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BACKGROUNDImprovements in systemic therapies have led to significantly improved survival in patients with breast cancer and have created a challenge with regards to management of brain metastases (BM) and leptomeningeal disease (LMD). LMD is a highly aggressive condition, resulting in rapid neurological decline and a short survival of weeks to months. The purpose of this study is to identify clinical factors that can predict for LMD when a patient is diagnosed with BM, and to assess outcomes with various treatment modalities.METHODSA retrospective analysis was conducted using a clinical database at a single institution and included 178 patients with breast cancer and treated BM between 2007-2020. Demographic, clinical, radiographic, and dosimetric data were collected. LMD was diagnosed by cytology or neuroimaging. Chi-square and t-test were used.RESULTSOut of 178 patients with breast cancer and treated BM, 41 (23%) developed LMD. Median age for the study cohort was 51.3 +-13.4 years; those with LMD was 47.9 +-12.3 (p=0.057) years. One of the 178 patients was a male and all 41 with LMD were females. There were 58.5% Caucasian women in the LMD group followed by African-American being 24.4% (p=0.31). Characteristics like number of brain lesions (p=0.57), median size of the largest brain lesion (p=0.70), hemorrhagic/cystic lesions (p=0.68), systemic disease being progressive in 42.6%, stable in 19.3% and 26.1% with no evidence of systemic disease at the time of diagnosis of BM (p=0.34) did not pose a higher risk in developing LMD. For 29% patients the brain lesions were supratentorial, 23.7% were infratentorial and 47.4% patients had both and had a higher risk for LMD (p=0.025). Patients with liver (p=0.45) and bone (p=0.48) lesions did not have higher risk for LMD which was seen in those without lung metastases (p=0.03). In the LMD group, 39% had HR+, 31.7% HER2+, and 41.4% had triple negative breast cancer (TNBC). The higher incidence of HR+ patients could be attributed to the fact that the more aggressive HER2+ and TNBC patients may have not gotten treatment for their BM as they pursued comfort care status. In the LMD group, 13.1% received prior stereotactic radiation, 39.5% whole brain radiation, 10.5% had surgery alone and 36.8% had surgery with pre/post-op radiation. Patients who had any surgery did not have a higher risk for LMD (p=0.26). Surgery did not pose a higher risk for local recurrence, seen in 28% patients (p=0.42) and occurrence of BM at another site, seen in 36.5% patients (p=0.16). CONCLUSIONSAmong breast cancer patients with brain metastases those who develop LMD tend to be younger, with higher risk in Caucasians and African-American women; however, this was not statistically significant. The number, size, hemorrhagic/cystic character of brain lesions did not pose a higher risk whereas occurrence of synchronous lesions in supratentorial and infratentorial locations increased risk of LMD. There was no statistically significant difference in the rates of LMD, local recurrence, CNS recurrence at another site with surgery and/or radiation. EthnicityBrain metastases (N=178)LMD group (N=41) (p=0.31)Caucasian58.4%58.5%Hispanic12.4%4.9%African-American19.1%24.2%Others10.1%12.2% Clinical characteristicsBrain metastasesLMD groupP valueNumber of brain lesions (Median interquartile range)3 (1-8)2.5 (1-9)P=0.57Median size of the largest brain lesion (cm)2.4 1.42.53 1.69p=0.70Hemorrhagic lesions223P=0.68Cystic lesions163 Citation Format: Akshjot Puri, Charisma Mylavarapu, Jiagiong Xu, Tejal A Patel, Bin S Teh, Ivo Tremont-Lukats, Jenny C Chang, Polly Niravath. Clinical factors and association with treatment modalities in patients with breast cancer and brain metastases who develop leptomeningeal disease [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-08.

Patients with primary brain tumors often experience seizures, which can be the presenting symptom or occur for the first time at any point along the illness trajectory. In addition to causing morbidity, seizures negatively affect independence and quality of life in other ways, for example, by leading to loss of driving privileges. Long-term therapy with antiepileptic drugs (AEDs) is the standard of care in brain tumor patients with seizures, but the role of prophylactic AEDs in seizure-naive patients remains controversial. In this article, experts in the field discuss the issues of AED efficacy and toxicity, and explain their differing recommendations for routine use of prophylactic AEDs.

Stereotactic radiosurgery (SRS) or radiotherapy (SRT) is commonly used to treat brain metastasis (BM). While effective in achieving tumor control, a significant number of BM patients exhibit lesion growth on follow-up MR imaging after SRS which cannot reliably distinguish between tumor growth, radiation necrosis (RN) or a mixture of both. SRS retreatment is a therapeutic option for tumor regrowth but contraindicated for RN. Here, we describe an instructive case of MRI progression of a breast BM previously treated by SRS where [18F] fludeoxyglucose-positron emission tomography (FDG-PET) proved useful to anatomically delineate metabolically active tumor from RN for re-treatment planning. Post-treatment FDG-PET and MRI studies indicated decreased uptake and enhancement respectively following treatment. This case study underscores the biological heterogeneity underlying MRI based BM progression after prior SRS and the potential utility of FDG-PET to guide treatment planning for repeat SRS.

