outcome of CNS involvement according to age at diagnosis of breast cancer (≤45 years vs. >45 years). Methods: A retrospective database of consecutive breast cancer patients who were treated in our institute and were diagnosed with CNS metastases during 2006-2019 was generated. Data analyzed included age at diagnosis of breast cancer, age at diagnosis of CNS involvement, histopathological factors (histology, grade, hormone receptor and HER2 status), treatments given before and after CNS involvement, characteristics of CNS involvement (location, number of brain deposits, clinical manifestations), overall survival, time to CNS progression, and survival after diagnosis of CNS disease. Results: Study cohort was comprised of 174 patients: 65 patients were age≤45 and 109 patients were older than 45 at breast cancer diagnosis. The percentage of patients with triple-negative breast cancer was higher among the younger age group (24.6% vs. 14.7%). Median overall survival from breast cancer diagnosis was significantly longer for younger patients [117.1 months (95% CI 67.2-167) vs. 88 months (95% CI 65.6-110.4), p=0.017]. Median time from breast cancer diagnosis to development of CNS metastases was also significantly longer in the younger age group [58.1 months (95% CI 46.5-69.6) vs. 37.5 months (95% CI 22.9-52.2), p=0.021]. Median survival as measured from time of CNS involvement was 18.7 months (95% CI 10.8-26.6) in the younger group vs. 11.1 months (95% CI 7.8-14.5) in the older patients (p=0.341). Survival of patients with triple-negative breast cancer from time of CNS metastases diagnosis was significantly longer for the younger age group [22.5 months (95% CI 1.2-43.8) vs. 7.9 months (95% CI .77-15.1), p=0.033]. The number, location and clinical presentation of CNS metastases were not statistically different between the two groups. Systemic and CNS-directed treatment approaches were also similar. Conclusion: While the presentation of CNS metastasis was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival. Numerically, after diagnosis of CNS involvement younger patients had longer survival, but the difference was statistically significant only for patients with triple-negative disease. Citation Format: Matan Ben-Zion Berliner, Shlomit Yust-Katz, Inbar Lavie, Alexandra Amiel, Dalia Zoref, Daniel Hendler, Hadar Goldvaser, Michal Sarfaty, Ofer Rotem, Olga Ulitsky, Tali Siegal, Victoria Neiman, Rinat Yerushalmi. Central nervous system metastases in breast cancer: The impact of age on patterns of development and outcome [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-41.

Background Combination of pertuzumab, trastuzumab and chemotherapy is standard of care for first-line treatment of patients with human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer. Most randomized studies used combination of taxanes and anti HER2 targeted treatment as 1st line treatment. The combination of vinorelbine, trastuzumab and pertuzumab has shown anti-tumor activity in a phase 2 trial. No trials have compared outcomes between vinorelbine to taxane in combination with pertuzumab and trastuzumab. Methods We retrospectively evaluated all patients with metastatic HER-2 positive breast cancer treated in two institutions between 3/2013 and 3/2018. Patients' clinical data were obtained from electronic medical records. We identified patients who were treated with vinorelbine (oral or intravenous) or a-taxane (docetaxel or paclitaxel) in combination with trastuzumab and pertuzumab as a first-line treatment. We compared progression free survival (PFS), overall survival (OS) and toxicity profiles between the two groups. Results The study included 120 patients (73 in the taxane and 47 in the vinorelbine group). There were several between-group differences: 65% of the taxane group patients were metastatic at diagnosis compared to 40% in the vinorelbine group (p=0.008), 18% of the taxane group received trastuzumab in the adjuvant setting vs. 45% in the vinorelbine group (p=0.003). More patients in the taxane group were asymptomatic (43.4% vs 23.4%, p=0.04). PFS was significantly longer in the taxane group compared to the vinorelbine group (35.4 months vs 13.9 months, p=0.0005). OS was also longer in the taxane group, but difference did not reach statistical significance (48.8 months vs 34.5 months, p=0.13). In the subgroup of patients with recurrent disease (excluding patients with de-novo metastatic disease), there was no difference for OS (32.6 vs 33.1 months for taxane and vinorelbine, respectively). Toxicity profiles differed between the groups, with more patients in the taxane group experiencing diarrhea, peripheral neuropathy and asthenia, and more patients in the vinorelbine group experiencing neutropenia. Discontinuation of chemotherapy due to toxicity was more common in the taxane group compared to the vinorelbime group. (38% vs. 17%, p=0.015). Conclusions In this retrospective analysis, first-line treatment with taxane combined with trastuzumab and pertuzumab for HER-2 positive metastatic breast cancer resulted in improved outcomes compared with the combination of vinorelbine, trastuzumab and pertuzumab. The vinorelbine arm revealed a favorable toxicity profile. Patients with recurrent disease (excluding de-novo metastatic disease) had similar outcomes with either chemotherapy. A randomized study is warranted. Citation Format: Daniel Jack Reinhorn, Irina Kuchuk, Judit Prus, Michal Sarfaty, Hadar Goldvaser, Ofer Rotem, Daniel Hendler, Dalia Zoref, Victoria Neiman, Tzipora Shohat, Olga Ulitsky, Shlomit Yust-Katz, Bella Nisenbaum, Maya Gottfried, Rinat Yerushalmi. Taxane versus vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with metastatic HER2-positive breast cancer - A retrospective two-center study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-33.

