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Introduction. Metastases of breast cancer are detected in 5 to 48% cases, depending on the biological tumor subtype, which is the second most common after lung cancer in men. Cytological liquor analysis is one of the “gold standards” for the metastatic brain lesion identification, and, among other modern approaches, it can increase the CNS metastasis detection. Breast cancer cell identification in cerebrospinal fluid is a poor prognostic factor. A cytological examination has a predictive significance for these patients: the absence of tumor cells in the cerebrospinal fluid can be considered the sign of the intrathecal therapy effectiveness. The accuracy of the cytological diagnosis directly depends on the detailed patient’s history. Immunocytochemical assays increase the sensitivity of the cytological diagnostics. The aim of the study was to evaluate the ca-pabilities of comprehensive cytological and immunocytochemical studies in the secondary cerebral lesions diagnosis in breast cancer patients. Materials and methods. We conducted 169 cytological studies in 55 breast cancer patients with brain metas-tases. Liquor samples were obtained using lumbar punctures. 36 patients underwent 44 immunocytochemical studies and 117 immunocytochemical reactions to clarify the cytological diagnosis. Results. The sensitivity of the cytological method was 69.8%. Immunocytochemistry increased the sensitiv-ity to 72.3%. In 29 patients, the tumor histogenesis was determined using an immunocytochemical assay. Conclusion. The liquor cytological analysis is frequently the only primary morphologic diagnostic method to detect breast cancer metastasis within the central nervous system. Immunocytochemical assay significantly expands the possibilities of cytological study, allowing health care specialists to detect single tumor cells in samples and determine the metastatic neoplasm histogenesis in most cases, which also increases sensitivity. Keywords: breast cancer, cytological and immunocytochemical study of cerebrospinal fluid

Despite the fact that prostate cancer is the most prevalent cancer in men, metastases to the central nervous system including leptomeningeal involvement by prostate carcinoma is a rare event. The prognosis of metastatic prostate cancer is very poor due to lack of CNS penetrating therapeutic agents., Despite the fact that prostate cancer is the most prevalent cancer in men, metastases to the central nervous system including leptomeningeal involvement by prostate carcinoma are a rare event. The prognosis of metastatic prostate cancer is very poor due to lack of CNS penetrating therapeutic agents.

Despite the important evolution of immunotherapeutic agents, brain tumors remain, in general, refractory to immune therapeutics. Recent discoveries have revealed that the glioma microenvironment includes a wide variety of immune cells in various states that play an important role in the process of tumorigenesis. Anti-tumor immune activity may be occurring or induced in immunogenic hot spots or at the invasive edge of central nervous system (CNS) tumors. Understanding the complex heterogeneity of the immune microenvironment in gliomas will likely be the key to unlocking the full potential of immunotherapeutic strategies. An essential consideration will be the induction of immunological effector responses in the setting of the numerous aspects of immunosuppression and evasion. As such, immune therapeutic combinations are a fundamental objective for clinical studies in gliomas. Through immune profiling conducted on immune competent murine models of glioma and ex vivo human glioma tissue, we will discuss how the frequency, distribution of immune cells within the microenvironment, and immune modulatory processes, may be therapeutically modulated to lead to clinical benefits.

A 68-year-old woman presented with a three-week history of confusion and anomic aphasia. Imaging of her head demonstrated a single large left frontal mass. Pathology revealed metastatic adenocarcinoma of Müllerian origin. Subsequent surgery revealed a small primary site in a fallopian tube, high left para-aortic lymphadenopathy, and no disseminated intraperitoneal disease. This case was remarkable in that CNS metastasis was her presenting symptom and was restricted to a solitary brain lesion, and other disease sites were limited to retroperitoneal lymphadenopathy and a small fallopian tube primary.

ZusammenfassungVom 2. bis 4. November 2017 fand in Lissabon unter Leitung von Frau Professor Fatima Cardoso die 4. Internationale Konsensuskonferenz ABC4 (Advanced Breast Cancer Forth Consensus) zu Diagnostik und Behandlung des fortgeschrittenen Mammakarzinoms (ABC) statt. Zur Vereinfachung wird im weiteren Text von ABC gesprochen, was im klinischen Alltag der metastasierten Brustkrebserkrankung oder der lokal weit fortgeschrittenen Erkrankung entspricht. Der inhaltliche Schwerpunkt lag dieses Jahr auf neuen Entwicklungen in der Behandlung des ABC. Diskutiert wurden unter anderem der Stellenwert der CDK4/6-Inhibition beim hormonrezeptor(HR-)positiven ABC, die duale Antikörperblockade beim HER2-positiven ABC, die PARP-Inhibition beim BRC-Amutierten tripel-negativen und luminalen ABC sowie potenzielle therapeutische Konsequenzen. Ein weiterer Fokus lag auf dem BRCA-assoziierten Mammakarzinom, der Behandlung von Hirnmetastasen sowie der individualisierten Therapieentscheidung auf der Grundlage einer molekularen Testung (sog. Präzisionsmedizin). Wie schon in den vergangenen Jahren ist die Zusammenarbeit mit den Vertretern von Patientenorganisationen aus aller Welt ein wichtiges Anliegen der ABC-Konferenz. Sie wurde auf der ABC4-Konferenz weiter intensiviert. Im Anschluss an die Konsensuskonferenz wurde die „Global Alliance“ gegründet mit dem Ziel, die erforderlichen Maßnahmen aus Sicht der Patientenvertreterinnen weltweit zu propagieren und zu koordinieren. In den ABC-Konsensus fließen aufgrund des international zusammengesetzten Expertenpanels zwangsläufig länderspezifische Besonderheiten ein. Wie schon in den vergangenen Jahren hat daher eine Arbeitsgruppe deutscher Brustkrebsexperten, die die Konsensusabstimmung der ABC-Panelisten vor Ort mitverfolgt und intensiv diskutiert haben, diese unter Berücksichtigung der deutschen Leitlinien zu Diagnostik und Therapie des Mammakarzinoms 1 2 für den Therapiealltag in Deutschland kommentiert. Die Abstimmungsergebnisse der ABC-Panelisten in Lissabon sind die Grundlage des ABC-Konsensus.

Innate inflammatory features have been found in melanoma tumors from patients at all stages, and molecular analysis has identified definitive inflammatory proteins expressed by tumors cells in patients who presents the worst prognosis. We have previously observed weakened outcomes in patients with constitutive expression of inducible nitric oxide synthase (iNOS), macrophage migration inhibitory factor (MIF) and improved outcomes with CD74 expression in stage III melanoma. In our current study, we tested our hypothesis on CD74-regulated inflammatory markers&rsquo, expression in stage IV melanoma tumors whether the signature is associated with survival outcome and/or risk of developing CNS metastasis. We retrospectively identified 315 patients with stage IV melanoma. In a tissue microarray (TMA), we examined the expression of cells with CD74, its receptor MIF, and downstream inflammatory markers iNOS, nitrotyrosine (NT), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES1). We analyzed the association of those inflammatory markers with overall survival time (OS) and time to CNS metastasis using Kaplan&ndash, Meier survival analyses. Our data validates CD74 as a useful prognostic tumor cell protein marker associated with favorable OS as in stage III melanomas, while the tumor NT expression strongly predicts an increased risk of developing CNS metastasis (p = 0.0008) in those patients.