There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial.In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18-70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/mBetween June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7-47·1) with temozolomide to 48·1 months (32·6 months-not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35-1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35-1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths.Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial.German Federal Ministry of Education and Research.

In this chapter, we describe central nervous system (CNS) complications of cancer commonly presenting to the emergency department, including altered mental status, high intracranial pressure/brain herniation, status epilepticus (convulsive and nonconvulsive), acute ischemic stroke, intracranial hemorrhage, and cerebral venous sinus thrombosis. We also briefly discuss the effects of SARS-CoV-2 on the CNS. Many patients present with more than one problem and more than one cause. This multiplicity can make diagnosis and management difficult. The goal is to preserve life and function, achieved by early, correct diagnosis. Still, patients come late in the disease course, or these neurological emergencies unfold quickly and catastrophically. Acute mental status change is the top neurological symptom in cancer patients; it is the final common path to intracranial hypertension, epileptic seizures, infection, electrolyte abnormalities, intracranial hemorrhage, ischemic stroke, and adverse effects from drugs. The emergency physician should also be comfortable in starting discussions on goals of care and advance care planning before admission to other hospital areas.

BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assgined to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantie 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.

Glioblastoma (GBM) is the most common type of malignant tumor found in the brain, and acts very aggressively by quickly and diffusely infiltrating the surrounding brain parenchyma. Despite its aggressive nature, GBM is rarely found to spread extracranially and develop distant metastases. The most common sites of these rare metastases are the lungs, pleura and cervical lymph nodes. There are also a few case reports of skin metastasis. We present the clinical, imaging and pathologic features of a case of a GBM with metastasis to the soft tissue scar and skin near the original craniotomy site. In addition, we discuss the details of this case in the context of the previously reported literature.

Amphetamine-associated CNS vasculitis is controversial. There are few reports but none as a tumor mimic to our knowledge. We describe a pathology-proven, amphetamine-associated CNS vasculitis resembling a tumor. A 41-year-old man presented with six weeks of progressive confusion and left-sided weakness. CT head reported a right thalamic mass with vasogenic edema. Laboratory tests were unremarkable except for cannabinoids and amphetamine in urine. MRI brain showed enhancement in right frontotemporal lobe, basal ganglia, and thalamus concerning for glioblastoma multiforme. After high-dose IV dexamethasone, an initial biopsy showed reactive gliosis, perivascular lymphocytic cuffing by CD3+, rare CD20+ cells and no infection. He continued to decline. MRI 22 days after admission showed increased T2/FLAIR hyperintensity, multifocal areas of enhancement, microhemorrhages, and ischemia. High-grade glioma, lymphoma and infectious encephalitis remained on differentials. Treatment included broad-spectrum antibiotics and acyclovir. Biopsy on 23rd day showed reactive gliosis with parenchymal macrophage infiltration and perivascular cuffing with mixed inflammatory infiltrates. CSF: slightly elevated WBCs (8/µL), elevated protein (139mg/dL), normal glucose, and no infection. MRI whole spine and CT body were unremarkable. The patient was transferred to MDACC 5.5 weeks after initial presentation. He was alert with expressive aphasia, right gaze preference, left hemiplegia, and right hemiparesis. He underwent a right anterior temporal lobectomy. Pathology showed extensive cortical laminar and white matter necrosis with macrophage infiltration and microglial activation. In areas of the preserved cortex, vasculocentric lymphocytic aggregates were present and reticulin staining showed lymphocytic infiltration of the vascular walls. Immunophenotyping (CD3, CD20) showed an almost pure T-cell population. The predominance of intramural T-lymphocytes reflected a vasculitic process. The final diagnosis was cerebral vasculitis with subacute infarction. The patient died six days later. The autopsy findings were identical to the previous resection without evidence of systemic inflammation.

