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Combined chemotherapy with temozolomide (TMZ), bevacizumab (BEV) and irinotecan (IRI) [TBI] has been used in patients with recurrent or progressive high-grade gliomas. Patients tolerated the regimen well with increased frequency of reversible clinical myelosuppression (CM), hypertension and proteinuria. However, organ-specific toxicities have never been evaluated by post-mortem examination. From 2009 to 2019, post-mortem examinations were performed in seventy-six decedents, including gliomas (N=68, 44/M and 24/F, median age: 59, ranging 23–80 years old) and brain metastases (N=8, 5/M and 3/F, ranging 39–75 years old). Twenty-four glioma subjects were treated with 1–25 cycles TBI (median 5.5) at glioma recurrence. All subjects’ clinical information, treatment histories and adverse events were collected. Five (7.7%, 5/65) glioma decedents (excluding three glioma patients who never received TMZ) permanently discontinued TMZ due to severe CM during concurrent chemoradiation therapy. There is no significantly elevated severity of CM from TBI when compared to standard of care therapies, nor when comparing extended TMZ treatment to the standard 12 cycles of TMZ. However, exposure to IRI significantly increased the CM occurrence (p< 0.05). Among glioma decedents, the most common cause of death was tumor progression (63.2 %, N=43), followed by aspiration pneumonia (48.5%, N=33). No deaths were attributed to acute toxicity from TBI. An electromicroscopic (EM) examination was performed in addition to routine autopsy procedures to investigate the cause of hypertension and proteinuria frequently developing in patients received BEV therapy. Ultrastructural evidence of thrombotic microangiopathy was observed in the kidneys among BEV users; however, it is difficult to conclude such changes were related to BEV due to rapid autolytic changes and artifacts. CONCLUSION: IRI, not the extended use of TMZ, significantly increased the frequency of reversible CM in recurrent glioma patients. There are no unexpected adverse events or organ-specific toxicities detected among glioma decedents who received the TBI regimen.

BACKGROUND Acute ischemic stroke is a common neurologic complication of cancer and contributes to worse prognosis. Hypercoagulable state is an important stroke mechanism in cancer. Nonbacterial thrombotic endocarditis (NBTE) represents an extreme manifestation of such hypercoagulability. Evidence comparing LMHW to unfractionated heparin or direct oral anticoagulants (DOACs) for secondary stroke prevention is lacking in cancer patients. It is also unknown whether certain tumor mutations are associated with increased risk of NBTE. METHODS We reviewed clinical documents at MD Anderson Cancer Center using a RichSearch Natural Language Processing application to search for terms related to marantic endocarditis. Each patient was assessed for documentation of both valvular thickening or vegetations on echocardiogram, and negative blood cultures. Targeted next generation sequencing (NGS) information was interrogated using the PROACTIVE database. RESULTS 100 patient records were reviewed and of these 41 patients were determined to have likely NBTE based on the above criteria. 12 patients had recurrent strokes despite anticoagulation, two of whom had two recurrent strokes despite different anticoagulation strategies (4 strokes through therapeutic dose LMWH, 4 through rivaroxaban, 3 through apixaban, 1 through fondaparinux). The most common primary malignancies were non-small cell lung cancer (n=14) and pancreatic cancer (n=11). NGS data was available for 13 patients, and the most common mutations were KRAS (n=8), TP53 (n=7), EGFR (n=4), and BRAF (n=2) CONCLUSIONS NBTE is an important stroke mechanism in cancer, and the optimal secondary prevention strategy is unknown. These results confirm that NBTE is common in NSCLC and pancreatic cancer. These cancer types commonly harbor mutations such as KRAS, TP53 and EGFR, and work is ongoing to clarify how such mutations might contribute to hypercoagulability. Recurrent stroke is possible with all anticoagulation strategies. Further analysis of outcomes, serum biomarkers (ex. D-dimer), and comorbid medical diagnoses known to confer increased cardiovascular risk is underway.