Detection of metastases especially intracranial metastases signals a poor prognosis in a patient with cancer. Solitary cystic metastasis is often difficult to differentiate from intra-cerebral abscess which can also occur in these patients. However, the co-existence of an abscess within a CNS metastasis is a rare event. At surgery, a purulent exudate within discrete metastatic tumours was identified. Pathological and microbiological examinations confirmed the coexistence of an abscess within a metastatic carcinoma. This case highlights the importance of considering intratumoral abscesses.

Background Patients with activating epidermal growth factor receptor (EGFR) mutations are highly responsive to EGFR-tyrosine kinase inhibitors (TKIs). However, it has been reported that approximately 15–30% of patients treated with EGFR-TKIs experience central nervous system (CNS) progression, and patients with EGFR mutations exhibit a higher incidence of brain metastasis than those without such mutations. The efficacy of osimertinib for treating CNS metastasis has been reported, but its efficacy for CNS metastasis in radiotherapy-naïve patients is unclear. Methods In the present prospective two-cohort phase II trial, 65 patients (T790M cohort, 40 patients; first-line cohort, 25 patients) with radiotherapy-naïve CNS metastasis of EGFR mutation-positive non-small cell lung cancer (NSCLC) will be included. Patients will be treated once-daily with osimertinib 80 mg. The primary endpoint is the response rate of brain metastasis as assessed using the PAREXEL criteria. Key secondary endpoints are progression-free survival and the response rate of brain metastasis as assessed using the RECIST criteria. We will exploratorily analyze the relationships of the blood concentration of osimertinib with its efficacy against brain metastasis of NSCLC and the accumulation of osimertinib in cerebrospinal fluid and evaluate tumor-derived DNA from plasma specimens for mutations in EGFR and other genes. Recruitment, which in October 2016, is ongoing. Discussion Although previous reports revealed the efficacy of osimertinib for CNS metastasis, these reports only involved subgroup analysis, and the efficacy of osimertinib for patients with previously untreated CNS metastasis remains unclear. The OCEAN study is the only trial of osimertinib for patients with untreated brain metastasis of NSCLC. This study should provide novel data about osimertinib. If the results of the OCEAN study are positive, then avoidance of radiotherapy will be recommended to patients harboring EGFR mutations and brain metastasis. Trial registration UMIN identifier: UMIN000024218 (date of initial registration: 29 September 2016). jRCT identifier: jRCTs071180017 (date of initial registration: 13 February 2019).

The fourth international advanced breast cancer consensus conference (ABC4) on the diagnosis and treatment of advanced breast cancer (ABC) headed by Professor Fatima Cardoso was once again held in Lisbon on November 2 - 4, 2017. To simplify matters, the abbreviation ABC will be used hereinafter in the text. In clinical practice, the abbreviation corresponds to metastatic breast cancer or locally far-advanced disease. This year the focus was on new developments in the treatment of ABC. Topics discussed included the importance of CDK4/6 inhibition in hormone receptor (HR)-positive ABC, the use of dual antibody blockade to treat HER2-positive ABC, PARP inhibition in triple-negative ABC and the potential therapeutic outcomes. Another major area discussed at the conference was BRCA-associated breast cancer, the treatment of cerebral metastasis, and individualized treatment decisions based on molecular testing (so-called precision medicine). As in previous years, close cooperation with representatives from patient organizations from around the world is an important aspect of the ABC conference. This cooperation was reinforced and expanded at the ABC4 conference. A global alliance was founded at the conclusion of the consensus conference, which aims to promote and coordinate the measures considered necessary by patient advocates worldwide. Because the panel of experts was composed of specialists from all over the world, it was inevitable that the ABC consensus also reflected country-specific features. As in previous years, a team of German breast cancer specialists who closely followed the consensus voting of the ABC panelists in Lisbon and intensively discussed the votes has therefore commented on the consensus in the context of the current German guidelines on the diagnosis and treatment of breast cancer 1 , 2 used in clinical practice in Germany. The ABC consensus is based on the votes of the ABC panelists in Lisbon.Vom 2. bis 4. November 2017 fand in Lissabon erneut unter Leitung von Frau Professor Fatima Cardoso die 4. Internationale Konsensuskonferenz ABC4 (Advanced Breast Cancer Forth Consensus) zu Diagnostik und Behandlung des fortgeschrittenen Mammakarzinoms (ABC) statt. Zur Vereinfachung wird im weiteren Text von ABC gesprochen, was im klinischen Alltag der metastasierten Brustkrebserkrankung oder der lokal weit fortgeschrittenen Erkrankung entspricht. Der inhaltliche Schwerpunkt lag dieses Jahr auf neuen Entwicklungen in der Behandlung des ABC. Diskutiert wurden unter anderem der Stellenwert der CDK4/6-Inhibition beim hormonrezeptor-(HR-)positiven ABC, die duale Antikörperblockade beim HER2-positiven ABC, die PARP-Inhibition beim BRCA-mutierten tripel-negativen und luminalen ABC sowie potenzielle therapeutische Konsequenzen. Ein weiterer Fokus lag auf dem BRCA-assoziierten Mammakarzinom, der Behandlung von Hirnmetastasen sowie der individualisierten Therapieentscheidung auf der Grundlage einer molekularen Testung (sog. Präzisionsmedizin). Wie schon in den vergangenen Jahren ist die Zusammenarbeit mit den Vertretern von Patientenorganisationen aus aller Welt ein wichtiges Anliegen der ABC-Konferenz. Sie wurde auf der ABC4-Konferenz weiter intensiviert. Im Anschluss an die Konsensuskonferenz wurde die „Global Alliance“ gegründet mit dem Ziel, die erforderlichen Maßnahmen aus Sicht der Patientenvertreterinnen weltweit zu propagieren und zu koordinieren. In den ABC-Konsensus fließen aufgrund des international zusammengesetzten Expertenpanels zwangsläufig länderspezifische Besonderheiten ein. Wie schon in den vergangenen Jahren hat daher eine Arbeitsgruppe deutscher Brustkrebsexperten, welche die Konsensusabstimmung der ABC-Panelisten vor Ort mitverfolgt und intensiv diskutiert haben, diese unter Berücksichtigung der deutschen Leitlinien zu Diagnostik und Therapie des Mammakarzinoms 1 , 2 für den Therapiealltag in Deutschland kommentiert. Die Abstimmungsergebnisse der ABC-Panelisten in Lissabon sind die Grundlage des ABC-Konsensus.

For two decades, HER2 has been an attractive therapeutic target. Anti-HER2 agents have transformed the care of HER2+ breast cancer and greatly improved its outcomes. However, treatment resistance remains a considerable clinical problem, and some patients still recur and progress despite optimal treatment. A particular challenge in advanced HER2+ breast cancer remains to be CNS metastasis. Special attention needs to be given to this devastating event given its serious sequelae, and its prevalence among patients battling this disease. As more agents are being approved in the early setting, improving outcomes in this setting, patients who suffer a recurrence may have more limited options and more resistant disease. The good news is that there is a number of anti-HER2 agents being explore in the advanced setting of HER2+ breast cancer. They fit into three major categories: new or optimized monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors. There is also great interest in studying other classes of agents in combination with anti-HER2 treatment, like immune-oncology agents, in this space. The plethora of agents being developed in this setting highlights the importance to understand more about potential mechanisms of resistance. This will help guide development strategies, deliver tailored treatment approaches, and design more effective agents and regimen. Resistance may be the end result of many possible molecular changes that mediate its emergence, and a variety of strategies are needed to elucidate them. That includes comprehensive in depth molecular profiling, as well as functional validation of detected alterations. Moreover, each tumor may have many underlying molecular changes in different cell sub-populations. It is therefore mandatory that development strategies for new agents and combinations should rely on clinical and biologic factors to help improve outcomes for patients with advanced HER2+ breast cancer. Citation Format: Rimawi M. Advanced HER2-positive breast cancer: Overcoming treatment resistance [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES1-3.