1093 Background: The treatment of patients with brain only metastatic breast cancer (BO-MBC) remains very challenging. There is also very limited literature informing on appropriate treatment or natural history of this entity. Systemic chemotherapy in addition to targeted therapy and/or anti-estrogen treatment is often used, but little is known if it adds to the overall or disease free survival. In this retrospective study, we examine this, as well as other factors which may be associated with increased risk of CNS or systemic recurrence in these patients. Methods: A database search at a single institution identified 178 patients with brain metastases (BM) from breast cancer out of which 45 patients had BO-MBC between 2007-2020. We collected demographic, clinical, radiographic and other treatment data. Leptomeningeal disease (LMD) was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. We used the Brookmeyer and Crowley method. Results: The patients were followed for a median of 17.9 months; 36 out of 45 patients (80%) received local treatment for BM (surgery/radiation/both) and HER2 directed antibodies or tyrosine kinase inhibitors and/or anti-estrogen treatment, whereas 9 out of 45 patients (20%) received systemic chemotherapy in addition. There were 22 out of 45 (49%) HER2 +, 5 out of 45 (11%) HR + and 18 out of 45 (40%) triple negative breast cancer (TNBC) patients. There were 17 out of 45 patients (38%) who were deemed to have low burden of BM (defined as one to three BM and largest being ≤3 cm) whereas there were 24 out of 45 patients (53%) who had high burden of BM (defined as four or more BM or largest being > 3 cm). Conclusions: Patients with BO-MBC represent a distinct entity. Despite having better survival than patients with BM and extra CNS disease these patients have a high risk of developing LMD, CNS and systemic recurrences. The addition of chemotherapy to targeted therapy and/or anti-estrogens does not decrease the rates of systemic or CNS recurrence. The ER+ subset have a lower rate of development of systemic disease, as expected due to their relatively indolent biology. The CNS and systemic recurrence seem to be higher in patients with HER2+ cancers and counterintuitively even in those with low burden of BM; albeit these were statistically insignificant.[Table: see text]

Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m(2)). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI 2.96-8.34) compared to the bevacizumab alone arm (4.11 months, CI 2.69-5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI 4.17-13.44) compared to the bevacizumab alone arm (3.22 months CI 2.5-6.01, p = 0.08). The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment.

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiographic diagnosis characterized by headache, confusion, visual disturbances, seizures and most commonly bilateral vasogenic edema. PRES during first trimester gestation is exceptional and in our report mimicking CNS tumor. An 18-year-old G1P0 Hispanic woman was admitted with headache, left-sided hemiparesis and left-sided visual loss for 4 days. Exam was consistent for drowsiness, dysarthria, left homonymous hemianopia, left facial droop and left hemiplegia with left hemi-sensory loss. By pelvic ultrasound she had a single 9-week intrauterine pregnancy with no detectable fetal heart tone. MRI brain: large area of increased T2 signal in the right parietal occipital and upper temporal and posterior right frontal lobe white matter with mass effect of 6mm midline shift and no evidence of hemorrhage. There was high suspicion for a glial neoplasm. MRA of head and neck and EEG were unremarkable. IR cerebral angiogram had no evidence of vascular abnormalities. Eventual MR spectroscopy, choline/NAA ratio was (< 2/1), elevated lactate/fat peak suggestive of inflammatory versus infectious process. She had D&C for missed abortion and pathology was negative for malignancy. Further brain biopsy on day 5 demonstrated reactive astrogliosis with microglial activation, scattered macrophages with white matter vacuolation. Biopsy specimen was negative for infections. TPO Ab, NMO/AQP4, Ttg IgA and rheumatologic panel were negative. The pathology was most compatible with PRES. Repeat MRI had decreasing mass effect and increased patchy subcortical restricted diffusion in the right occipital and temporo-parietal lobes. She had inpatient rehabilitation leading to complete recovery.

PURPOSE Treatment with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) is increasingly common for brain metastases (BM) from lung adenocarcinoma. Rates of radiation necrosis (RN) with SRS in the setting of ICIs is an ongoing area of research. We investigated rates of RN in patients with BM from lung adenocarcinoma treated with SRS with or without concurrent ICIs. METHODS We identified 39 patients at a single institution who underwent SRS treatment for BM from lung adenocarcinoma. Of these, 19 (49%) received SRS without ICIs and 20 (51%) patients received ICIs within a month of SRS. The rate of RN, defined by MRI features and histology when available, was compared between each group using multivariate analysis. Kaplan Meier survival estimates were calculated based on overall survival and compared to median survival predicted by the graded prognostic assessment. RESULTS Overall survival for all patients from diagnosis of brain metastases was 16.6 months (range 3.6–45.9) and median survival predicted by the graded prognostic assessment was 13.7 months (range 6.9–26.5). In total 11 (28%) patients developed MRI and/or histologic evidence for RN during the follow-up period; 5 of 20 (25%) from the SRS with ICI group and 6 of 19 (31%) from the SRS without ICI group. In multivariate analysis, ICI treatment had no significant impact on rates of RN between groups (OR 0.72 [95% CI: 0.17–2.93]; p=0.65) while bevacizumab treatment was associated with a decreased RN risk (OR 0.88 [95% CI: 0.43–0.99]; p=0.02). CONCLUSION Retrospective analysis of patients with BM from lung adenocarcinoma treated with SRS suggested that administration of ICIs does not increase risk for development of RN. Further, concomitant treatment with bevacizumab may decrease risk of RN. These findings suggest that patients with BM from lung adenocarcinoma can be treated with combination therapy without increased risk of neurologic toxicity.

Background Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known. Methods In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary ...