Background Osimertinib is selective for both epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) sensitizing and Thr790Met mutations. While intracranial activity of osimertinib is documented in larger trials, a prospective study focusing exclusively on patients with asymptomatic brain metastases has not been reported. Methods In this nonrandomized, phase II, open-label, 3-arm prospective proof-of-concept pilot study, 48 patients with metastatic EGFR-mutant lung adenocarcinoma (LUAD) received osimertinib 80 mg daily. Patients were either treatment naive (arm A = 20) or previously treated with an EGFR-TKI and Thr790Met positive (arm B = 18) or negative (arm C = 10). In cases of isolated intracranial progression, osimertinib dose was escalated (160 mg). The primary endpoints were intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). The secondary endpoint was intracranial progression-free survival (iPFS). This study is registered at Clinicaltrials.gov, NCT02736513. Results The iORRs were 84.2%, 66.7%, and 50% and the iDCRs were 94.7%, 94.4%, and 80% in arms A, B, and C, respectively. The median iPFS was 11.8 months (95% CI 7.7 to NA), 7.6 months (95% CI 5.3 to NA), and 6.3 months (95% CI 3.9 to NA) in arms A, B, and C, respectively. Following dose escalation, pooled iORR was 54% (arm A = 5, arm B = 4, arm C = 2). Adverse events were similar to those in previously published literature. Conclusion Osimertinib demonstrated high efficacy on brain metastases. All trial arms displayed a significant decrease in the number and diameter of target lesions. These findings indicate that osimertinib is effective for Thr790Met-positive and -negative LUAD patients with asymptomatic brain metastases. Therefore, osimertinib should be considered a viable option for EGFR-mutant patients with brain involvement regardless of their Thr790Met mutation status.

A 35 years old woman was diagnosed with clinical stage 2, grade 3, hormone receptor positive, human epidermal growth factor receptor 2 (HER2) negative invasive ductal carcinoma, with ki-67 of 60%. She was treated with neoadjuvant chemotherapy with dose dense adriamycin and cyclophosphamide followed by paclitaxel. Six days following the third cycle of paclitaxel the patient presented with rapidly progressive weakness, proximal paresthesia and decreased sensation in both legs. Physical examination revealed hypoesthesia below level, proximal and distal weakness in both lower limbs and absence of reflexes. MRI of the spine demonstrated diffuse leptomeningeal enhancement from T11 to S1 including the cauda equina roots. The rapidly progressive neurological symptoms and the MRI findings were initially interpreted as leptomeningeal spread. High dose dexamethasone was promptly initiated and the patient was urgently planned for radiotherapy and received the first fraction of 3 Gy to level T11-S1. Further workup included lumbar puncture which showed elevated protein level (350 mg/dL), negative cytology for malignancy and EMG which demonstrated demyelinating injury compatible with Guillain-Barre syndrome (GBS). A diagnosis of GBS was made and treatment with intravenous immunoglobulins (IVIG) was initiated, followed by a gradual clinical improvement. Two months after the initial diagnosis, she had a near complete resolution of her neurological deficits. This case illustrates both the tendency to ascribe new symptoms and clinical findings in cancer patients to progressive disease, and the importance of keeping a wide differential diagnosis for non-cancer etiologies when treating our patients.

BACKGROUND Grade II and III meningiomas are invasive tumors which tend to recur following initial treatment and are associated with shorter survival (relative to grade I). Hemangiopericytoma (HPC) is a dural based tumor that originates in the pericytes. Treatment options for these tumors include surgical resection and radiation. There are no defined standard treatments after failure these modalities, and effective systemic treatments are lacking. This trial concept was developed following previous reports of high PD-L1 levels in anaplastic meningioma. We currently report our initial experience with pembrolizumab for refractory atypical/anaplastic meningioma (RAM) and HPC patients. METHODS This is a single arm, single institute, phase 2 trial. Inclusion criteria included patients with RAM or HPC whose all previous lines of treatment were exhausted. All patients were treated with pembrolizumab (200mg every 3 weeks) until disease progression. Primary endpoint was 6- and 12-months progression free survival (PFS). The study was planned for 25 patients and we report here preliminary results. RESULTS Through February 2021, 12 patients were enrolled to this study (two with HPC, 10 with RAM). After a median follow up of 18.5 months, the 6 and 12 months PFS were 25% and 16.7% respectively, with a median PFS of 2.75 months. Two patients had a partial response while all others progressed, making the overall response rate 16.7%. One of the responders had HPC and has been stable for 30 months, while the second had atypical meningioma and was stable for 13 months. Median survival has not been reached yet; 1 year survival rate was 82.5%. Grade 3 toxicities included hyperglycemia, elevated liver enzymes and fatigue, with no grade 4 or 5 toxicities. CONCLUSIONS Pembrolizumab induced a low response rate for RAM and HPC. However, a subset of patients might benefit from this treatment with a prolonged response period.

Purpose Immunogenicity of Covid-19 vaccines may be negatively impacted by anti-cancer treatment. The management of primary brain tumor (PBT) patients routinely includes temozolomide and steroids, which are immune-suppressive. In this study, we aimed to determine the rate of seropositivity in PBT patients following receipt of two doses of the BNT162b2 vaccine. Methods We prospectively evaluated IgG antibody levels against SARS-CoV-2 spike protein in 17 PBT patients following two doses of the BNT162b2 mRNA vaccine. IgG levels were collected at two time points: T1 - after a median of 44 days from the second vaccine dose and T2 - after a median of 130 days from the second dose. Titers were compared against a group of healthy controls (HC) comprised of patients’ family members/caregivers. Results At T1, 88.2% (15/17) of PBT patients achieved seroconversion, compared with 100% (12/12) of HCs. Median IgG titer was significantly lower in the PBT group compared to the HC group (1,908 AU/mL vs 8,198 AU/mL, respectively; p=0.002). At T2, 80% (12/15) of PBT achieved seroconversion, compared to 100% (10/10) of the HCs. Median IgG titer remained significantly lower in the PBT group (410 vs 1687; p=0.002). All three PBT patients who failed to seroconvert at T2 had been treated with corticosteroids during vaccination. In a univariate analysis, steroid use was negatively associated with antibody titer. Conclusion Most PBT patients achieve seroconversion after receiving the BNT162b2 vaccine, but with lower IgG titer compared to HCs. Steroid use during the vaccination period is associated with lower titer.