Purpose This systematic review aims to better define the limitations and patterns with which patients with MBC and CNS metastasis are enrolled into early phase developmental therapeutics trials. Methods In June 2016, PubMed search was conducted using the following keywords: “Breast cancer”. Drug-development phase 1, phase 2 or phase 1/2 trials for patients with MBC were included. Multiple-histology trials and trials without an efficacy endpoint were excluded. Results In total, 1474 studies were included; Inclusion criteria for 423 (29%) allowed for CNS metastasis, 770 (52%) either excluded or did not document eligibility of patients with CNS disease. Trials accruing patients with HER2-positive MBC and including targeted therapies had higher odds of allowing for patients with CNS disease (adjusted OR 1.56, 95% CI 1.08–2.2.6; p = 0.019 and 1.49, 95% 1.08–2.06; p = 0.014, respectively). There were also higher odds of accrual of patients with CNS involvement into clinical trials over time (odds ratio = 1.10, 95% CI 1.07–1.12; p Conclusion Most published early phase clinical trials either did not clearly document or did not allow for accrual of patients with CNS disease. Early phase trials with targeted agents or enrolling HER2+ MBC had higher odds of permitting CNS metastases.

To determine some of the key clinical features that help prompt clinicians to pursue additional work-up for evaluation of CNS involvement of MF, we conducted a systematic review to better define characteristics, treatments, outcomes, and mortality in these patients. Our analyses indicated that neurologic surveillance after the diagnosis of MF is crucial. Review of systems should include change in mentation, vestibular, and ocular symptoms. Progression to CNS involvement does not always occur in tandem with cutaneous disease burden. Single-agent therapies can delay disease progression and improve prognosis. Multi-agent treatment does not improve survival.

Leptomeningeal metastasis (LM), a spread of cancer to the meninges and cerebrospinal fluid, carries extremely poor prognosis due to fast progression and no effective treatment. Given that LM mostly develops in specific types of cancer, notably melanoma, breast and lung cancer, it is likely that predisposition for LMD is shaped by specific genetic footprints and/or anti-cancer therapies. In this regard, it is interesting that among all breast cancers the triple-negative (i.e. estrogen and progesterone receptor-negative and HER2 overexpression-negative) breast cancer (TNBC) type develops a disproportionally high percentage of LM, accounting for the majority (~40%) of all breast cancer LM cases. TNBCs trace their origin to the genomic instability stemming from defects in DNA repair (notably homology-directed repair, HDR). We have recently shown that the efficiency of HDR depends on dynamin 2 (DNM2) best known for its role in endocytic protein trafficking. Higher DNM2 was associated with more efficient HDR and the resistance to DNA-crosslinking chemotherapy. Importantly, elevated DNM2 was associated with lower relapse-free survival and shorter times to relapse after chemotherapy only in TNBCs and not in other types of breast cancer. As DNM2 also fuels migration and invasion, the cells with high DNM2 are not only the most resistant to chemotherapy but also are the most mobile, and thus may represent the core population of LM. Here we test the inhibition of the DNM2-dependent endocytic trafficking as a potential therapeutic strategy to halt LM in TNBC. As a model of LM we use the human-in-mouse model of brain metastasis based on internal carotid injection of MDA-MB-231-BR3 cells, which we have shown to faithfully recapitulate human LM. We show that DNM2 knockdown delays metastatic spread to the brain and potentiates the effect of DNA-crosslinking chemotherapeutic cyclophosphamide, providing justification for further testing of DNM2 inhibitors for targeted therapy of LM.

INTRODUCTION We aim to evaluate the use of stereotactic radiosurgery (SRS) among patients who received radiotherapy for melanoma brain metastases (MBM), and the associated outcomes. METHODS This is a population-based cohort of patients who received radiotherapy for MBM between 2013 and 2016, as captured in the Victorian Radiotherapy Minimum Dataset. Brain radiotherapy was classified as SRS (including multi-fraction stereotactic radiotherapy) and non-SRS. Mortality data was obtained through linkage with the Victorian Cancer Registry. The primary outcomes were: proportion of patients who had SRS for MBM, and overall survival (OS) following radiotherapy. Multivariate logistic regression was used to evaluate factors associated with SRS use, Kaplan Meier method for estimation of OS, and multivariate Cox regression for evaluation of factors associated with OS. RESULTS 294 patients received 551 courses of radiotherapy for MBM in this study, of which 39% (116/294) patients received SRS. Patients from higher socioeconomic status were more likely to have SRS – 49% in top quintile vs. 22% in lowest quintile (P< 0.009). Patients treated in regional centres were less likely to have SRS compared to metropolitan centres (3% vs. 48%,P< 0.001). In multivariate logistic regression, treatment in regional centres was the only factor independently associated with lower likelihood of receiving SRS (OR=0.04;95%CI=0.01–0.18;P< 0.001). The median follow-up of the cohort was 3.8 months (range: 0.1–42 months). There were 227 death observed, with 12-month OS of 23%. There was significant difference in 12-month OS between patients who received SRS compared to those who did not receive SRS (43% vs. 11%; P< 0.001). In multivariate Cox regression, the use of SRS was the only factor independently associated with OS (HR=0.38;95%CI=0.28–0.51;P< 0.001). CONCLUSION We observed sociodemographic and institutional disparities in SRS use for MBM. The observed impact of SRS use on OS is most likely confounded by patient selections for SRS.

Brain metastasis (BM) in patients with EGFR-mutant lung adenocarcinoma is a major determinant of overall survival. Novel insight into the genetic and epigenetic underpinnings of BM development is lacking. The aim of this study is to compare the methylome of EGFR-mutant primary lung adenocarcinoma (EGFRM-PLA) and matched BM to identify important alterations for the mechanisms of BM. Matched EGFRM-PLA and BM tumors from seven patients were profiled using the Illumina Infinium MethylationEPIC BeadChip array. Unsupervised clustering analyses of the 14 samples showed a similar whole DNA methylation signatures between EGFRM-PLA and BM tumors. Furthermore, PCA plot highlighted that seven matched BM and lung tumor samples were clustered together closely based on matching pairs for the most variable probes (2.5K to 10K). These observations indicate high level of concordance and the same cell of origin. However, these fourteen samples clustered into two groups based on tumor site being lung or brain based on 83K differentially methylated CpG sites. Of the 83K probes, 2.4K were either hypermethylated or hypomethylated in all lung samples. A quarter of these 2.4K probes were located in promoter regions. Specifically, we identified differences in methylation status of EGFR/ALK promoter regions in lung tumors versus BM. CNV analyses showed higher deep deletions of chromosomes and genes in BM compared to EGFRM-PLA. Leukocytes unmethylation for purity (LUMP) scores which indicate immune cell infiltration were similar between lung and BM pairs (Mean LUMP_score=0.64) consistent with high immune cell infiltration. Our results indicated a similar whole DNA methylation signature of EGFRM-PLA and matched BM, while comprehensive analysis identified important differentially methylated probes. Distinct differences in CNV alterations were observed in lung versus brain samples. The BM and EGFRM-PLA showed similar tumor purity and immune cell components. Overall, tumor methylation profiling provides clinically important information regarding biology of BM in EGFRM-PLA.