BACKGROUND Paraneoplastic syndromes traditionally precede tumor diagnosis. With recent greater use of immune checkpoint blockade therapy there is ever-increasing recognition of various immune related adverse effects. This abstract highlights PCA 1 paraneoplastic syndrome triggered by non-immune based chemotherapy, surgery, tumor recurrence and prior to development of second cancer. METHODS This is retrospective case review of patients seen at MD Anderson Cancer Center who developed PCA 1 paraneoplastic syndrome. RESULTS 64 yr old female with ovarian cancer on ERK inhibitor develops lower extremity weakness, ataxia and difficulty ambulation. Serum and CSF showed positive PCA-1 antibody. 59 yr old female with ovarian serous carcinoma develops cerebellar dysfunction after receiving caroboplatin and doxil. Serum and CSF were positive for PCA-1 antibody. 57 yr old female with ovarian carcinoma develops tremors, progressive ataxia after second cycle of carboplatin,taxol and avastin. Serum was positive for PCA-1 antibody. 45 yr old female with ovarian carcinoma completes 6 cycles of taxol and carboplatin. 3 months later develops gait ataxia. CSF was positive for PCA-1 antibody. Workup showed progressive ovarian carcinoma. 59 yr old with invasive ductal breast cancer develops lower extremity weakness and ataxia. Serum and CSF were positive for PCA-1 antibody. Work up revealed ovarian carcinoma. 63 yr old female with newly diagnosed breast cancer undergoes mastectomy. In the immediate postoperative time period develops diplopia, gait ataxia. Serum and CSF were positive for PCA-A antibody. All patients were aggressively treated with steroids. Most received additional therapies including plasma exchange, IVIG, tacrolimus, Rituxan, Cytoxan. All patients remained with permanent cerebellar dysfunction. CONCLUSIONS Case series highlights the recognition of paraneoplastic syndrome following traditional cytotoxic chemotherapy. There is need for early recognition of this neurological urgency. Work up includes prompt LP, serum and CSF paraneoplastic antibody panel, and evaluation for primary tumor recurrence or development of second cancer.

Neurological side effects after chimeric antigen receptor-modified (CAR) T cell therapy are common and potentially devastating. Termed immune effector cell-associated neurotoxicity syndrome (ICANS), symptoms range from mild encephalopathy to diffuse cerebral edema. No predictive biomarkers exist to identify individuals at risk for developing ICANS. Serum neurofilament light chain (NfL) is a well-established marker of neural injury known to dynamically change in neuro-inflammatory disorders (e.g. multiple sclerosis). We hypothesized individuals undergoing CAR T cell therapy who ultimately developed ICANS would have early and sustained elevations in serum NfL. We performed a retrospective analysis of serum samples from 11 individuals treated with tisagenlecleucel or axicabtagene ciloleucel (mean age 61.3, 18% female, 27% ICANS, all with peak severity score 3). Most individuals had a longitudinal sampling at baseline, pre-infusion, post-transfusion day (PTD) 1, PTD 3, PTD 7, PTD 14, and PTD 30. Serum NfL were assayed using a Simoa HD-1/HD-X kit (QuanterixTM). We found that individuals who developed ICANS had early and sustained elevations in serum NfL levels at baseline (p = 0.0075), pre-infusion (p = 0.0172), and PTD 3 (p = 0.0026) and PTD 30 (p = 0.0066). All group comparisons survived multiple comparison testing using false-discovery rate (FDR). Receiver operating characteristic (ROC) curve classification by logistic regression of serum NfL revealed an area under the curve (AUC) of 1.0 with a cut-off of 44 pg/mL. No correlation was observed between NfL levels and age, sex, or history of central nervous system involvement of the underlying malignancy. In summary, we found serum NfL levels are a robust, early marker for the development of ICANS. Our findings suggest the risk of developing ICANS reflects pre-transfusion host-factors, permitting the screening well in advance of drug administration.

PURPOSE Breast cancer is the most common solid tumor to metastasize to the leptomeninges, affecting up to 5% of breast cancer patients. Overall survival for patients with leptomeningeal metastases (LM) is poor, with median survival of 4–6 months following diagnosis. There is limited data available on the efficacy of intrathecal (IT) trastuzumab in the treatment of Her-2 positive LM. METHODS A total of 30 patients with Her-2 positive breast cancer with LM treated at the University of Michigan from 2008–2020 were identified retrospectively. Of these, 13 patients were treated with IT trastuzumab beginning in June 2010 and followed through April 2020. Initial dose was 50–80 mg twice weekly for a minimum of 4 weeks, followed by slow taper. The 17 patients with Her-2 positive breast cancer with LM who did not receive IT trastuzumab served as control. RESULTS The median age of patients in the treatment group was 42 and 52 in the control group. Whole brain radiation therapy was received by 92% of patients in the treatment group and 76% in the control group. The median overall survival from diagnosis of LM to death was 20 months (interquartile range [IQR] 13–60 months) in the treatment group and 6 months (IQR 2–17 months) in the control group. Survival at 3 years and 5 years was 40% and 13%, respectively for the treatment group and 8% and 0% (no data available at 60 months), for the control group. Hazard ratio for death with IT trastuzumab 0.38 (95% CI 0.16–0.91, p=0.024). IT trastuzumab was overall well-tolerated (one patient developed meningitis, while another had shunt malfunction necessitating removal of the reservoir). CONCLUSIONS Patients with HER2+ LM who received IT trastuzumab demonstrated significantly improved OS compared to control with minimal toxicity.