BACKGROUND Brain metastases are a common complication of non small cell lung cancer (NSCLC). Approximately 10 percent of newly diagnosed patients with advanced NSCLC have brain metastases. The purpose of this study was to determine whether using magnetic resonance imaging (MRI) for early screening of brain metastases can improve survival. Material and METHODS A retrospective analysis of newly diagnosed stage IV NSCLC treated at Davidoff Cancer Center, Israel, between the years 2019-2020. Only patients who were neurologically asymptomatic were included in the study. The study population was divided into two groups. Group A included patients who underwent screening MRI within 12 weeks form diagnosis and group B included those who did not undergo screening MRI. Clinical and radiographic data were collected form the medical records. RESULTS 379 patients were included in the study, of whom 170 underwent screening MRI. Of the patients who underwent screening MRI 54 were diagnosed with brain metastases. On univariate analysis screening MRI was corelated with better survival [group A median survival 24 month, group B median survival 18 month, p=0.003 HR 1.4 CI 1.12-1.75]. On multivariate analysis that included functional status (ECOG 0-2 compared to 3 and above) and age- screening MRI corelated with survival (p=0.04 HR 1.28 CI 1.02-1.6). Subgroup analysis according to molecular subgroup will be presented in the conference. CONCLUSION In this study screening MRI among stage IV NSCLC correlated with better survival even when adjusted to functional status and age.

Background Professional burnout is a syndrome characterized by emotional exhaustion, depersonalization, and loss of personal achievement. Burnout is a significant issue among health care providers, and neuro-oncology providers may be at high risk. We conducted a survey to evaluate burnout and career satisfaction among those caring for patients with brain tumors, and to identify risk factors for burnout. Methods We distributed an anonymous online survey to Society for Neuro-Oncology (SNO) members in 2016 and to European Association of Neuro-Oncology (EANO) members in 2017. The survey comprised questions about personal and professional characteristics and the validated Maslach Burnout Inventory–Human Services Survey (MBI-HSS) questionnaire. Statistical analysis included descriptive statistics, univariate and multivariate analyses, and incorporation of recently defined burnout profiles. Results Sixty-three percent of SNO and 61% of EANO participants were identified as having high burnout according to MBI-HSS. Among SNO participants, physicians had a lower rate of high burnout (61%) compared with allied health professionals (68%, P Conclusions The prevalence of burnout among neuro-oncology professionals is high and personal risk factors were identified. Burnout profiles recognize a continuum of well-being and warrant further research.

Background Bevacizumab was shown to be effective in the treatment of brain radiation necrosis (RN) attributed to the use of stereotactic radiosurgery (SRS). Data on its efficacy and safety in non-small cell lung cancer (NSCLC) patients treated with immune check-point inhibitors (ICI) is lacking. Methods A multi-center retrospective analysis of all consecutive patients with NSCLC treated with ICI, who received bevacizumab for post-SRS RN between April 2017 and June 2020. Improvement in RN-associated symptoms, RN radiological improvement, and decrease in corticosteroid dose following bevacizumab initiation were assessed. Results Thirteen patients were identified. The median time from diagnosis of RN to initiation of bevacizumab was 3 months (range 1.1–7.8 months), and the median number of bevacizumab cycles before assessment was 2 (range, 1–5). Patients continued ICI during treatment with bevacizumab. Improvement in RN-associated symptoms was observed in 11 patients (85%). In ten patients (77%) the daily dose of dexamethasone was decreased. Radiological improvement of RN occurred in all 11 cases available for radiological assessment (100%). Treatment was withheld in two patients for grade 3–4 toxicity. At a median follow up of 11.9 months (range 2.0–35.4 months), one patient experienced a recurrent episode of RN; the estimated median survival since RN diagnosis was 21.9 months (95% CI 3.8–40.2 months). Conclusion Treatment with bevacizumab appears to be safe and effective for the treatment of SRS-induced RN in patients with NSCLC treated with ICI. This is the first series to report on the use of bevacizumab in this clinical scenario.

Background Venous thromboembolism (VTE) is a very common adverse event for astrocytoma patients, but validation of proposed risk biomarkers has been elusive. We examine whether the status of the isocitrate dehydrogenase (IDH) gene is a risk factor for the development of venous thromboembolism (VTE) in astrocytoma patients. Methods We conducted a retrospective chart review of 282 astrocytoma patients enrolled in the PROACTIVE (Prospective Assessment of Correlative Biomarker) study at MD Anderson Cancer Center (MDACC) from 9/1/2000 until 12/31/2013. Results We identified 282 astrocytoma patients consisting of 49 IDH mutant astrocytomas and 233 IDH wildtype astrocytomas. Glioblastoma was the initial histopathologic diagnosis in 30 (61.2%) of the IDH mutated astrocytomas compared to 227(97.4%) of the IDH wild type astrocytomas. VTE was identified in 52 (18.4%) of patients. VTE was diagnosed in 7 (14.3%) of the IDH mutated astrocytomas compared to 45(19.3%) of the IDH wild type astrocytoma s (p = 0.4094). Median time to VTE from diagnosis was 2.71 months. Median time to VTE from diagnosis was 2.6 months for IDH mutated astrocytomas compared to 3.06 months for the IDH wild type astrocytomas (p = 0.8663). Conclusions IDH gene status did not appear as a significant risk factor for the development of venous thromboembolism (VTE) in our cohort of astrocytoma patients. Further research into potential biomarkers for VTE may be warranted.

The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial. The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013–2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile. The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36–0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4–1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5–1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2–0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2–0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39–1.23)] or the subgroups. Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial.The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013-2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile.The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36-0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4-1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5-1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2-0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2-0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39-1.23)] or the subgroups.Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

Paraneoplastic syndromes can commonly occur due to lung cancer, especially small cell lung cancer. Frequently paraneoplastic syndromes can precede the diagnosis of the neoplasm or present with limited stage disease. However, these syndromes can also occur at the time of recurrence or metastasis of disease. This review focuses on the epidemiology, pathogenesis, clinical features, and current management of the most common paraneoplastic syndromes encountered in patients with small cell lung cancer. Manifestations of paraneoplastic syndromes in small cell lung cancer include endocrine syndromes with secretion of excess hormones, and neurologic syndromes due to the production of antibodies causing an autoimmune condition. Recent advances have allowed for greater understanding of these syndromes and for the development of improved diagnostic as well as therapeutic tools. Awareness of paraneoplastic syndromes in small cell lung cancer can lead to an earlier diagnosis and recognition of both the condition and in some cases the disease potentially improving the overall survival and prognosis for patients. Further research examining effective methods to improve recovery from neurologic deficits in patients with a paraneoplastic neurologic illness is warranted.