BACKGROUND: Leptomeningeal metastasis (LM) is a devastating complication of cancer resulting in progressive neurologic decline. Although intrathecal (IT) methotrexate and cytarabine are commonly used for solid tumor LM, we routinely use IT topotecan due to previously demonstrated similar efficacy and modest side effect profile. We report updated data on our experience. METHODS: We reviewed clinical records of patients with solid tumor LM treated with IT topotecan at MD Anderson Cancer Center from 2008–2018. Patient characteristics and course were summarized by descriptive statistics. Overall survival (OS) was estimated with Kaplan-Meier, and the association of KPS with OS evaluated with log-rank test. RESULTS: 138 patients were treated with IT topotecan. The median age was 54 years (range, 22–76), 81% were female. Breast cancer (62%) was the most common primary, then lung (21%), melanoma (4%). Median time from primary diagnosis to LM was 3.4 (range, 0.07–25.2) years. LM was diagnosed by CSF cytology alone in 8 (6%), MRI alone in 21 (15%), CSF+MRI in 108 (78%). Patients most commonly presented with headache (39%) or sensory changes (18%), and had a median KPS of 80 (range, 60–100). 66% had prior/concurrent brain metastasis. 71 patients (52%) received WBRT following LM diagnosis. 41% had adverse effects, most commonly nausea/vomiting (22%) and headache (20%). The majority were grade 1 (63%); 7 were grade 4 (2 Ommaya malfunctions and 5 infections). Patients received a median of 9 (range, 1–79) doses, most stopped due to CNS progression (42%). Median OS was 6.5 months (95% CI 4.7, 7.8). OS was 3.8 mos with KPS ≤70, vs. 7.5 mos with KPS >70 (p< 0.001). CONCLUSIONS: IT topotecan has a modest side effect profile. Patients with higher functional status at diagnosis had significantly better survival. This study supports the continued use of IT topotecan as a well-tolerated option for LM.

Gliomatosis cerebri is a rare malignant tumour originating from cerebral glial cells. Most experts currently view gliomatosis cerebri as a pattern of extensive glioma infiltration encompassing at least three cerebral lobes.1 It occurs at any age, with peak incidence between 40 years and 50 years and it is slightly more common in men.2 On MRI, gliomatosis cerebri shows no, or minimal, contrast enhancement; however, it has a diffuse hyperintense infiltrative process on T2-weighted fluid-attenuated inversion recovery (FLAIR) sequence. It is usually possible to diagnose gliomatosis cerebri using an open biopsy or a stereotactic biopsy. Despite treatment, its median survival varies from 6 months to 39 months.3 We report an unusual presentation of gliomatosis cerebri, which underscores the difficulty in pinpointing the correct diagnosis after corticosteroids have modified the disease course. A 78-year-old woman had an episode of acute onset slurred speech and confusion. Her initial CT scan of head showed diffuse left hemispherical white matter hypodensity with sulcal effacement and minimal midline shift to the right. Cerebrospinal fluid (CSF) examination suggested viral encephalitis for which she was empirically given intravenous dexamethasone and acyclovir, with oral levetiracetam 500 mg twice daily. After initially improving, she rapidly worsened with corticosteroid tapering. A repeat CT scan of head showed no change. She took dexamethasone 4 mg twice daily before undergoing a brain biopsy, which showed mild hypercellularity suspicious but not definitive for glioma. Two weeks later, we saw her for a second opinion. The MRI of …

In this chapter, we succinctly describe and explain the major complications in the central nervous system of patients with cancer seen in emergency areas. Many patients present with more than one of these problems and with more than one cause. This multiplicity can make the diagnosis and management of these neurologic conditions complex. The ideal outcome is to preserve life and function, many times determined by an early, correct diagnosis and management that begins in the emergency department. Unfortunately many patients come late in the disease course, or these neurological complications develop quickly and catastrophically despite the best effort. A change in mental status is the most frequent neurological symptom in cancer patients, and its correct diagnosis is challenging as there are many possible causes including increased intracranial pressure, epileptic seizures, infection, electrolyte abnormalities, intracranial hemorrhage, and adverse effects from drugs including opioids, benzodiazepines, antihistaminics, chemotherapy agents, immunosuppressors, and antibiotics. Finally, it is important to remember that in many cases, recognition of poor prognosis and institution of advance care planning, supportive care, and ultimately hospice case are the right interventions to make even in the emergency department.