BACKGROUND AND PURPOSE To assess whether radiomics features on DTI and conventional postcontrast T1-weighted (T1C) images can differentiate the epidermal growth factor receptor (EGFR) molecular status in brain metastases from non-small cell lung cancer (NSCLC). MATERIALS AND METHODS Radiomics features (n = 5046) were extracted from preoperative MRI including T1C and DTI from pathologically confirmed brain metastases of 59 patients with underlying NSCLC and known EGFR mutation status (31 EGFR wild type, 28 EGFR mutant). A subset of 4317 features (85.6%) with high stability (intraclass correlation coefficient > 0.9) were selected for further analysis. After feature selection by the least absolute shrinkage and selection operator, the radiomics classifiers were constructed by various machine learning algorithms. The prediction performance of the classifier was validated by using leave-one-out cross-validation. Diagnostic performance was compared between multiparametric MRI radiomics models and single imaging radiomics models using the area under the curve (AUC) from ROC analysis. RESULTS Thirty-seven significant radiomics features (6 from ADC, 6 from fractional anisotropy [FA], 25 from T1C) were selected. The best performing multiparametric radiomics model (AUC 0.97, 95% CI 0.94–1) showed better performance than any single radiomics model using ADC (AUC 0.79, p = 0.007), FA (AUC 0.75, p = 0.001), or T1C (AUC 0.96, p = 0.678); the accuracy, sensitivity, and specificity of this model were 94.4%, 96.6%, and 92.0%, respectively. CONCLUSION Radiomics classifiers integrating multiparametric MRI parameters may be useful to differentiate the EGFR mutation status in brain metastases from lung cancer.

INTRODUCTION Brain metastases are widely held to reach the CNS through the blood stream. We provide evidence that the initial site of most CNS metastases is the CSF, with subsequent invasion of brain parenchyma. We also model the therapeutic implications of this novel hypothesis. METHODS Two neuro-radiologists independently assessed whether brain metastases were contiguous with CSF spaces in 200 consecutive patients using pre-treatment MRI. CSF was examined for malignant cells in 66 newly diagnosed, previously untreated patients. We contoured normal brain MRIs of 3 patients to calculate the percentage of brain within 5 mm of a CSF space. We queried an international neoplastic meningitis database to document response of brain metastases to intra-CSF chemotherapy. RESULTS Mean age was 64.2. One hundred patients were male; 143 had lung cancer, 15 melanoma, 12 gastrointestinal, 11 breast, 9 renal, 7 bladder. Mean number of metastases was 4.63. Eighty-five percent of metastases touched a CSF space. In 67% of patients, all metastases touched a CSF space. Neither histology, number or size of metastases, nor patient age predicted contiguity with CSF spaces. In our consecutive subset of patients, 44% (10/23) with one, 46% (5/11) with two, 63% (5/8) with three, and 71% (17/24) with >3 metastases had malignant cells in the CSF (R2=0.93, p=0.037). Five of 7 patients with both brain and CSF metastases receiving only IT chemotherapy experienced a substantial reduction in the size of at least some metastases. Up to 75% of the brain parenchyma lies within 5 mm of CSF spaces. CONCLUSIONS Our data suggest that brain metastases may access the CNS through the CSF rather than the bloodstream. IT chemotherapy may treat brain metastases. We suggest that the CSF should be monitored in all patients with, or at risk for, brain metastases. True cures may require treatment of the CSF space.

Leptomeningeal metastases (LM) is associated with limited survival and treatment options for patients with solid tumor malignancies. While focal radiotherapy is effective for local palliation, it lacks durability due to cerebrospinal fluid (CSF) tumor cells reseeding. Craniospinal irradiation (CSI) in contrast treats the entire central nervous system (CNS) compartment thus potentially improves disease control. We performed a phase IB study of proton CSI using 30CGE in 10 fractions for treating solid tumor LM (NCT03520504). The primary end point is dose-liming toxicity (DLT) within 1 month of treatment. Clinical outcomes and CSF circulating tumor cells (CTCs) by CellSearch® were evaluated. Overall (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier estimates. Of the 24 patients enrolled, 4 were excluded from analysis: 3 did not complete treatment due to CNS or systemic disease progression (PD), and 1 completed treatment outside study window. The majority of patients had metastatic lung (55%) and breast (30%) malignancies. At this submission, the median follow-up was 2.8 months (0.5–9.4 months). No DLT was observed. Treatment-related grade 2+ toxicities were: fatigue (G2=43%), anorexia (G2=5%), anemia (G2=10%), thrombocytopenia (G3=5%, G2=10%), and leukopenia (G3=14%, G2=14%). Median survival is not reached with 17 patients (85%) alive with stable/improved LM including 2 with durable CNS control for >9 months, 1 patient alive with CNS and systemic PD at 3.7 months, 2 patients died at 3.6 and 5.1 months with CNS and systemic PD. At 3-month, OS and PFS were 100% and 90% (95% CI 100–72%), respectively. In the 13 patients with CSF CTCs evaluation, decreased quantifiable CTCs at 1-month after proton CSI correlated significantly with improved CNS PFS (log-rank p=0.014). These early findings suggest that proton CSI is a safe and potentially effective treatment for patients with solid tumor LM. CSF biomarkers assessment is needed to better elucidate predictors of response.

INTRODUCTION Despite increasing use of stereotactic radiosurgery (SRS) for management of brain metastases (BM), published Australian data is scarce. We aim to report on the outcomes following SRS for limited BM in a single Australian institution. METHODS This is a retrospective cohort of patients with limited BM treated with SRS between August 2015 and March 2019. A dose of 24Gy/3# were prescribed to intact lesion, and 21Gy/3# to surgical cavity post-surgical resection. All patients were followed with 3-monthly surveillance MRI brain. Primary outcomes were: local failure (LF: increased in size of SRS-treated BM lesion/ recurrence in surgical cavity), distant failure (DF: intracranial progression outside of the SRS-treated lesion/ cavity), and overall survival (OS). LF, DF and OS were estimated using the Kaplan-Meier method. Multivariate Cox regressions were used to evaluate factors associated with outcomes of interest, with death as competing-risk events for LF and DF. RESULTS 76 courses of SRS were delivered in 65 patients (54 unresected BM lesions, and 22 surgical cavities). 43 (66%) patients were ECOG 0–1. 35 (54%) patients had solitary BM. 41 (63%) had symptomatic BM. Half of the patients had primary lung cancer. Median follow-up was 4.8 months (range:0.1–39 months). 10 LF were observed at a median of 3.5 month post-SRS, with 6- and 12-month LF cumulative incidence of 14% and 24% respectively. 30 DF were observed at a median of 3.3 months, with 6- and 12-month DF cumulative incidence of 38% and 63% respectively. The 12- and 24-month OS were 39% and 26% respectively. In multivariate analyses, better ECOG status, solitary BM lesion, resection of BM pre-SRS, and use of subsequent systemic therapy were independently associated with improved OS. CONCLUSION This is one of the few Australian series reporting on outcomes following SRS for limited BM, with comparable outcomes to published international series.