Bacteria have been found to play major roles in many physiologic/disease processes including cancer. The presence of bacteria within brain tumors has never been explored. The aim of this study was to examine the microbiome of Glioblastoma. A cohort of 40 glioblastoma samples (FFPE), from two medical centers served for DNA extraction using a specialized extraction protocol that includes a bead beating step to ensure complete bacterial DNA recovery. A set of negative controls was introduced at different steps of the assay to identify and monitor contaminating bacterial DNA. We measured the levels of bacterial DNA in the samples using a RT-qPCR assay, amplifying the bacterial 16S rRNA gene and detected bacterial DNA in over 40% of the samples. To characterize the bacterial taxa that are present in GBM tumors, we applied 16S DNA sequencing on the samples. After implementing a stringent set of filters on the sequencing data, eliminating contaminating signal, we detected a total of 22 bacterial taxa in GBM tumors. To visualize bacteria in GBM tissues and learn about their localization within the tissue we used immunohistochemistry staining with anti-lipopolysaccharide (LPS) and anti-lipoteichoic acid (LTA) antibodies detecting gram negative and gram positive bacteria (correspondingly). Bacteria were also visualized by staining bacterial RNA using a 16S rRNA in situ hybridization assay. Staining of a human GBM tissue microarray (TMA) containing 32 cases of GBM showed that the majority of cases stained positive for LPS and ~40% were positive for 16S rRNA staining. Bacterial LPS and 16S rRNA were localized mainly inside the tumor cells. Our study demonstrates, for the first time, that bacteria or bacterial components are present in human Glioblastoma tumors. We are currently expanding our study cohort in order to better define the bacteria found within glioblastoma samples and assess their possible effects

OBJECTIVE Examine whether the status of the isocitrate dehydrogenase (IDH) gene is a risk factor for the development of venous thromboembolism (VTE) in astrocytoma patients. BACKGROUND The risk of venous thromboembolism (VTE) is high for patients with gliomas (10–30%). Unfortunately, biomarkers and predictive models for development of a VTE in brain cancer have not been validated. Prior research has suggested that IDH wildtype gliomas are at higher risk for development of VTE compared to IDH mutant tumors. DESIGN/METHODS We conducted a retrospective chart review of glioma patients enrolled in the PROACTIVE (Prospective Assessment of Correlative Biomarker) study at MD Anderson Cancer Center (MDACC). We obtained demographics, date of tumor diagnosis, initial pathology, IDH status (mutated or wildtype), extent of initial resection, KPS at time of initial resection, history of VTE, development of VTE, type of VTE (PE/DVT), KPS at time of VTE, treatment for VTE, bleeding complications, glioma treatments, date of last follow up and/or death. RESULTS We identified 282 astrocytoma patients consisting of 49 IDH mutant and 233 IDH wildtype astrocytomas. Glioblastoma was the histopathologic diagnosis in 30 (61.2%) of the IDH mutated astrocytomas compared to 227(97.4%) of the IDH wild type astrocytomas. VTE was identified in 52 (18.4%) of patients. VTE was diagnosed in 7 (14.3%) of the IDH mutated astrocytomas compared to 45 (19.3%) of the IDH wild type astrocytomas (p = 0.4094). Median time to VTE from diagnosis was 2.71 months. Median time to VTE from diagnosis was 2.6 months for IDH mutated astrocytomas compared to 3.06 months for the IDH wild type astrocytomas (p =0.8663). CONCLUSIONS IDH gene status did not appear as a significant risk factor for the development of venous thromboembolism (VTE) in our cohort of astrocytoma patients. Further research into potential biomarkers for VTE may be warranted.

BACKGROUND Guillain-Barre syndrome (GBS) is an immune acute polyradiculoneuropathy usually presented as an ascending peripheral paresis with absent tendon reflex and albumino-cytologic dissociation on cerebrospinal fluid (CSF) exam.We describe two oncologic patients with GBS who presented with atypical symptoms. RESULTS The first patient was a 35 years old woman with newly diagnosed grade 3 invasive breast ductal carcinoma. During the sixth courses of neo-adjuvant chemotherapy she complained at back pain and within 24 hours developed progressive severe bilateral proximal paraparesis with a D10 sensory level. Spine MRI demonstrated diffuse leptomeningeal enhancement. Since leptomeningeal spread (LMD) is uncommon at this stage of breast cancer CSF was obtained. CSF sample revealed albumin-cytologic dissociation (4 cells, protein level 340 mg/dl). EMG showed acute demyelinating neuropathy consistent with GBS. Intravenous immunoglobulins (IVIG) therapy was initiated with clinical improvement. The second patient was a 45 years old woman with newly diagnosed T-Cell lymphoma. Before initiating chemotherapy she presented with a rapidly progressive tetraparesis, hyperreflexia and cervical sensory level. Spine MRI was intact. CSF showed 22 cells without atypia, FACS negative, protein level was 74 mg/dl. The patient worsened clinically. A second CSF sample was obtained and demonstrated an albumin-cytologic dissociation (8 cells without atypia, protein level 115 mg/dl) raising the possibility of GBS. EMG showed acute axonal polyneuropathy consistent with AMSAN variant of GBS. The patient was treated with IVIG with partial recovery. CONCLUSION Atypical presentation of GBS could be challenging among oncologic patients and could lead to misdiagnosis and delay in treatment.