BACKGROUND: Immune checkpoint inhibitors (ICI) are an increasingly common therapy for metastatic solid tumors. Despite their efficacy, many patients develop brain metastasis requiring stereotactic radiosurgery (SRS) or fractionated stereotactic radiation therapy (SRT). Radiation necrosis (RN) is a known risk. Recent observations suggest that patients receiving SRT/ICI may experience synergism albeit with potential increased risk of symptomatic RN. The best treatment in this setting remains unknown. VEGF inhibitors have demonstrable efficacy in treatment of RN and may be beneficial in treating neurotoxicity associated with combination SRT/ICI. METHODS: Data were analyzed retrospectively from 169 consecutive patients at a single institution undergoing SRS/SRT for brain metastasis from 2015–2017. 10 patients were eligible for evaluation having received SRT and ICI within a 6 month timeframe and with a minimum 3 months survival for assessment of RN. 7 patients were treated for lung adenocarcinoma, 2 for high-grade neuroendocrine tumor, and 1 with triple-negative breast cancer. RESULTS: 10 patients were treated with SRS (90%), SRT (60%), both (50%), or SRS followed by whole-brain radiation (10%) to a total of 65 brain metastases. ICI (nivolumab, pembrolizumab, atezolizumab, ipilimumab) was administered before, during, or after SRS/SRT. 6 patients (60%) developed symptomatic grade ≥ 1 neurological adverse events. Of these 6, 4 (40%) developed grade 3 RN requiring bevacizumab. Symptoms resolved rapidly in 3 of 4 patients (75%), the 4(th) patient died of complications of disease shortly after bevacizumab administration. Mean 12 month survival from initial immunotherapy treatment was 89% and mean 18 month survival from initial SRT was 78%. CONCLUSION: Combination treatment with SRT/ICI for brain metastases appears to be associated with high rates of RN compared to historical standards. Given the prolonged survival seen, appropriate management of this complication is paramount. Short course bevacizumab appears highly effective in treating symptomatic RN associated with ICI. Further evaluation with a larger sample size is warranted.

2044Background: Repurposing non-cancer drugs may represent a new source of novel therapies for glioblastoma (GBM). Memantine, mefloquine, and metformin have putative anticancer activity potentially...

BACKGROUND: Limited treatment options exist for patients with recurrent Malignant Gliomas (rMG), especially after Bevacizumab (BEV). Everolimus targets mTOR and sorafenib targets Raf, VEGF and PDFG. Combining these agents can block two parallel pathways simultaneously. We performed a phase I trial of Everolimus and Sorafenib in patients with rMG in preparation for a phase II study. METHODS: Patients with rMG > 18 yrs, KPS ≥ 60, normal laboratory data and no history of HIV or hepatitis were eligible. No limit on prior relapses and BEV exposure was allowed. Enzyme inducing seizure drugs were not allowed. A 3 + 3 dose escalation was used to determine the MTD. The starting dose was Everolimus 5 mg a day + Sorafenib 400 mg twice a day with a dose de-escalation level of Everolimus 5 mg/day + Sorafenib 400 mg twice a day for 7 days on and 7 days off. RESULTS: 11 men and 2 women were enrolled with a median age of 50 years (19-66) and median KPS of 80 (70-100). All patients had a GBM with 7 receiving prior BEV. In cohort 1, 3 of 6 patients experienced a DLT which were grade 3: fatigue, chest pain, HTN, elevated ALT, hypercholesterolemia and hyperglycemia and one grade 4 hypertriglyceridemia. Dose de-escalation occurred with 1 of 7patients having a DLT of myositis, nausea, fatigue, hypertension and hypercholesterolemia-all grade 3. All patients died due to disease progression with a median PFS of 4 weeks and OS of 20.9 weeks. CONCLUSION: This phase I study determined a phase II dose of Everolimus at 5 mg daily and Sorafenib at 400 mg BID 7 days on and 7 days off. A phase II trial is on-going for Bev naive recurrent anaplastic gliomas and GBMs as well as recurrent GBM who failed BEV.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

Patients with gliomas are at risk of cerebrovascular accidents (CVA) with potential consequences on survival, function, and local tumor control. Our objective was to provide information about CVA in patients with gliomas and to estimate survival in this group. We reviewed all adult glioma patients with ischemic CVA at the University of Texas-M.D. Anderson Cancer Center from 2003 through 2014. We extracted demographic, clinical, imaging, treatment and outcome data. We used descriptive summary data and estimated or compared survival rates where appropriate. 60 of 6500 patients (0.1%) with high-grade (HGG, n = 47) or low-grade glioma (LGG, n = 13) had ischemic CVA Thirty-two (53%) patients had postoperative strokes, and 20 (33%) had CVA after 2 weeks of surgery. Forty-one patients (68%) had gross total resection. For HGG and CVA, the poststroke median overall survival was 17 months versus 61 months in LGG and CVA (P = 0.03; hazard ratio (HR): 2.8; 95% CI 1.07-4.60). Survival stratified by modified Rankin Scale grade was significant (X(2) = 9.8, P = 0.007). Five patients received bevacizumab before stroke onset; none responded to antiangiogenic therapy. There was no stroke-related death. At our institution for 10 years, ischemic CVA in glioma patients was a rare complication, clearly associated in half of cases to surgery, and with a variable negative impact on performance status and neurologic function. In this group, patients with more neurological deficits lived less. The survival difference between and within subgroups was most likely due to tumor grade. More research is necessary to improve prevention of postoperative stroke in glioma patients.