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.

The risk of intracranial hemorrhage (ICH) associated with the use of bevacizumab (BEV) has been a topic of several reviews in the literature, and is considered to be a potential adverse effect of BEV when used in patients with malignant glioma. We performed a single-center retrospective chart-review identifying glioma patients treated with BEV at our institution. 595 unique patients who received BEV with documented follow up were identified. Of these patients, 23 (3.9%) developed ICH within 12 weeks (five half-lives) of a BEV infusion (median 9 days post infusion, 1-24 days IQR). There was a trend towards statistical significance between dose administered and the incidence of hemorrhage (P=0.06), with all 23 hemorrhages occurring in patients treated with 10 mg/kg (n=21/490) per infusion or 15 mg/kg per infusion (n=2/35) (n=525, 88.2% of cohort). No patient on dosing regimens of 7.5 mg/kg (n=72) or 5 mg/kg per infusion (n=16) (n=88, 14.7% of cohort) developed ICH. Therapeutic anticoagulation and concomitant BEV therapy was observed in 103 (17%) patients with 10 patients (10/93, 9.7%) developing an ICH (n=10), at a rate significantly higher than in patients treated with bevacizumab alone (13/479, 2.6%) (p=0.0025). When hemorrhages occurred (with or without concomitant anticoagulation) they were associated with high morbidity and mortality (ECOG 3.54 versus 1.26, p = < 0.0001), with 12 patients (52%) suffering severe debility (n=2) or death (n=10). CONCLUSION: Bevacizumab associated intracerebral hemorrhages remain uncommon events, similar to the baseline rate of spontaneous hemorrhage associated with malignant glioma. We observed a trend towards significance with higher doses per infusion associated with an increased rate of intracerebral hemorrhage. The combination of anticoagulation and BEV appears to confer a greater risk of hemorrhage than BEV alone.

BACKGROUND Epilepsy is a common symptom in glioma patients, requiring antiepileptic drug (AED) treatment. However, comprehensive data on the efficacy and tolerability of AED treatment is currently lacking. In this systematic review we specifically assessed the efficacy of AEDs in patients with a grade II-IV glioma. METHODS Electronic databases PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane library were searched up to April 2020. Three different outcomes were extracted from all eligible articles: (I) seizure freedom; (II) ≥50% reduction in seizure frequency; and (III) treatment failure. To overcome variation with respect to sample sizes, weighted averages (WA) were calculated for outcomes at 6 and 12 months. RESULT A total of 64 studies were included. For monotherapy, the 6-months seizure freedom rate was highest for phenytoin (WA=72%), whereas the 12-months seizure freedom rate was highest for pregabalin (WA=75%). For achieving ≥ 50% seizure reduction, levetiracetam was the most effective AED at 6 and 12 months, with WA of 82 and 97% respectively. Considering the provided polytherapy combinations, levetiracetam combined with phenytoin was most effective followed by levetiracetam with valproic acid. Seizure freedom rates with polytherapy at 6 months and 12 months were highest for combinations with phenytoin and topiramate, respectively. For achieving a ≥ 50% seizure reduction, combinations with perampanel were found to be the most effective at 6 and 12 months. CONCLUSION Based on the current literature, phenytoin, levetiracetam and pregabalin are most effective as AED monotherapy in glioma patients with epilepsy. Well-controlled prospective studies are needed to help further guide clinician’s treatment choices.