Background Gemistocytes (GCs) in low grade gliomas are associated with rapid growth and worse prognosis. However, their clinical significance in glioblastomas (GBM) is a matter of debate. Aim of study To investigate the clinical significance of the presence of GCs in newly-diagnosed GBM patients in the modern era. Methods Computerized medical records from newly diagnosed GBM patients were retrospectively reviewed and extracted for demographic, clinical, radiological and pathological variables. Patients with at least 5% GCs of neoplastic cells were considered GC-GBM (group 1). All other cases were considered non-GC GBM (group 2). Group 1 was further divided into two subgroups: Low percentage GCs (group 1a, ≤ 20% GCs) and high percentage GC (group 1b, >20% GCs). Results A total of 220 patients with newly diagnosed GBM were included. 14.5% were defined as GC-GBM (group I, n = 32) and 85.5% were defined as non-GC GBM (group 2, n = 188). 8.5% had ≤ 20% GCs (group 1a, n = 19) and 5.9% had > 20% GCs (group 1b, n = 13). Groups were similar for most epidemiological and clinical variables. There was a trend toward worse prognosis in group 1b. Several distinguished radiological and molecular features were observed in group 1. Conclusion GCs are found in minority of naive, newly diagnosed, GBM cases in adults. They seem to carry minimal implications on daily clinical practice. Higher percentage of GCs is associated with distinct radiological features such as multifocality that might be correlated with decreased OS. High-percentage GC-GBMs are also associated with increased prevalence of isocitrate dehydrogenase (IDH) mutations.

Background VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM). Methods Patients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS). Results VB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease. Conclusions Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.

Prophylactic cranial irradiation (PCI) exclusion in favor of brain magnetic resonance imaging (MRI) staging and surveillance in the management of small cell lung cancer (SCLC) is controversial yet accepted by some centers. The use of MRI suggests performing stereotactic radiosurgery (SRS) treatment for limited brain metastases. Data regarding SRS efficacy in this setting is limited.To assess intracranial objective response rate (iORR), progression-free survival (iPFS), intracranial failure patterns, overall survival (OS) and time-to-whole-brain radiation therapy (WBRT)/death, whichever occurred first (TTWD) with SRS in SCLC.The study comprised 10 consecutive SCLC patients with brain metastases treated with SRS and followed-up at Davidoff Cancer center between Aug 2012 and March 2019. Brain MRI images were reviewed by a neuro-radiology specialist.iORR was 57% as assessed by response assessment in neuro-oncology brain metastases. Intracranial progression developed in 8 patients. Median iPFS was 4.0 months (95% confidence interval [95%CI] 1.7-7.2). In-site, off-site and combined pattern of intracranial failure was seen in 0, 5, and 3 patients, respectively; median number of new brain lesions following SRS was 4 (range, 1-12). SRS was performed 10 additional times in 6 patients (median number of lesions irradiated per round was 1, range 1-5). WBRT was administered in 3 patients. Median TTWD was 20.9 months (95% CI, 1.9-26.8). Median OS since SRS administration was 23.2 months (95% CI, 4.2-not reached).MRI surveillance with multiple rounds of SRS may serve a reasonable alternative to PCI or therapeutic WBRT in SCLC.

Profiling tumor bacteria Bacteria are well-known residents in human tumors, but whether their presence is advantageous to the tumors or to the bacteria themselves has been unclear. As an initial step toward addressing this question, Nejman et al. produced an exhaustive catalog of the bacteria present in more than 1500 human tumors representing seven different tumor types (see the Perspective by Atreya and Turnbaugh). They found that the bacteria within tumors were localized within both cancer cells and immune cells and that the bacterial composition varied according to tumor type. Certain biologically plausible associations were identified. For example, breast cancer subtypes characterized by increased oxidative stress were enriched in bacteria that produce mycothiol, which can detoxify reactive oxygen species. Science , this issue p. 973 ; see also p. 938

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.

Importance: Patients with cancer undergoing treatment are at high risk of COVID-19 following SARS-CoV-2 infection; however, their ability to produce an adequate antibody response to messenger RNA SARS-CoV-2 vaccines is unclear. Objective: To evaluate rates of antispike (anti-S) antibody response to a BNT162b2 vaccine in patients with cancer who are undergoing systemic treatment vs healthy controls. Design, Setting, and Participants: This prospective cohort study included 102 adult patients with solid tumors undergoing active intravenous anticancer treatment and 78 controls who received the second dose of the BNT162b2 vaccine at least 12 days before enrollment. The controls were taken from a convenience sample of the patients' family/caregivers who accompanied them to treatment. The study was conducted between February 22, 2021, and March 15, 2021 at Davidoff Cancer Center at Beilinson Hospital (Petah Tikva, Israel). Interventions: Blood samples were drawn from the study participants. Serum samples were analyzed and the titers of the IgG antibodies against SARS-CoV-2 spike receptor-binding domain were determined using a commercially available immunoassay. Seropositivity was defined as 50 or greater AU/mL. Main Outcomes and Measures: The primary outcome was the rate of seropositivity. Secondary outcomes included comparisons of IgG titers and identifying factors that were associated with seropositivity using univariate/multivariable analyses. Results: The analysis included 180 participants, which comprised 102 patients with cancer (median [interquartile range (IQR)] age, 66 [56-72] years; 58 men [57%]) and 78 healthy controls (median [IQR] age, 62 [49-70] years; 25 men [32%]). The most common tumor type was gastrointestinal (29 [28%]). In the patient group, 92 (90%) were seropositive for SARS-CoV 2 antispike IgG antibodies after the second vaccine dose, whereas in the control group, all were seropositive. The median IgG titer in the patients with cancer was significantly lower than that in the controls (1931 [IQR, 509-4386] AU/mL vs 7160 [IQR, 3129-11 241] AU/mL; P < .001). In a multivariable analysis, the only variable that was significantly associated with lower IgG titers was treatment with chemotherapy plus immunotherapy (s, -3.5; 95% CI, -5.6 to -1.5). Conclusions and Relevance: In this cohort study of patients with cancer who were receiving active systemic therapy, 90% of patients exhibited adequate antibody response to the BNT162b2 vaccine, although their antibody titers were significantly lower than those of healthy controls. Further research into the clinical relevance of lower titers and their durability is required. Nonetheless, the data support vaccinating patients with cancer as a high priority, even during therapy.