BACKGROUND The prognosis for neoplastic meningitis (NM) remains dismal and single-agent (rather than multi-agent) chemotherapy remains the standard of care. Objective: To analyze survival of patients with NM receiving multi-agent vs. single-agent intrathecal chemotherapy and evaluate the safety of antitumor intrathecal biological agents. METHODS We compared a standardized multi-agent intrathecal treatment cohort to the corresponding patient level data acquired from 6 of the 7 randomized controlled trials (RCTs) conducted in patients with NM, all of which used single-agent intraventricular therapies. The toxicity of intrathecal biological agents was studied by analyzing the outcome data form patients with NM treated with at least 1 intrathecal biological drug. RESULTS 283 patients receiving multi-agent therapy were compared to 290 patients from the RCTs. Patients and tumor characteristics did not differ between groups. All patients from the multi-agent patient group were included in an intent-to-treat model. For all solid tumors, median survival (multi-agent vs. single-agent treatment) was 211 vs. 97 days, hazard ratio (HR) 3.39, p< 0.001. For lymphoma, survival was 304 vs. 81 days, HR 2.10, p< 0.001. Stratified by tumor histology, median survival for breast cancer NM was 315 days [95% CI 248–449], for lung cancer 193 days [127- 200]; for melanoma 307 days [65–1492], and for primary brain tumors 253 days [187- 348]. No additional toxicity was seen in the multi-agent compared to the single-agent treatment groups. In 110 patients, grade III toxicity occurred in 5.3%, 3.1%, 0% and 0% of patients receiving rituximab, trastuzumab, panitumumab, and alpha interferon. No difference in survival was seen when comparing patients with and without treatment related toxicity in any histological groups. CONCLUSION Multi-agent intraventricular chemotherapy was associated with dramatically increased survival in patients with solid tumor and lymphomatous NM. Incorporating biologic agents as part of a multi-agent intrathecal treatment regimen is very safe.

PURPOSE Immune checkpoint inhibitors (ICIs) are approved for the treatment of non-small cell lung cancer (NSCLC), but the safety and efficacy of the combined treatment with ICIs and gamma knife radiosurgery (GKS) remain undefined. METHODS We retrospectively reviewed the medical records of patients with brain metastases from NSCLC who were treated with ICIs between January 2015 and December 2017 at our institute. Of the 134 patients identified, 77 who were assessable for brain responses were categorized into three groups based on the medication administered and GKS: Group A, ICI alone; Group B, ICI with concurrent GKS within 14 days; and Group C, ICI with non-concurrent GKS. RESULTS The median follow-up duration after the diagnosis of brain metastases was 19.1 (range, 1–68.7) months. At the last follow-up, 48 patients (62.3%) died. The overall survival was shorter in Group A than in Groups B and C (P=0.001). There were no statistically significant differences in the intracranial disease progression-free survival (P=0.514), local progression-free survival (P=0.358), and complication rates among the three groups. Twelve patients presented with leptomeningeal seeding (LMS) during follow-up. There was a significant difference in the LMS-free duration from the time of administering ICIs (P=0.011) and the diagnosis of metastasis (P< 0.001). CONCLUSION GKS in combination with ICI showed no favorable overall survival outcome in the treatment of brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS.

Leptomeningeal metastasis (LM) is a late stage manifestation of advanced breast cancer frequently managed with whole brain radiotherapy (WBRT) and/or intrathecal chemotherapy. A subset of breast cancer patients who undergo stereotactic radiosurgery (SRS) for limited brain metastases (BM) ultimately develop LM. We hypothesized that this subset of high-risk patients may be identified by patient, disease, and/or treatment parameters. Clinical records from 133 breast cancer patients from a single institution who underwent SRS for BM between February 2010 and March 2018 were retrospectively analyzed. Variables including histopathology, BM features, systemic disease burden, and prior treatments were analyzed. Cumulative incidence rates were estimated with death as a competing risk. Dichotomous variable cutoffs were based on the 75th percentile value. In our cohort, 27 (20.3%) patients ultimately developed LM. With a median follow up of 21.2 months after diagnosis of BM, the actuarial rate of LM at 24 months was 15.2% (95% CI, 8.7%-21.7%). Median OS after diagnosis of LM was 7.0 (95% CI, 3.1–15.4) months. There was significantly increased risk of LM with ≥9 vs < 9 BM at BM diagnosis (28.1% vs 10.8% [24-month actuarial risk], subdistribution HR 2.4, p=0.027), and ≥11 vs < 11 cumulative number of BM treated (25.7% vs 11.7% [24-month actuarial risk], subdistribution HR 2.7, p=0.01). Variables not significantly associated with the risk of LM included tumor receptor status (ER, PR, HER2, triple negative), graded prognostic assessment, KPS, extracranial metastases, total BM volume, prior WBRT, or prior surgical resection. Time intervals between SRS treatments immediately preceding LM diagnosis was not significantly different from other time intervals. In conclusion, patients with a larger number of brain metastases at BM diagnosis (≥9) or cumulatively treated (≥11) appear to be at higher risk of developing LM and may benefit from stronger consideration of WBRT, intrathecal chemotherapy, and/or brain-penetrating systemic therapy.

BACKGROUND Pituitary gland metastasis is a rare disease which represents only 1% of pituitary gland lesions. Intracranial solitary pituitary metastasis tends to be misdiagnosed as pituitary adenoma, resulting in a delayed anti-tumor treatment. METHODS Five cases of patients with pituitary gland metastasis recorded between 2014 and 2018 in our hospital were investigated with reference to patient demographics, symptoms at presentation, radiological and histological findings, management and outcomes. RESULTS Five patients (4 male and 1 female) were included and the median age was 48 years (range: 21 to 66). In those five cases, central nervous system related symptoms were the first sign of malignancy, including visual loss (5 in 5 patients), visual field defects (5 in 5 patients), apituitarism (5 in 5 patients), headache (4 in 5 patients), hypothroidism (4 in 5 patients) and diabetes insipidus (2 in 5 patients). All patients received total or partial hypophysectomy and pathologically revealed metastatic adenocarcinoma in 4 patients and metastatic squamous carcinoma in 1 patient. Further examinations by Computed Tomography (CT) or Positron Emission Computed Tomography (PET) indicated lung as primary site in five cases. EGFR mutation and ROS1 fusion were found in 3 and 1 adenocarcinoma patient, respectively, through gene detection of tissue. Postoperative radiotherapy (5 patients), target therapy (4 patients) and chemotherapy (1 patient) were given as subsequent treatment. During the follow-up, four patients died and the overall survival was 2, 8, 28 and 30 months, respectively. CONCLUSION We found that pituitary symptoms usually presented as the first sign of malignancy in intracranial solitary pituitary metastasis. Lung is the most frequently primary site, particularly in adenocarcinoma with driver gene mutation. Patients may benefit from multidiscipline treatment, including resection of pituitary metastasis combined with radiotherapy and targeted therapy.