Neurotoxicity is a common occurrence and a major form of morbidity in adult patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) patients treated with anti-CD19 directed chimeric antigen receptor (CAR) T-cell therapy. Variables related to the incidence and severity of neurotoxicity have been relatively well delineated, but the association between neurotoxicity and the efficacy of CAR T-cell therapy has not been well studied. We performed a retrospective analysis of the outcomes of DLBCL patients who developed neurotoxicity following anti-CD19 CAR T-cell treatment. The analysis included 26 patients with R/R DLBCL who received commercial anti-CD19 CAR T-cell therapy. All patients received a lymphodepleting chemotherapy regimen consisting of fludarabine and cyclophosphamide. Twenty-five patients received axicabtagene ciloleucel, and 1 received tisagenlecleucel. The overall incidence of neurotoxicity was 88%; 31% developed severe neurotoxicity (Grade III-IV by CTCAE). Higher neurotoxicity was associated with better PFS by both CTCAE (CR 2.4 ± 1.1 vs. PD 1.4 ± 1.3, p = 0.051) and CARTOX-10 (CR 3.78 ± 4.6 vs. PD 7.7 ± 3.8, p = 0.044) grading systems. Higher neurotoxicity continued to show a trend at 6, 9, and 12 months by the CTCAE grading system (CR 2.4 ± 1.0 vs. PD 1.7 ± 1.3, p = 0.085), and no patients had disease recurrence after 6 months. In this limited cohort, neurotoxicity severity was paradoxically positively correlated with progression-free survival with commercial CAR T-cell therapy and may therefore indicate an effective therapeutic response.

BACKGROUND Brain metastases (BMs) incidence in patients with extra-pulmonary neuroendocrine neoplasms (EP-NENs) is unclear, with no available management recommendations. This study aimed to review the clinical presentation, management and survival outcomes of patients with EP-NENs and BMs at a European Centre of Excellence. METHODS A retrospective single-centre analysis of consecutive patients with EP-NENs (Aug 2004-Feb 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis were estimated (Kaplan Meier). RESULTS Of 786 patients, 15 (1.9%) had BMs, median age 61y (range 15–77); 8 (53%) male, primary NEN site: unknown 40%; oesophageal 13%; small bowel 13%; pancreas 13%; gastric 7%; cervix 7% and bladder 7%. Most patients with BMs had grade 3 (G3) NENs (11, 73%), 3 (20%) were G2 and 1 (7%)G1. Eight (53%) had poorly-differentiated NENs, 6 well-differentiated and 1 not recorded. Two (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. Median time to development of BMs after initial NEN diagnosis: 15.9 months (range 2.5–139.5). Five patients had a solitary BM, 4 had 2–9 lesions and 6 had >10 BMs. The most commonly affected sites were the cerebrum (13, 87%), cerebellum (6, 40%), leptomeninges (2, 13%) and orbit (1, 7%). The most common presenting symptoms were limb weakness, headache, confusion, visual disturbance (each n=3, 20%), seizures (2, 13%), word-finding difficulty (2, 13%) and facial weakness/ptosis (1, 7%). Median OS from initial NEN diagnosis was 23.6-months [95%-CI 15.2–31.3]; median time to death from BMs diagnosis was 3.0-months [95%-CI 0.0–8.3]. Treatment of BMs was surgery (n=3); radiotherapy (n=6); 5 had WBRT, one localised radiotherapy (orbit). Six (40%) had best supportive care. CONCLUSION BMs in patients with EP-NENs are rare and predominantly in G3 NENs, with diverse intracranial distribution. Although uncommon, BMs from NENs behave aggressively and greater understanding is needed to improve therapeutic outcomes.

BACKGROUND LMC is a rare complication of systemic cancer metastasis to the leptomeninges. Although first described in 1870 treatment options remain few for this rapidly fatal condition commonly excluded from clinical trials and disease site guideline updates. Whole brain radiation therapy (WBRT) and intrathecal (IT) chemotherapy are commonly employed and there is growing evidence for systemic therapies that cross the blood brain barrier. Disseminated necrotizing leukoencephalopathy (DNL) is a self-limited rare treatment-related radiographic finding variably associated with clinical decline and often misdiagnosed as progression or infection. DNL has been reported in patients exposed to IT chemotherapy and CNS irradiation. Our lab recently published improved LMC control with extended survival after standardization of Ommaya clinic IT treatment regimens, although with increased incidence of DNL. METHODS We retrospectively analyzed patients with LMC treated with IT chemotherapy after WBRT between 2017 – 2020. We reviewed sequential brain imaging over the treatment course to determine if there were predictive CSF markers associated with the development of DNL. RESULTS Of the 41 patients evaluated, 24% (n=10) developed DNL at a median 24-weeks after start of IT chemotherapy and WBRT. Of the patients with radiographically assessed DNL, 80% (n=8) experienced elevated CSF protein and 40% (n=4) had elevated white blood cells within 8-weeks prior to radiographic determination of DNL. Cytology remained benign and glucose was not significantly changed prior to DNL development. CONCLUSION Given the poor outcome of LMC, there is a need for treatment standardization and better understanding of treatment-associated radiographic changes. Evaluation of CSF markers to predict impending development of DNL in this treatment population might limit radiographic misdiagnoses and patient clinical decline as well as offer a potential window of opportunity for treatment de-escalation.