Background Analysis of cerebrospinal fluid (CSF) obtained by lumbar puncture (LP) is essential for diagnosis of meningitis. What is the impact of the procedure upon the natural history of headache and associated signs in patients with lymphocytic meningitis and what factors can have prognostic value for the future progression of symptomatology? This study was aimed at looking into these questions. Methods One hundred and one patients with clinical and laboratory diagnosis of aseptic meningitis answered a questionnaire intended at assessing the severity and nature of headache and meningeal irritation signs before and one, and twenty four hours after the LP. Later they were divided into three groups according to presence and type of headache after 24 h. Demographic and clinical data was obtained from patients files. Results There was almost 50% improvement in headache severity and associated signs after 24 hours from LP in the whole group of patients. Patients that did not have pain after 24 hours had higher BMI and lower headache severity one hour after LP compared to patients in the other groups ( p = 0.064 and p = 0.005). Patients with papilledema had higher incidence of post dural puncture headache (PDPH). Conclusions Our study shows that patients with aseptic meningitis undergo improvement in all parameters of headache and also in signs of meningeal irritation following LP. Higher BMI and low headache intensity are positive prognostic factors for improvement of headache after 24 hours while papilledema is associated with a higher incidence of PDPH.

BACKGROUND Meningiomas are the most common primary central nervous system tumors. Risk factors for meningiomas including obesity, height, history of allergy/atopy or autoimmune diseases, have been previously assessed with conflicting results. We reviewed a large cohort of Israeli adolescents in order to assess potential risk factors for the development of meningiomas. METHODS This study analyzed a cohort of 2,035,915 Jewish men and women who underwent obligatory physical examination when aged 16 to 19 years, from 1967 to 2011. Meningioma incidence was identified by linkage to the national cancer registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, history of allergic and autoimmune disease. RESULTS Linkage of the adolescent military database with the Israeli cancer registry identified 480 cases (152 males and 328 females) of meningioma during a follow up of 40,304,078-person years. The median age at diagnosis of meningioma was 42.1 ± 9.4 (range 17.4–62.6). On univariate analysis, only female gender (p< 0.01) and height (p< 0.01) were associated with risk for meningioma in the total study population. When stratified by gender, height remained a significant risk factor only in men. Spline analysis in the men group showed the minimum risk at a height of 1.62 meters and a statistically significant increase in the risk for meningioma at heights taller than 1.85 meters. BMI, past medical history including asthma, diabetes, and atopic and autoimmune diseases, were not associated with meningioma risk. CONCLUSION in this large population study, we found that sex and taller height in adolescent males was associated with an increased risk of adult meningioma.

INTRODUCTION The risk of venous thromboembolism (VTE) remains high for patients with glioblastoma (GBM) throughout the disease trajectory. Our previous work demonstrated the Khorana scale lacks specificity in this population. We therefore constructed, and attempted to validate a predictive model specific for the development of VTE during adjuvant chemotherapy in glioblastoma patients. METHODS A prior study of GBM patients treated at MD Anderson (MDACC) during the years 2005–2011 found from a multivariate analysis that male sex, BMI ≥ 35, KPS ≤ 80, and steroid therapy were significantly associated with the development of VTE. A predictive model from the MDACC cohort was created using these risk factors, and we attempted to validate the model in an independent cohort of GBM patients treated at Henry Ford from 2010–2015. RESULTS To develop the model 315 patients from the MDACC cohort were randomly divided into two parts: training (75% of data) used for model building, and validation (25% of data) used for model validation. Using the predictive model, the MDACC validation cohort found 80% sensitivity and 80% specificity. We then validated the model in the Henry Ford cohort of 190 GBM patients of which 50 developed a VTE. In the external validation set, the predictive model was found to have a sensitivity = 78% and specificity = 49.3% (Fisher test p-value = 0.0008). CONCLUSIONS Our predictive model for the development of VTE during adjuvant chemotherapy in GBM patients retained high sensitivity in an external data set, however high specificity was lost. While the specificity in our model was higher than in previous studies examining the Khorona scale in GBM patients, further refinement to improve the models reliability to correctly identify people who will not later develop a VTE may be helpful.

BACKGROUND Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment proved to prolong PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas. MATERIAL AND METHODS Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate-based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and maintenance ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months. RESULTS Of the 14 patients screened for the study 2 were excluded due to relapse while on screening. 12 patients have been enrolled with a median age of 74 (61–80) years. The median interval between diagnosis of PCNSL and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months and she is still alive after 24 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed. CONCLUSION Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-Methotrexate based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.

Background cranial X radiation therapy was the standard of care for treating dermatological conditions until the 1960s, when its association to cancer and particularly high rates of brain tumors was discovered. This study examines associations found between incidence of brain tumor and ethnicity. Methods This study analyzed two cohorts who underwent examination at age 17 and were followed by linkage to the national cancer registry. The first cohort included 376,336 participants born in 1948–1959 (when treatment with cranial X radiation was standard care for treating tinea capitis), and the second 474,923 participants born in 1960–1971. Results In the first cohort, ethnicity was strongly associated with the incidence of brain tumor (BT), with higher incidence observed among patients with origins in North Africa or the Middle East. This effect was ablated in the second cohort, and a significant decrease in the rate of meningiomas was noted. Conclusion The association of brain tumor with ethnicity was present only during the period when treatment with cranial X radiation was the standard of care for TC in Israel, therefore it is most likely that radiation exposure was a confounding factor, and that ethnic susceptibility for brain cancer was not causative in these cohorts.

Recent improvement in the prognosis of brain tumor patients has resulted in an increase of young women with glial brain tumors who consider pregnancy. Currently, there is no clear answer whether becoming pregnant increases the risk of tumor progression or effects overall survival in patients previously diagnosed with gliomas.