Objectives: To determine the dose-response effect and safety of IV lidocaine at different dose infusion rates on spontaneous ongoing neuropathic pain. Methods: In this double-masked, placebo-controlled, parallel study conducted in an outpatient clinical research center, patients with peripheral neuropathic pain received a 6-hour infusion of three doses (1, 3, and 5mg/kg) of lidocaine or placebo. The main outcome measure was relief of pain intensity (percentage pain intensity difference [PID %]). Other measures were responder rate, adverse events, and correlation between lidocaine levels and PID %. Results: There was a significant difference in the median PID % between the group treated with lidocaine 5mg/kg/h (-34.60) and the placebo group (- 11.96, P = 0.012). Such effect began 4 hours after the onset of treatment and lasted until the end of the study. Lidocaine at lower infusion rates was no better than placebo in relieving pain. A modest but significant correlation was found between methylethylglycinexylidide (MEGX) levels and pain relief (R 2 = 0.60). There were no serious adverse events, but in two patients lidocaine was stopped prematurely. Conclusions: Lidocaine at 5mg/kg/h was more effective than placebo at relieving neuropathic pain. The effect started 4 hours after the onset of treatment and continued for at least 4 hours after the end of the infusion. Additional research is needed using higher infusion rates with larger sample sizes to confirm these results and to explore the role of MEGX in the relief of neuropathic pain.

We reviewed randomized controlled trials to determine the efficacy and safety of systemically administered local anesthetics compared with placebo or active drugs. Of 41 retrieved studies, 27 trials of diverse quality were included in the systematic review. Ten lidocaine and nine mexiletine trials had data suitable for meta-analysis (n = 706 patients total). Lidocaine (most commonly 5 mg/kg IV over 30-60 min) and mexiletine (median dose, 600 mg daily) were superior to placebo (weighted mean difference on a 0-100 mm pain intensity visual analog scale = -10.60; 95% confidence interval: -14.52 to -6.68; P < 0.00001) and equal to morphine, gabapentin, amitriptyline, and amantadine (weighted mean difference = -0.60; 95% confidence interval: -6.96 to 5.75) for neuropathic pain. The therapeutic benefit was more consistent for peripheral pain (trauma, diabetes) and central pain. The most common adverse effects of lidocaine and mexiletine were drowsiness, fatigue, nausea, and dizziness. The adverse event rate for systemically administered local anesthetics was more than for placebo but equivalent to morphine, amitriptyline, or gabapentin (odds ratio: 1.23; 95% confidence interval: 0.22 to 6.90). Lidocaine and mexiletine produced no major adverse events in controlled clinical trials, were superior to placebo to relieve neuropathic pain, and were as effective as other analgesics used for this condition.

B lymphoblastic leukemia/lymphoma (B-LBL) typically presents with symptoms related to anemia, thrombocytopenia, and neutropenia. CNS involvement is not uncommon during the disease course; however, it is rare as the initial presentation, making B-LBL with cranial nerve (CN) palsy a diagnostic challenge. Our objective is to show that B-LBL can present initially as CN palsy, and to share our approach to this challenge.

The outcome of patients with brain metastases is generally poor. Survival alone is not necessarily a good measure of clinical outcome. Measures of neurocognitive function and the impact of the disease and treatments on functional status also need to be considered. Although these parameters have been measured in patients with primary brain tumors, they have not been as thoroughly evaluated in patients with brain metastases. The Mini-Mental State Examination provides limited assessment of neurocognitive domains impaired in brain tumor patients. It is less sensitive to mild impairment, does not avoid memorized learning from repeat administration, and does not have validated alternative forms necessary for non-English speaking patients. To determine the feasibility of using a more comprehensive neurocognitive test battery, motor, verbal, executive, and daily functions were assessed in 30 patients with brain metastases. The test battery included the Hopkins Verbal Learning Tests, Controlled Oral Word Association Test, Grooved Pegboard Test, Trailmaking Tests A and B, and the Barthel Index. In this study, there was complete patient compliance, with average test completion time of 23 +/- 6 minutes. Despite high functional status, most patients demonstrated impairment in memory and fine motor domains. Neurocognitive test batteries can and should be used in patients with brain metastases enrolled in clinical trials.

We are witnessing the development of new treatment modalities for primary brain tumors. An area under intense investigation is the use of small molecules targeting intracellular signaling pathways that interfere with growth, invasion, and metastasis of high-grade gliomas.We review clinical trials of small molecules in adults with brain tumors. This search included electronic databases, specialty journals, textbooks, proceedings, and Web sites of the National Cancer Institute and other cooperative brain tumor groups in Europe and the United States.Several drugs with the ability to down-regulate the growth and invasion of malignant gliomas are at various stages of testing. Most of these focus on interfering with oncogenic and tumor survival pathways. Examples include inhibitors of tyrosine kinases, farnesyltransferases, and matrix metalloproteinases. These molecules are at different stages of testing, and a conclusive picture of which drug is most effective, either alone or in combination, needs better definition. The metalloproteinase inhibitor marimastat with temozolomide has given the best results to date in phase II trials, increasing the rate of 6-month progression-free survival for recurrent glioblastoma multiforme and anaplastic gliomas.As our understanding of the biology of gliomas increases and new drugs targeting specific molecular pathways enter well-designed cooperative trials, the control and prognosis of these tumors should improve.