INTRODUCTION NM is defined clinically by multilevel neurologic dysfunction. Seizures occur in less than 15% of patients. We describe a curable phenomenon (“plateau wave events”) that mimics and may be more common than seizures, but is not responsive to anticonvulsant medication. METHODS We queried a multinational NM registry to identify patients with episodic neurologic dysfunction suspected of having seizures. Detailed demographic, disease, treatment, and outcome data were collected. RESULTS Forty-three patients (21.2% of 203) were identified. Twenty patients (46.5% of 43) demonstrated a stereotyped constellation of symptoms including episodic severe headache and loss (19 patients) or impaired level (1 patient) of consciousness, nausea, vomiting, and gait instability lasting 30–180 seconds, with abrupt resolution and without post-ictal symptoms. Events developed a median of 74 (0–350) days following NM diagnosis. Fourteen patients (74%) were female. Median age was 54.8 [IQR 46.8, 61.6] years. Fourteen patients had solid tumors (11 breast), 5 had hematologic malignancies, and 1 had a primary brain tumor. Thirteen (68%) had ventriculomegaly. All patients demonstrated increased ICP [median 30.0 cm H2O, IQR 22.5, 30.0]. CSF cytology was positive and CSF protein was increased in 100% of patients, but no demographic, laboratory, or disease characteristic was associated with plateau wave events on multivariate analysis. Inter-ictal EEG in 8 patients showed no epileptiform activity. One intra-ictal EEG showed marked brainwave slowing and bradycardia during the clinical event. One intra-ictal ICP tracing showed an abrupt and dramatic increase in intracranial pressure during the event. Nineteen patients underwent ventriculoperitoneal shunting and experienced immediate symptom resolution. Anticonvulsant medication, initiated in 11 of these patients prior to shunting, provided no benefit. CONCLUSIONS Plateau wave events are common in patients with NM. They are frequently mistaken for seizures but are easily recognized by a constellation of defining signs and symptoms. Ventriculoperitoneal shunting is curative.

INTRODUCTION Gliosarcoma is a rare variant of glioblastoma that accounts for approximately 0.48% of all adult brain tumors. Although, metastatic potential of gliosarcoma via hematogenous route has been proposed in the past, we report the first case of metastasis to the sacrum while undergoing treatment on bevacizumab. CASE REPORT: A 40-year-old woman presented with acute onset severe headache with pertinent examination findings of left upper extremity pronator drift. Imaging revealed right frontal lobe enhancing mass measuring 4.5 x 3.7 cm associated with edema and 10 mm leftward midline shift. A right frontal craniotomy for tumor debulking showed gliosarcoma (IDH wild-type, WHO grade 4). She was initiated on radiotherapy with concomitant and adjuvant temozolomide via Stupp’s protocol after second debulking surgery. Chemotherapy regimen was changed to bevacizumab when tumor progression was identified. Within six months of initiation of bevacizumab, she developed left leg shooting pain. Imaging revealed heterogeneously enhancing mass in the left hemisacral region measuring 6.2 cm concerning for metastatic process. Sacral bone biopsy showed malignant cells which were negative for an extensive immunohistochemical panel (including GFAP and Olig2), suggesting metastasis of the sarcomatous element of gliosarcoma and arguing against a second malignancy. Next generation sequencing performed on both the intracranial and sacral tumor showed an identical molecular prolife (including PTEN, NF1, TERT and TP53 genomic alterations), confirming common origin. After completion of radiation therapy to sacral region, chemotherapy regimen included lomustine followed by pembrolizumab. The patient died at 14 months after initial presentation due to disease progression. DISCUSSION To the best of our knowledge, this is the first case primary of gliosarcoma with metastases to the sacrum while evolved on chemotherapy with bevacizumab. The aim of this report is to bring awareness to medical community in order to expedite the diagnosis and management.

BACKGROUND Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.

OBJECTIVE To study whether the neurocognitive functions were affected by brain metastases in patients, and what are the potential risk factors. METHODS A total of 172 patients with brain metastases were retrospectively analyzed. Prior to radiotherapy of brain metastases, the neurocognitive functions were evaluated by a wide range of tests including MOCA, VFT, HVLT-R, TMT-A, TMT-B and TOL. Kappa test was used to analyze the consistency of physical examination and neurocognitive assessment results. The related factors were analyzed with univariate and multivariate analysis. RESULTS 53 out of 172 patients (30.8%) were identified with cognitive impairments by physical examination. The assessment with neurocognitive scales revealed that there were 148 cases of cognitive impairment (86.0%) and 24 cases of normal cognition (14.0%). Kappa=0.025, indicating that the difference between neurocognitive assessment results and physical examination was significant. The univariate analysis on the factors related to neurocognitive impairment revealed that the risk factors that may affect the neurocognitive functions included age, KPS, m-GPA score, RPA classification, whether the original tumor was under control, with or without brain metastases. After adjusting for education, the multivariate analysis showed that age≥45 years old, KPS≤70, RPA classification >2 and m-GPA score< 3 were independent risk factors for neurocognitive impairment. CONCLUSION Patients with brain metastases were found to have various degrees of neurocognitive impairment prior to radiotherapy. The neurocognitive functions of patients can be more precisely evaluated by a comprehensive scale assessment. Age, KPS, RPA classification and m-GPA score are the main factors associated with neurocognitive impairment.

BACKGROUND Capmatinib is a highly potent, selective MET-inhibitor known to cross the BBB, and intracranial activity with capmatinib has been previously reported. Updated results for overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and brain metastases (BM) activity from the GEOMETRY mono-1 study are presented here. METHODS GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in METΔex14-mutated or MET-amplified NSCLC patients. Patients (≥18 years) with ECOG PS 0–1, ALK-/EGFR-wt, and stage IIIB/IV NSCLC were eligible. Patients with asymptomatic BM were allowed. METΔex14-mutated patients were assigned to Cohorts 4 (1–2 prior lines of treatment) and 5b (treatment-naive) and received capmatinib 400mg BID. Endpoints by BIRC: ORR (primary, RECIST v1.1), DOR, and PFS. Ad hoc BIRC neuro-radiologic assessments of all Cohort 4 and 5b patients with baseline BM were performed. RESULTS As of April 15, 2019, 97 patients (Cohort 4: 69 patients; Cohort 5b: 28 patients) were evaluable for efficacy. BIRC assessments: ORR (95%CI): 40.6% (28.9–53.1) in Cohort 4; 67.9% (47.6–84.1) in Cohort 5b. Median DOR (95%CI): 9.7 (5.55–12.98) and 11.1 (5.55-NE) months and median PFS (95%CI): 5.4 (4.17–6.97) and 9.7 (5.52–13.86) months for Cohorts 4 and 5b, respectively. Of 13 evaluable patients with BM at baseline, 7 (54%) had intracranial response by BIRC, including 4 patients with complete resolution of brain lesions, and 12/13 had intracranial disease control. Responses in the brain were as fast as systemic responses. Most common treatment-related AEs (≥15%, all grades) across all cohorts (N=334): peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%); most AEs were grade 1/2. CONCLUSION These data confirm capmatinib to be a promising new treatment option for patients with METΔex14-mutated advanced NSCLC regardless of line of therapy, with deep and durable responses including in patients with brain metastases, and a manageable toxicity profile.