2064 Background: Grade II and III meningiomas are invasive tumors which tend to recur following initial treatment and are associated with shorter survival (relative to grade I). Hemangiopericytoma (HPC) is a dural based tumor that originates in the pericytes in the walls of capillaries. Treatment options for these tumors include surgical resection and radiation. There are no defined standard treatments after failure of these modalities, and efficient systemic treatments are lacking. This trial concept was formed following previous reports of high PD-L1 levels in anaplastic meningioma. We currently report our initial experience with pembrolizumab for refractory atypical/anaplastic meningioma (RAM) and HPC patients. Methods: This is a single arm, single institute, phase 2 trial. Inclusion criteria included patients with RAM or HPC whose all previous lines of treatment were exhausted. All patients were treated with pembrolizumab (200mg every 3 weeks) until disease progression. Primary endpoint was 6- and 12-months progression free survival (PFS). The study was planned for 25 patients and we report here preliminary results. Results: Through February 2021, 12 patients were enrolled to this study (two with HPC, 10 with RAM). After a median follow up of 18.5 months, the 6 and 12 months PFS were 25% and 16.7% respectively, with a median PFS of 2.75 months. Two patients had a partial response while all others progressed, making the overall response rate 16.7%. One of the responders had HPC and has been stable for 30 months, while the second had atypical meningioma and was stable for 13 months. Median survival has not been yet reached; 1 year survival rate was 82.5%. Grade 3 toxicities included hyperglycemia, elevated liver enzymes and fatigue (that did not cause treatment discontinuation), with no grade 4 or 5 toxicities. PD-L1, mutation burden, MSI and other genomic analyses are still pending. Conclusions: Pembrolizumab induced a low response rate for RAM and HPC. However, a subset of patients might benefit from this treatment with a prolonged response period. To define this subpopulation further molecular studies are needed. Clinical trial information: NCT03016091.

BACKGROUND GBM is characterized by intratumoral heterogeneity. Tumor heterogeneity, clonal diversity and mutation acquisition hamper the ability to tailor personalized therapy for GBM. Tumor sampling has limited ability to accurately capture the molecular landscape of the tumor and to disclose acquired molecular aberrations. Mutation analysis of cfDNA is a non-invasive procedure which may overcome these limitations as it may reflect the real composition of the tumor and track the molecular evolution. We sequenced cfDNA of GBM patients and assessed mutation patterns and fusion genes. METHODS We collected blood and respective tumor samples from 27 GBM patients and blood samples from 14 healthy controls. Tumor DNA, cfDNA and WBC DNA were sequenced using deep sequencing procedures. The data were analyzed for detection of single nucleotide polymorphism (SNPs) and gene-gene fusions. RESULTS GBM cfDNA concentrations were significantly elevated (median: 23.63 ng/mL; range 12.6–137) compared to healthy controls (median 2.06; range 1.68–7.62) (p < 0.0001). We identified unique SNPs in each glioma patient’s cfDNA and the corresponding tumor DNA including the top-10 most frequently mutated genes in GBM. For example, mutation of TP53 was detected in18.75%; EGFR in 37.5%; NF1-12.5%; LRP1B-25% and IRS4 in 25%. For gene-gene fusion we used the in-house fusion gene database, ChiTaRS 5.0, and identified fusions in cfDNA and tumor DNA. Thus, KMT2A-FLNA was the most frequent fusion found in 16.4% of samples. BCR-ABL1 in 8.82% and FGFR1-BCR in 2.94%. Other fusions included COL1A1-PDGFB (5.88%), NIN-PDGFRB (5.88%), KIF5B-RET (5.88%) and also TPM3-ROS1(2.94%), TFG-ALK(2.94%), MSN-ALK (2.94%) and NPM1-ALK (2.94%) which may be targeted by brain penetrating drugs that are ROS1 and ALK inhibitors. CONCLUSIONS Our study suggests that plasma cfDNA analysis may help to uncover real time mutational and gene fusion status of GBM by a non-invasive procedure. It may identify drug targets based on personalized gene-gene fusions.

BACKGROUND Central nervous system (CNS) metastases occur frequently in oncogene-driven non-small cell lung cancer (NSCLC). Standard treatment (i.e surgery, whole brain radiation therapy or stereotactic radiosurgery) approaches can potentially delay systemic treatment and/or result in neurocognitive impairment. Recently, next generation tyrosine kinase inhibitors (TKIs) have demonstrated a remarkable intracranial activity. However, most clinical trials did not enroll patients with neurological symptoms. Our study aims to assess the CNS activity of targeted therapy in this patient population. METHOD We present a case series of nine NSCLC patients with either EGFR mutation of ALK rearrangement and symptomatic CNS metastases that were treated with TKIs, without radiation therapy or surgery. Clinicopathological characteristics, treatment and outcome were analyzed. RESULTS Most patients presented with symptomatic CNS metastases at time of metastatic disease presentation (6/9 patients). Additionally, the majority of patients had leptomingeal disease (6/9 patients) and multiple parenchymal metastases. Patients presented with a variety of CNS symptoms with the most common being nausea, vomiting, headache and confusion. Five patients were treated with Osimertinib. One patient with ALK rearrangement was treated with Lorlatinib. The remaining 3 patients received either Gefitinib or Afatinib. Most patients (6/9 patients) responded rapidly both clinically and radiographically to the targeted treatment, with a marked correlation between systemic and intracranial radiographic response. CONCLUSION Upfront use of next generation TKIs in patients with oncogene-driver NSCLC with symptomatic CNS metastases is associated with reasonable intracranial activity and represents a valuable treatment option.

BACKGROUND: Primary glioblastoma multiforme (GBM) have a high proportion (~80%) of TERT-expressing tumors, indicating that this is the primary mechanism of telomerase (hTERT) activation. Exosomes are nano-sized secreted vesicles containing nucleic acids and proteins, which reflect the content of the mother cells. We have previously shown that hTERT transcripts in serum exosomes may serve as a “pan-cancer” diagnostic method, reflecting the load of hTERT in systemic cancer cells. The goal of the current study was to evaluate whether exosomal hTERT may serve as a circulating biomarker for GBM. METHODS: hTERT mRNA levels were determined in serum derived exosomes obtained from 20 GBM patients and 45 healthy controls. The level of exosomal hTERT mRNA was measured prior to surgery in all GBM patients. In 10 patients additional longitudinal evaluation was performed in blood samples obtained prior to and after concurrent radio/chemotherapy and again during adjuvant temozolomide treatment. RESULTS: Circulating hTERT transcripts were absent in controls and were variably detected in 40% of GBM patients with significantly elevated mean level at diagnosis (p=0.049). These transcripts were gradually downregulated on longitudinal evaluations and during treatment period with significant reduction observed after 3 months of adjuvant treatment when compared to initial sampling (p=0.026). In 10 patients an analysis of hTERT promoter mutation was performed and in 8/10 one of the two common mutations (C228T and C250T) was detected on tumor samples. CONCLUSIONS: hTERT mRNA levels may reflect the tumor burden and the clinical status of patients with GBM. In systemic tumors exosomal hTERT mRNA expression is detected in about 60% of cases while in GBM the percentage is probably lower. In patients with detectable levels, this assay may serve as a serum biomarker. These results warrant further confirmation and an update on an extended cohort of patients will be presented at the meeting.