OBJECTIVES Chemotherapy-related cognitive impairment (CRCI) is an adverse sequela of cancer treatment commonly reported in cancer survivors. Cisplatin is used for the treatment of various malignancies including ovarian, testicular, head and neck cancers, and pediatric brain tumors. More than 30% of advanced ovarian cancer patients develop CRCI during and after platinum-based chemotherapy. We examined the role of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in cisplatin-induced CRCI, and whether the small molecule p38 MAPK inhibitor Neflamapimod and JNK inhibitor SP600125, can prevent cisplatin-induced neuronal damage. The p38 and JNK MAPK signaling pathways are involved in various stress response pathways in the CNS including oxidative stress. METHODS The effect of cisplatin on cognition in an ovarian cancer female rat model was assessed by novel object recognition (NOR). Hippocampal glutathione levels were measured post-behavioral testing. P38 and JNK MAPK signaling activation were assessed in the neural cell lines PC12 and SH-SY5Y by Western blot. Cultured hippocampal neurons were pretreated with Neflamapimod or SP600125 followed by cisplatin for 24 hours, and dendritic spine density and branch length were quantified. RESULTS Cisplatin increased phospho-p38 and phospho-JNK MAPK protein levels in PC12 and SH-SY5Y cells. Cisplatin reduced dendritic branching and spine density, which was prevented by Neflamapimod and SP600125 pre-treatment in hippocampal neurons, in vitro. Chronic cisplatin treatment decreased hippocampal glutathione levels and impaired cognitive function in the ovarian cancer rat model. DISCUSSION The cognitive deficits caused by cisplatin results in part from dendritic damage and neural apoptosis, which is mediated by oxidative stress and the p38 and JNK MAPK pathways. P38 and JNK MAPK inhibition mitigated cisplatin-induced dendritic spine loss and branching in vitro. Next, we will examine whether Neflamapimod and SP600125 administration in an ovarian cancer rat model is safe and if they can prevent cognitive impairment.

Skull base chondrosarcomas are often low grade tumors that do not metastasize, but are locally invasive and often recur locally. Thus, when patients with these tumors re-present with new onset symptoms, even decades later, recurrent tumor is presumed. A 50 year old woman with skull base chondrosarcoma initially diagnosed 30 years prior developed the subacute onset of worsening confusion and vision, with progressive blindness. Imaging disclosed a bony-erosive skull base mass without associated sinusitis/sinus opacification; additional small cerebral infarcts were identified. She had been on physiologic replacement therapy for panhypopituitarism since the original surgery, but had not received recent radiation therapy or chemotherapy and did not have neutropenia. RESULTS: Biopsy disclosed a chronic inflammation and necrotic debris; only on permanent sections were septated, 45-degree angle-branching fungi identified in one area. These had morphological features of, and were polymerase chain reaction-proven, Aspergillus fumigatus. No recurrent tumor was present. Given the lack of perceived risk factors, further questioning of the patient and her mother disclosed that precisely 1 year prior to surgery she and her family had participated in “cleaning out an old very dirty and dusty barn” in southern Colorado without the use of face masks; only the proband experienced sequelae. Anti-fungal therapy (voriconazole) was recommended although patient use was intermittent and symptoms have progressed. CONCLUSION: Community-acquired Aspergillus infections due to exposure to silage or barn detritus contaminated by fungal hyphae is almost never seen today, in comparison to opportunistic infections due to known risk factors of neutropenia and/or steroid usage. Replacement therapy may have added to this patient’s risk. Infections all too often mimic recurrent tumor.

INTRODUCTION Adverse effects from chemotherapy such as high dose methotrexate (HD-MTX) are seen during and after chemotherapy. During this coronavirus disease 2019 (COVID-19) pandemic period, COVID-19 infection symptoms following chemotherapy due to immune compromise could mimic chemotherapy associated side effects. Differentiation on time is needed for correct management. CASE REPORT A 50-year old male with clinical history of ocular lymphoma underwent HD-MTX therapy. Before admission, his routine COVID-19 test was negative. After receiving HD-MTX, he developed fatigue, nausea and vomiting. The symptoms resolved before discharge. Next day after discharge, he developed diarrhea, fatigue, subjective fever and feeling cold. His temperature was normal. His symptoms have been persistent for 4-5 days and have resolved gradually and spontaneously. Family members have had no symptoms. The patient denies COVID-19 contact history. The above symptoms were considered adverse effects from chemotherapy. The patient did not seek medical attention. Prior to admission for next cycle of HD-MTX, COVID-19 test was found positive. Chemotherapy was on hold. The patient started home quarantine. The patient has been doing well and practiced COVID-19 infection precaution at home. DISCUSSION The fatigue, nausea and vomiting during HD-MTX treatment are adverse effects from chemotherapy while the diarrhea, fatigue, subjective fever and chills developed after discharge are symptoms of COVID-19 infection. Our case highlights the importance of keeping in mind and differentiating between side effects from chemotherapy and symptoms of COVID-19 viral infection in cancer patients who receive chemotherapy.