BACKGROUND Patients with multiple large brain metastases (LBMs) are subject to cause intracranial hypertension, which remains a clinical difficulty so far. The present study is to investigate whether staged stereotactic radiosurgery (SRS) is a feasible solution to improve clinical symptoms and life quality in palliative management. METHODS Patients with brain metastases treated between 1 January 2016 and 30 March 2019 were retrospectively studied. The patients inclusion criteria included were: 1) metastatic lesions ≥ 3; 2) tumor lesions with a supratentorial invasion ≥ 3 cm or a subtentorial invasion ≥ 2 cm; 3) with neurological impairment or with a high risk for intracranial hypertension. The first stage of SRS dose regimens for utmost risk supratentorial lesions were 20-24Gy within 2-fractions (fx); whereas 24Gy/3-fx for subtentorial lesions. For the 2nd stage, the rest metastatic lesions with relatively lower risk were treated with 16-18Gy/1-fx one week after that. RESULTS A total of 30 patients were enrolled included in this study. The neurological symptoms were significantly relieved following 1st stage of SRS, with a median period of 3 days (2–14 days). 13 out of 30 patients were randomly selected for MR imaging two weeks after SRS. It suggested that 84.6% (11/13) of the patients were observed with a clear reduction of tumor volume. The median reduced diameter was 0.38 (0.17–0.83) cm and a median volume reduction was 3.22 (0.01–9.08) mm3. According to RANO-BM, the objective remission rate of utmost risk lesions was 100%, whereas the less critical lesions was 95.16% (59/62). One patient (3.33%) was identified with acute adverse reaction (> grade 3). CONCLUSIONS Staged SRS with a priority for utmost risk lesions was indicated to be an effective approach for multiple large brain metastases. Further prospective study is highly warranted.

INTRO/OBJECTIVE Immune checkpoint inhibitors (ICI) have improved outcomes in a subset of patients with lung cancer. However, data describing the efficacy of ICI in lung cancer brain metastasis (LCBM) is limited. We analyzed overall survival (OS) in patients with LCBM treated with upfront ICI, defined as having received ICI within 90-days of LCBM diagnosis, compared to non-ICI therapies. METHODS We reviewed 665 patients with LCBM diagnosed between 2000 and 2018 at a major tertiary care institution. Of those patients, 240 received ICI, 164 of which received ICI after 90-days and 76 received ICI within 90-days. Propensity score (PS) was calculated by logistic regression model including age, KPS, number of baseline brain lesions, and presence of extra-cranial metastasis (ECM) at time of LCBM diagnosis. OS from LCBM diagnosis between PS matched cohorts were compared using Kaplan-Meier, the Log-Rank test, and Cox proportional hazards models. RESULTS Prior to PS matching, median survival between ICI and non-ICI cohorts was not significantly different (10.9 months for both, p=0.81), although more ICI patients had ECM (57.1% vs 40.9%, p=0.006). Following PS matching, the ICI (n=76) and non-ICI (n=76) cohorts had median age (62.4 vs 62.3 years), KPS (80 for both), lesion number (2 for both), and ECM (56.6% for both). Of matched patients, 94% received SRS, 52% received WBRT, and 29% underwent surgical resection. Compared to non-ICI, the ICI cohort had a 2-year OS hazard ratio=0.87 (95% CI=0.58–1.31, p=0.51). Median and 1-year survival were not significantly different between ICI and non-ICI cohorts (median: 10.9 vs 9.1 months; 1-yr: 43.0% vs 42.4%). CONCLUSION Patients with LCBM who received ICI within 90-days of their diagnosis did not have improvement in OS compared to patients who received non-ICI therapies. Evaluation of clinical factors that may affect the efficacy and durability of immunotherapy is ongoing and will be presented.

INTRODUCTION We aim to evaluate the use of stereotactic radiosurgery (SRS) among lung cancer (LC) patients who received radiotherapy (RT) for brain metastases (BM), and the associated outcomes. METHODS This is a population-based cohort of LC patients who received RT for BM between 2013 and 2016, as captured in the Victorian Radiotherapy Minimum Dataset. Brain RT was classified as SRS (including multi-fraction stereotactic RT) and non-SRS. Mortality data was captured through data linkage with the Victorian Cancer Registry (VCR). The primary outcomes were: proportion of patients who had SRS for BM, and overall survival (OS) following brain RT. Multivariable logistic regression was used to evaluate factors associated with SRS use. Kaplan-Meier method was used to estimate OS. Multivariable Cox regression was used to evaluate factors associated with OS. RESULTS 1,002 LC patients were included in the study. 1,395 courses of RT for BM were delivered, of which one quarter (362/1,395) were SRS. Almost all SRS were delivered in metropolitan centres (347/362), and two-third in public institutions (235/362). In multivariate logistic regressions, increasing age (OR=0.91;95%CI=0.82–0.99;P=0.04) and treatment in regional centres (OR=0.13;95%CI=0.06–0.28;P< 0.001) were independently associated with lower likelihood of SRS use. Median follow-up was 3.3 months (IQR=1.3–7.8 months). 876 deaths were observed with 12-month OS of 16%. The 12-month OS for patients who had SRS were 38% vs. 12% in patient did not have SRS (P< 0.001). In multivariable Cox regressions, the use of SRS (HR=0.44,95%CI=0.37–0.54;P< 0.001) and female (HR=0.76;95%CI=0.67–0.87;P< 0.001) were associated with improved OS, while increasing age was associated with worse OS (HR=1.02;95%CI=1.01–1.03;P< 0.001). CONCLUSION This is the largest Australian study reporting on SRS use for BM in LC patients. We observed geographical variations in SRS use. We believe the impact of SRS use on OS is most likely due to patient selection for SRS.

BACKGROUND This retrospective study evaluated the relationship between histologic subtype and treatment outcomes following SRS for the treatment of multiple brain metastases (MBM). METHODS We analyzed patients with MBM, defined here as >= 3 lesions, treated with SRS at our institution. Primary histologies examined were NSCLC, breast, and melanoma. Patients were categorized according to histology-specific subtypes (NSCLC-EGFR, ALK, KRAS, PD-L1%; breast-HER2, ER, PR; melanoma-BRAF). The primary outcome was local control (defined by RANO-BM) and secondary outcomes included intracranial progression-free survival (iPFS) and overall survival (OS). RESULTS 141 patients met inclusion criteria (66 NSCLC, 61 breast, and 14 melanoma). HER2+ and BRAF V600E+ lesions had increased rates of local control following SRS (P=0.0048 and P=0.0256, respectively) compared to other breast/melanoma subtypes. EGFR mutation was not associated with increased local control with SRS (71 vs 74%), but increased iPFS (P=0.0031). On multivariable analysis, EGFR+ was independently associated with a decreased time-dependent risk of death (P=0.011). The use of progressively newer generations of EGFR-directed therapies was associated with stepwise decreasing risk of intracranial progression and death. HER2+ disease had improved iPFS and OS (P=0.0058 and P< 0.0001, respectively; it was not an independent risk factor for progression or death; however, the use of HER2-directed antibodies was associated with decreased risk of death (p=0.036). The use of tyrosine kinase inhibitors (i.e. lapatanib) was not associated with improvements, although this was a small subset. CONCLUSIONS Some histologic subtypes appear to have better control with SRS, with HER2+ breast cancer and BRAF V600E+ melanoma associated with improved outcomes – this requires further validation; a volumetric analysis is pending. This the protective effect of EGFR mutation appears to be partly related to use of EGFR inhibitors, with the use of newer-generation therapies leading to improved outcomes; although local control with SRS remains excellent regardless of the mutation.