INTRODUCTION: Gadolinium-based contrast agents (GBCAs) are routinely used in MRI studies performed for evaluation of brain tumors. Recent studies have demonstrated, progressively increased signal intensity in the globus pallidus (GP) and dentate nucleus (DN) on T1-weighted brain images obtained in patients undergoing repeated MR studies. Linear GBCAs result in more retention and longer time of retention than macrocyclic GBCAs. The aim of this study is to evaluate changes in signal intensity ratios of the GP and the DN on unenhanced T1-weighted images after multiple administrations of macrocyclic GBCAs in brain tumor patients. METHODS: The study included 37 patients with primary brain tumors who had more than 3 MRI evaluations (range: 4–10 studies). Ten of them (27%) have not receive radiation therapy. Patients were divided into two groups: Group 1 included 24 patients who had Gadoterate meglumine (Dotarem®) enhanced MRI and group 2 included 13 patients who had Gadobutrol (Gadavist®) enhanced MRI. Median age of group 1 patients was 46 (24–69) years and of group 2 it was 56 (32–67). Two radiologists conducted a quantitative analysis of unenhanced T1-weighted images by using region of interest measurements. The difference in mean GP-to-thalamus (GP\TH) signal intensity ratio, DN-to-middle cerebellar peduncle (DN\MCP) signal intensity ratio between the first and last examinations for each patient were calculated. RESULTS: In both groups GP \TH Ratio difference was greater than 0 (Gadavist 0.08 ± 0.06, Dotarem 0.02 ± 0.08 [P=0.035]) following multiple MRI examinations. There was no significant change in DN\MCP ratio in both groups (Gadavist 0.02 ± 0.07, Dotarem -0.01 ± 0.08 [P=0.230]). CONCLUSION: A significant increased GP\Thal ratio is associated with multiple administrations of both macrocyclic agents, but to a greater extent with administration of Gadavist possibly reflecting the difference in elimination and stability of both contrast agents. Further studies are needed to identify clinical implications, if any, of these findings.

INTRODUCTION: Gadolinium-based contrast agents (GBCAs) are routinely used in MRI studies performed for evaluation of brain tumors. Recent studies have demonstrated, progressively increased signal intensity in the globus pallidus (GP) and dentate nucleus (DN) on T1-weighted brain images obtained in patients undergoing repeated MR studies. Linear GBCAs result in more retention and longer time of retention than macrocyclic GBCAs. The aim of this study is to evaluate changes in signal intensity ratios of the GP and the DN on unenhanced T1-weighted images after multiple administrations of macrocyclic GBCAs in brain tumor patients. METHODS: The study included 37 patients with primary brain tumors who had more than 3 MRI evaluations (range: 4–10 studies). Ten of them (27%) have not receive radiation therapy. Patients were divided into two groups: Group 1 included 24 patients who had Gadoterate meglumine (Dotarem®) enhanced MRI and group 2 included 13 patients who had Gadobutrol (Gadavist®) enhanced MRI. Median age of group 1 patients was 46 (24–69) years and of group 2 it was 56 (32–67). Two radiologists conducted a quantitative analysis of unenhanced T1-weighted images by using region of interest measurements. The difference in mean GP-to-thalamus (GP\TH) signal intensity ratio, DN-to-middle cerebellar peduncle (DN\MCP) signal intensity ratio between the first and last examinations for each patient were calculated. RESULTS: In both groups GP \TH Ratio difference was greater than 0 (Gadavist 0.08 ± 0.06, Dotarem 0.02 ± 0.08 [P=0.035]) following multiple MRI examinations. There was no significant change in DN\MCP ratio in both groups (Gadavist 0.02 ± 0.07, Dotarem -0.01 ± 0.08 [P=0.230]). CONCLUSION: A significant increased GP\Thal ratio is associated with multiple administrations of both macrocyclic agents, but to a greater extent with administration of Gadavist possibly reflecting the difference in elimination and stability of both contrast agents. Further studies are needed to identify clinical implications, if any, of these findings.

Neurologic complications of allogeneic hematopoietic cell transplantation (allo-HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient’s condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD.

Several recent phase III studies have attempted to improve the dismal survival seen in glioblastoma patients, with disappointing results despite prior promising phase II data. Areas covered: A literature review of prior phase II and phase III studied in glioblastoma was performed to help identify possible areas of concern. Numerous issues in previous phase II trials for glioblastoma were found that may have contributed to these discouraging outcomes and discordant results. Expert commentary: These concerns include the improper selection of therapeutics warranting investigation in a phase III trial, suboptimal design of phase II studies (often lacking a control arm), absence of molecular data, the use of imaging criteria as a surrogate endpoint, and a lack of pharmacodynamic testing. Hopefully, by recognizing prior phase II trial limitations that contributed to failed phase III trials, we can adapt quickly to improve our ability to accurately discover survival-prolonging treatments for glioblastoma patients.

BACKGROUND Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment prolongs PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas. METHODS Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate–based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months. RESULTS Of the 16 patients screened for the study 2 were excluded due to relapse while on screening. 14 patients have been enrolled with a median age of 74 (61–80) years. The median interval between PCNSL diagnosis and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed. CONCLUSIONS Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-MTX based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.