Sporadic Burkitt’s Lymphoma accounts for only 1–2% of Non Hodgkin’s Lymphoma, and metastasizes to the central nervous system (CNS) is uncommon, occurring in about 13–17% of adult patients. 1 Melanoma is far more likely to metastasize to the CNS, occurring in about 37% of adult patients.2 Here we present the case of a 69 year old Gambian female with a prior medical history of plantar melanoma. She initially presented to her primary care provider with back pain and adenopathy, and was referred to surgical consultation for diagnosis and concern for recurrent melanoma. Her workup revealed metastatic Burkitt’s Lymphoma with disease in the abdomen, lungs and likely CNS involvement. This report chronicles her disease course and approach to management.

INTRODUCTION Severe Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) occurs in ~ 30% of Diffuse Large B Cell Lymphoma (DLBCL) patients treated with CAR-T cell therapy. The current treatment for severe ICANS is glucocorticoids, and this may be combined with tocilizumab for concurrent cytokine release syndrome. Even with these treatments, neurotoxicity can persist. It is essential, therefore, to find additional treatments to more effectively reverse CAR-T neurotoxicity. OBJECTIVE We summarize our institutional experience using IVIG to treat severe or refractory ICANS after glucocorticoids alone. METHOD This is a single center retrospective cohort study of neurologic and oncologic outcomes among patients who received axicabtagene ciloleucel (axi-cel) for DLBCL or its variants from May 2015 to February 2019. We identified those patients who developed severe ICANS subsequently treated with glucocorticoids alone (n = 10) or glucocorticoids plus IVIG (n = 9). RESULTS The median age of all 19 patients was 63 (range 47-75, and 68% were males). All IVIG recipients received glucocorticoids prior to IVIG administration. There was no significant difference in time to resolution (TTR) of severe ICANS between both groups (median 3 vs. 3 days, Log-rank p = 0.331). However, we found that all IVIG recipients had experienced either escalation of their neurotoxicity grade or persistent severe neurotoxicity after initiation of steroids (p = 0.001). Moreover, IVIG recipients had worse ECOG performance status prior to axi-cel therapy (p = 0.03). CONCLUSION Although we found no difference in TTR of severe ICANS with addition of IVIG to glucocorticoids, our analysis suggests that the addition of IVIG blunted the effects of steroid-refractory neurotoxicity. Patients who received IVIG had worsening ICANS despite administration of steroids and therefore might have benefited from the earlier addition of IVIG. Controlled studies may clarify the potential efficacy of IVIG in severe neurotoxicity after CAR-T therapy.

For decades, the central nervous system was considered to be an immune privileged organ with limited access to systemic immunity. However, the leptomeninges, the cerebrospinal fluid (CSF)-filled anatomical structure that protects the brain and spinal cord, represent a relatively immune-rich environment. Despite the presence of immune cells, complications in the CSF, such as infectious meningitis and a neurological development of cancer known as leptomeningeal metastasis, are difficult to treat and are frequently fatal. We show that immune cells entering the CSF are held in an ‘idle’ state that limits their cytotoxic arsenal and antigen presentation machinery. To understand this underappreciated neuroanatomic niche, we used unique mouse models and rare patient samples to characterize its cellular composition and critical signaling events in health and disease at a single-cell resolution. Revealing the mediators of CSF immune response will allow us to re-evaluate current therapeutic protocols and employ rational combinations with immunotherapies, therefore turning the patient’s own immune system into an active weapon against pathogens and cancer.