Sinking skin flap syndrome (SSFS) is a rare neurological complication in patients with traumatic haemorrhage, stroke or cerebral oedema who undergo decompressive craniectomy to relieve increased intracranial pressure. Hallmark of SSFS is the sinking of the scalp to a plane lower than the edges of the skull defect in the setting of neurological deterioration. Our objective is to report that SSFS can present after small craniotomy without cerebral cortex compression and to share our diagnostic/therapeutic approach. A 62-year-old woman with a glioblastoma developed SSFS after a small craniectomy and tumour resection without cerebral cortex compression but a decrease in the surgical cavity volume. Brain MRI showed decreased size of the surgical cavity. Interestingly, the patient also developed posterior reversible encephalopathy syndrome (PRES). This case highlights an atypical presentation of SSFS and the possible association with PRES. It also illustrates how an early cranioplasty can successfully reverse SSFS.

Imaging has become a central part of the evaluation of lesions of the central nervous system. Despite patterns of the appearances of several types of central nervous system malignancies and improving resolution of imaging techniques, there are other processes that can display similar characteristics. Time and again, vascular, inflammatory, and vascular lesions will mimic a neoplastic process, requiring tissue diagnosis. With the introduction of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging in the evaluation of the brain tumor, there has been improvement in determining whether a lesion is neoplastic, and further advances may lead to noninvasive pathological and molecular diagnoses.

Neuropathic pain, a form of chronic pain caused by injury to or disease of the peripheral or central nervous system, is a formidable therapeutic challenge to clinicians because it does not respond well to traditional pain therapies. Our knowledge about the pathogenesis of neuropathic pain has grown significantly over last 2 decades. Basic research with animal and human models of neuropathic pain has shown that a number of pathophysiological and biochemical changes take place in the nervous system as a result of an insult. This property of the nervous system to adapt morphologically and functionally to external stimuli is known as neuroplasticity and plays a crucial role in the onset and maintenance of pain symptoms. Many similarities between the pathophysiological phenomena observed in some epilepsy models and in neuropathic pain models justify the rational for use of anticonvulsant drugs in the symptomatic management of neuropathic pain disorders. Carbamazepine, the first anticonvulsant studied in clinical trials, probably alleviates pain by decreasing conductance in Na+ channels and inhibiting ectopic discharges. Results from clinical trials have been positive in the treatment of trigeminal neuralgia, painful diabetic neuropathy and postherpetic neuralgia. The availability of newer anticonvulsants tested in higher quality clinical trials has marked a new era in the treatment of neuropathic pain. Gabapentin has the most clearly demonstrated analgesic effect for the treatment of neuropathic pain, specifically for treatment of painful diabetic neuropathy and postherpetic neuralgia. Based on the positive results of these studies and its favourable adverse effect profile, gabapentin should be considered the first choice of therapy for neuropathic pain. Evidence for the efficacy of phenytoin as an antinociceptive agent is, at best, weak to modest. Lamotrigine has good potential to modulate and control neuropathic pain, as shown in 2 controlled clinical trials, although another randomised trial showed no effect. There is potential for phenobarbital, clonazepam, valproic acid, topiramate, pregabalin and tiagabine to have antihyperalgesic and antinociceptive activities based on result in animal models of neuropathic pain, but the efficacy of these drugs in the treatment of human neuropathic pain has not yet been fully determined in clinical trials. The role of anticonvulsant drugs in the treatment of neuropathic pain is evolving and has been clearly demonstrated with gabapentin and carbamazepine. Further advances in our understanding of the mechanisms underlying neuropathic pain syndromes and well-designed clinical trials should further the opportunities to establish the role of anticonvulsants in the treatment of neuropathic pain.

This study estimated the frequency of nine primitive reflexes (PR) and assessed their possible clinical value in a group of patients with acquired immunodeficiency syndrome. We studied 78 patients with human inmunodeficiency type 1 (HIV-1) infection in WHO clinical stage 3 or 4 and 81 matched seronegative controls. All participants were examined using a standardized neurological examination and the Mini-Mental State Examination. Cognitive impairment and PR was found in 36% of patients but in none of the controls (P < 0.0001; logistic regression odds ratio: 14.7). Overall, PR were 2–36 times more frequent in patients with HIV-1 infection. This association was stronger for the glabellar, snout, Rossolimo, and digital signs. At least two PR were observed in 92% of patients vs. 8% of controls (P < 0.0001; 95% confidence interval: 68%–100%; logistic regression odds ratio: 10.8). These data support the association of PR with cognitive decline in patients with advanced HIV-1 infection without overt neurological disease. Larger follow-up studies with multivariate techniques are needed to identify which PRs are useful as indicators of HIV-1-associated cognitive/motor complex and minor neurocognitive disorders.