INTRODUCTION Treatment-induced cerebral necrosis (TN) is a challenging complication encountered in neuro-oncology. Diagnosis and treatment of TN remains poorly defined. METHODS In this single institution, retrospective study, consecutive patients with gliomas and TN between 01/01/2012 and 04/20/2020 at the OSUCCC were identified. Details of the tumor treatment, molecular markers, radiological and pathological findings of TN, as well as treatment, recurrence rate and management upon recurrence were collected. RESULTS Of the 53 patients analyzed, 37 had glioblastoma, 7 had anaplastic oligodendroglioma and 9 had grade II or III astrocytoma. MGMT promoter hypermethylation was present in 31/50 (59%) and IDH mutation in 17/53 (32%). Diagnosis of TN was based on histology in 43/53 (81%) or clinical/radiographic features in 10/53 (19%). Worsening of focal weakness (36%), seizures (9%) or being (30%) were common presentations at TN diagnosis. Patient with right compared to left hemisphere involvement were more symptomatic at TN diagnosis. (p=0.049). Bevacizumab (BEV) (51%), resection (28%), steroids only (9%) or Laser Interstitial Thermal Therapy (6%) were used to treat TN. Steroids were weaned off in 20/27 (74%) after receiving BEV. Among all treatments, BEV was significantly associated with a better outcome (resolution or partial improvement of enhancement in 84.6%) (p=0.0006, Bonferroni corrected p< 0.005). TN Recurrence occurred in 36%, 70% and 100% of the patients treated with BEV, resection and LITT respectively. The median duration to TN recurrence was 10 weeks (range: 3–70 weeks). Initial treatment used for TN, MGMT methylation and IDH mutation status did not predict TN recurrence. (p=0.074; p=0.819; p=0.607 respectively). CONCLUSIONS BEV appears to be a superior treatment to control TN overall. Recurrence of TN in patients previously treated with BEV was 36%. There was no difference in the risk of developing recurrent TN based on MGMT or IDH status.

Second malignant neoplasms following treatment for primary central nervous system (CNS) tumors in children are rare occurrences but may often have dire consequences, particularly, if thought to be induced by prior therapies. The authors retrospectively reviewed pediatric patients with primary CNS malignancies from the University of Wisconsin over the last 25 years (1994 – 2019) with any secondary malignant neoplasm and determined seven patients met criteria. Treatment modalities were reviewed with all patients receiving surgery, chemotherapy, and radiotherapy for treatment of their first malignancy. The second neoplasms found included 4 high-grade gliomas, 1 meningioma, 1 thyroid carcinoma, and 1 myelodysplastic syndrome. The median latency time between diagnoses was 9 years (range 4 -17 years). The outcomes varied according to histopathology of the second neoplasm with the high-grade glioma patients all deceased from progressive disease. The high-grade gliomas were thought to have been induced by prior radiation in most cases. The remaining patients are still alive, at the time of this writing, and in follow up after treatment for their second neoplasm. Thus, long-term follow up is essential for children treated for a primary CNS tumor given the variety of second neoplasms that could arise with differential consequences. In addition to our single institutional outcomes, we will also present an updated review of the literature of pediatric patients with primary CNS tumors and second malignancies.

Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

60 year old female was admitted with difficulty swallowing, slurred speech and gait instability resulting in multiple falls worsening over 2-3 weeks. Her exam revealed subtle spastic dysarthric speech, spasticity in all four extremities (lower > upper and right > left), hyperreflexia, and bilateral Babinksi and Hoffman signs consistent with pure upper motor neuron syndrome. An MRI brain and total spine were without evidence of neurological pathology but revealed an incidental finding of lymphadenopathy concerning for neoplastic process. Her symptoms continued to worsen over the next few weeks and she developed severe, nearly continuous, extensor spasms of BLE (right > left) with stimulus sensitivity causing inability to walk. She was started on baclofen, tizanidine and diazepam for spasticity with only mild improvement. An MRI cervical spine was repeated (please see below) and revealed hyperintense T2 signal in lateral corticospinal tract (right > left) without enhancement and no cord compression. Given strong clinical concern for paraneoplastic process patient received 0.4 g/kg IVIG for 5 days and concurrent 1000 mg methylprednisolone for 3 days with dramatic improvement within days. Cervical lymph node biopsy lead to diagnosis of nodal marginal zone lymphoma. A CT abdomen revealed an ovarian mass concerning for teratoma vs dermoid cyst (pending resection and final pathology). She was treated with weekly boosters of IVIG and IV methylprednisolone and was started on Rituximab for her Lymphoma. When seen in clinic a month post discharge nearly all of her symptoms had resolved. Neurological exam showed subtle residual spasticity making this presentation most consistent with a reversible pure upper motor neuron syndrome.

INTRODUCTION Radiation necrosis (RN) is a potential complication after radiation therapy to primary brain tumors and brain metastases. The pathophysiology of RN is not well understood but it is hypothesized that vascular endothelial growth factor (VEGF) plays an important role. Bevacizumab, a monoclonal antibody against VEGF-A, is often successful in the management of RN. The objective of this study is to assess whether VEGF receptor (VEGFR) inhibitors, a group of oral tyrosine kinase inhibitors (TKIs), can prevent or reverse cerebral radiation necrosis METHODS We retrospectively studied a cohort of 102 patients with renal cell carcinoma (RCC) and brain metastases seen at The Ohio State University James Cancer Center between 01/01/2011 and 04/30/2019. We identified those who developed RN and analyzed the temporal relationship between the use of VEGFR TKIs and the development of RN. RESULTS The cumulative incidence of RN in our cohort is 13.7% after radiation treatments that included LINAC-based stereotactic radiosurgery, fractionated stereotactic radiotherapy, or Gamma Knife radiosurgery. There was no statistically significant difference in the cumulative incidence of RN between patients taking TKIs and patients who were off TKIs (9.9% and 11.5% respectively, p= 0.741). The median time to development of RN was only numerically shorter in patients taking TKIs (151 versus 315 days, p=0.315). One patient developed RN after stopping cabozantinib. Three other patients developed RN while on cabozantinib. Two patients developed RN while on pazopanib, and 3 patients developed RN while on sunitinib. One patient was started on axitinib during active RN without significant improvement subsequently. CONCLUSIONS VEGFR TKIs do not consistently prevent or reverse cerebral radiation necrosis and do not seem to have the efficacy that bevacizumab has against RN.

INTRODUCTION Posterior fossa syndrome (PFS) is a known consequence of medulloblastoma resection. Our aim was to clinically define PFS, its evolution over time, and ascertain risk factors for its development and poor recovery. METHODS Children with medulloblastoma treated at St Jude Children’s Research Hospital from 6/2013-7/2019 received standardized neurological examinations, before and periodically after radiation therapy. Most (98.3%) were enrolled on the ongoing multi-institutional protocol (SJMB12; NCT 01878617). RESULTS Sixty (34%) of 178 evaluated children had PFS. Forty (23%) had complete mutism (PFS1) and 20 (11%) had diminished speech (PFS2). All children with PFS had severe ataxia and 42.5% of PFS1 had movement disorders. By multivariable analysis, younger age (p=0.0005) and surgery in a low-volume surgery center (p=0.0146) increased PFS risk, while SHH tumors had reduced risk (p=0.0025). Speech and gait returned in PFS1/PFS2 children at a median of 2.3/0.7 and 2.1/1.5 months respectively, however, 12 (44.4%) of 27 PFS1 children with 12 months of follow-up were non-ambulatory at one-year. Movement disorder (p= 0.037) and high ataxia score (p< 0.0001) were associated with delayed speech recovery. Older age (p= 0.0147) and high ataxia score (p< 0.0001) were association with delayed gait return. Symptoms improved in all children but no child with PFS had normal neurologic examination at a median of 23 months after surgery. CONCLUSION Categorizing PFS in to types 1 and 2 has prognostic relevance. Almost half of the children with PFS1 remained non-ambulatory at 12-month follow-up. Surgical experience was a major modifiable contributor to the development of PFS.

Leptomeningeal disease in the setting of malignant melanoma metastatic to the brain provides a dismal prognosis. The relationship between intraventricular metastatic tumor seeding following surgical resection and development of leptomeningeal disease (LMD) is not completely clear, although there appears to be correlation. While the mechanisms that drive the development of LMD is not well understood, monitoring of cerebrospinal fluid (CSF) for circulating tumor cells (CTCs) in high risk patients may allow for early intervention for LMD prior to radiographical diagnosis. This report describes a patient with metastatic melanoma who developed ventricular trapping from an intraventricular melanoma metastasis. The patient underwent endoscopic assisted resection of the tumor. Due to concern for leptomeningeal seeding given the location of the tumor and use of surgical resection, CSF analysis was performed. CTC count was increased shortly after surgical resection along with cytology that was suspicious for malignancy. Due to the increase in CTCs, the patient was treated for LMD with whole brain radiation therapy and intrathecal pembrolizumab. Subsequent CSF analysis revealed clearing of malignant cells in the CSF. The patient developed symptoms consistent with LMD approximately 9 months after the surgery and died 21 months after resection of his brain metastasis. This case illustrates a rare occurrence of an intraventricular melanoma metastasis, and the use of CTC presence within the CSF to diagnose LMD for early intervention. This emphasizes that the risk of developing LMD must be considered with intraventricular metastasis or ventricular exposure during tumor resection, and that CTCs may be an effective factor to monitor for early development of disease with possible prolonged survival benefit.