Background The etiology of encephalitis presents a diagnostic challenge and often remains a mystery. However, current technological advances using antibodies can enable a definitive diagnosis in cases that would previously have been suspected to be idiopathic or viral encephalitis. Our objective is to show that tonsil neuroendocrine carcinoma can present initially as limbic encephalitis mediated by N-type calcium channel antibodies and to highlight the diagnostic confusion before cancer detection. Methods We report a rare case of neuroendocrine cancer presenting as limbic encephalopathy, Lambert–Eaton myasthenic syndrome and neuropathy. The patient was diagnosed and treated at The University of Texas MD Anderson Cancer Center in November 2011. Results Paraneoplastic limbic encephalitis was diagnosed based on clinical presentation of seizures, short-term memory loss, retrograde amnesia, disorientation, distractibility, and abulia; on the exclusion of brain metastases, CNS infection, stroke, metabolic or nutritional deficits, or medication-related events; and on CSF results with inflammatory findings and an abnormal electroencephalography study that showed seizure activity in the left temporal lobe. Serum paraneoplastic panel was positive for P/Q-type calcium channel antibody and N-type calcium channel antibody. Magnetic resonance imaging of brain was unremarkable. Conclusion This case highlights limbic encephalitis as an atypical presentation of neuroendocrine cancer. It also illustrates how treatment of the underlying cancer can reverse limbic encephalitis and Lambert–Eaton myasthenic syndrome in a neuroendocrine carcinoma patient even before the paraneoplastic panel becomes negative.

This study describes the presence of alpha-galactosyl epitopes on 12 cervical biopsy samples with features of human papillomavirus infection (HPV) and different stages of cervical intraepithelial neoplasia. An avidin-biotin-peroxidase assay with a monoclonal antibody recognizing gal(alpha 1--3)gal residues was strongly positive in 5 of 12 cases. None of the controls stained (p = 0.02). Immunostaining was intense in the areas with the highest viral load (koilocytes and keratinocytes) and absent in malignant foci. Immunostaining was also absent in normal exo- and endocervical epithelium of 12 controls with no features of HPV infection. A faint background staining in cases and controls was evident, but similar. These initial findings suggest that alpha-galactosyl epitopes are expressed in cervical squamous cells infected with HPV, turning them vulnerable to lysis by natural anti-alpha-galactosyl antibodies.

Key Clinical Message In immunocompromised patients, the pulmonary computed tomography halo sign is highly suggestive of angioinvasive aspergillosis. Early recognition may be life-saving.

Background Seizures can present at any time before or after diagnosis of a brain tumor. The risk of seizures varies by tumor type and its location in the brain. For a long time we believed that preventing seizures with antiepileptic drugs (seizure prophylaxis) was effective and necessary, but the supporting evidence was little and mixed. Such evidence was the basis for previous reviews to conclude that seizure prophylaxis was ineffective in people with brain tumors. Objectives To estimate the effectiveness of seizure prophylaxis in people with brain tumors, and to estimate the adverse event rates in the identified clinical trials. Search methods A search strategy that included free-text and MeSH terms in LILACS, EMBASE, PubMed, CENTRAL, and The Cochrane Library (1966 to 2007). Selection criteria Controlled clinical trials with random allocation, blinded or unblinded, and placebo or observation in the control groups. Data collection and analysis We screened the articles, extracted the data, and rated the validity of each trial to assess the risk of bias. Our primary outcome was the occurrence of a first seizure. The secondary outcome was adverse events. We pooled the aggregate data for each outcome into a random-effects model meta-analysis using the relative risk (RR). For adverse events, we also included the number needed to harm (NNH) using the absolute risk increase to compute the NNH. Main results There was no difference between the treatment interventions and the control groups in preventing a first seizure in participants with brain tumors. The risk of an adverse event was higher for those on antiepileptic drugs than for participants not on antiepileptic drugs (NNH 3; RR 6.10, 95% CI 1.10 to 34.63; P = 0.046). Authors' conclusions The evidence is neutral, neither for nor against seizure prophylaxis, in people with brain tumors. These conclusions apply only for the antiepileptic drugs phenytoin, phenobarbital, and divalproex sodium. The decision to start an antiepileptic drug for seizure prophylaxis is ultimately guided by assessment of individual risk factors and careful discussion with patients.

e13020 Background: We know little about what hospitalization indicates for patients with recurrent glioblastoma (rGB). Our objectives were to determine the reasons for admission; discharge disposit...