INTRODUCTION CSF cytology and neuraxis MRI scanning are complementary examinations for diagnosing NM. Positive cytology is the current gold standard despite relatively low sensitivity. Although MRI is an accepted alternative diagnostic tool for both treatment and clinical trial inclusion, its sensitivity and specificity are poorly understood. METHODS We conducted an exhaustive, PRISMA-compliant systematic review of the literature from January 1990 to September 2016 comparing MRI to CSF cytology (the gold standard) for the diagnosis of NM. Relevant studies were assigned a level of evidence using AAN criteria. Pre-specified data was extracted, and summary statistics were calculated using the inverse variance method and random effects model. Survival of patients diagnosed with various combinations of CSF cytology and MRI was also extracted and summary statistics were calculated. RESULTS Thirteen studies (2 class-I, 5 class-II, 5 class-III, 1 class-IV, 1646 solid and hematologic tumor patients) provided data sufficient to calculate the diagnostic characteristics of MRI. Sensitivity and specificity were low (63.4% [56.5–71.2] and 40.1% [30.2–53.1] respectively). False positive and false negative rates were high (59.9% [46.9–69.8] and 36.6% [28.8–43.5] respectively). Various sensitivity analyses (recent studies, class I/II studies, only class I studies, specific tumor histologies) yielded very similar results. Overall survival in patients with MRI (+)/CSF (+), MRI (+)/CSF (-), and MRI (-)/CSF (+) disease (3 studies, 347 patients) were 50.8 [39.8–64.8], 115.4 [70.4–189.4] and 228.7 [130.5–400.7] days respectively (p < 0.001). CONCLUSIONS MRI scanning can diagnose leptomeningeal metastases, but is a very poor surrogate for CSF cytology. Patients with NM diagnosed by various combinations CSF cytology and MRI positivity have dramatically different survivals, suggesting that these categories define subsets of patients with NM with different natural histories. This finding has important implications for patient care and clinical trial design and interpretation. Novel diagnostic strategies for NM should be subjected to similar analysis.

INTRO Programmed cell death protein 1 (PD1)-inhibitor, nivolumab, and cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-inhibitor, ipilimumab, have been shown to be efficacious in treatment of metastatic renal cell carcinoma (RCC). Clinical trials utilizing PD1- and CTLA4-inhibitors to treat RCC have demonstrated an increase in survival, however history of brain metastases (BM) has typically excluded patients from these trials. This study evaluated the benefit of these agents in terms of overall survival from RCC diagnosis (OSRCC), from BM diagnosis (OSBM) and frequency of BM occurrence in patients with metastatic RCC. METHODS A retrospective single-center review between 2011–2018 identified 1149 patients treated for RCC. The study group included patients who received immunotherapy and/or non-immunotherapeutic agents during the course of their disease. Data analyzed included demographic information, systemic treatments, OS and status of BM. Two-sided Fisher’s exact test was used to evaluate frequency of BM occurrence. OSRCC and OSBM were assessed using Kaplan-Meier curves and log-rank tests. RESULTS Of 1149 patients, 425 (35.6%) were treated with systemic therapies during their clinical course and divided into two treatment groups: those receiving immunotherapy (n=125) and those receiving non-immunotherapeutic agents (n=300). OSRCC was improved in the immunotherapy group (80.3months 95%CI 58.7–101.9 vs 45.0 95%CI 36.4–53.6, p=0.003), with 1-, 3- and 5-year survival of 93.6%, 74.2% and 62.6%. BM were diagnosed in 113 of 425 patients. Use of immunotherapy was associated with increased OSBM (21.7months vs 8.5, p=0.001). In patients receiving systemic treatment prior to a potential BM diagnosis, BM occurred at a frequency of 8.0% in the immunotherapy group compared to 17.7% for the control (n=100 and n=266 respectively, p=0.021). CONCLUSION Immunotherapy not only improves OSRCC and OSBM, but also decreases the incidence of BM in patients with metastatic RCC. Prospective clinical trials are needed to further evaluate the activity of immunotherapy in treatment of RCC BM.

BACKGROUND Urothelial carcinoma is a common malignancy with ~79,000 new cases diagnosed annually. However, urothelial brain metastases (UBM) are encountered uncommonly. Herein we evaluate their national prevalence, predictors, and treatment outcomes in the contemporary era. METHODS The characteristics, management, and overall survival (OS) of UBM patients (2010–2015) were evaluated using the National Cancer Database, which comprises >70% of all newly diagnosed cancers in the U.S. OS was analyzed with Kaplan-Meier methods and log-rank tests. National outcomes were compared to our institutional cohort of UBMs. RESULTS Out of 208,600 patients diagnosed with urothelial carcinoma, 8.4% presented with stage IV disease--of these only 216 (1.2%) had BMs at the time of diagnosis. Patients presenting with bone, liver, or lung metastases were more likely to present with synchronous BMs. Brain involvement demonstrated significantly worse median OS (3.9mos, 95%CI: 3.1–4.9) than non-BM stage IV disease (10.9mos, 95%CI: 10.6–11.2, p< 0.001). Compared to non-BM stage IV disease, UBMs were more likely to have surgery for metastatic disease and receive radiotherapy (p< 0.001); but were less likely to have primary resection or chemotherapy. In multivariable analysis of stage IV urothelial cancer, BMs demonstrated significantly worse OS (HR 1.43, 95%CI: 1.20–1.72, p< 0.001). In our institutional data, 10 urothelial cancer patients developed BMs; of which 7 were male, median age and KPS at diagnosis were 64.9yo (IQR 56.4–72.0) and 85 (IQR 75–100). Four patients had synchronous metastases; the median number of BM lesions was 2 (IQR 1–2), with a median size of 2.6cm (IQR 1.6–3.3). All 10 underwent GTR, 3 also with SRS and 7 with WBRT, associated with a median OS of 16.5mos. CONCLUSIONS Our results confirm the rarity of UBMs and suggest that BM screening may only be indicated in stage IV patients with neurological symptoms. Systemic therapies demonstrate improved OS in these patients.

Wenjun Yu,1,* Mengya Si,2,* Li Li,3,* Ping He,4 Zhiqiang Fan,4 Qiaoxin Zhang,2 Xiaoyang Jiao4 1Department of Hematology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, People’s Republic of China; 2Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, People’s Republic of China; 3Obstetrics Department, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, People’s Republic of China; 4Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyang JiaoDepartment of Cell Biology and Genetics, Shantou University Medical College, 22 Xinling Road, Guangdong 515041, People’s Republic of ChinaEmail xyjiao@stu.edu.cnObjective: We aimed to identify the biomarkers in cerebrospinal fluid (CSF) that facilitate the diagnosis of lymphomas with central nervous system (CNS) involvement.Methods: Four cases of non-Hodgkin’s lymphoma (NHL) patients with/without CNS involvement were enrolled respectively, and non-CNS tumor patients (n=3) were selected to be the controls. Lab biomarkers, cytokines, and tight junction proteins (TJs) in CSF and serum were measured.Results: When comparing the CNS to non-CNS group, cytokine including MMP-9 (15.24 vs 0.36 ng/mL), CCL-2 (1922.04 vs 490.68 pg/mL), and sVCAM-1 (61.36 vs 9.00 pg/mL), TJs including OCLN (6.68 vs 2.59 pg/mL), and ZO-1 (710.04 vs 182.98 pg/mL) in CSF were significantly higher in lymphomas patients with CNS involvement than those without CNS involvement. However, serum biomarkers were not significantly elevated. Contrary to the major findings, all conventional biomarkers and MRI results showed no significant change.Conclusion: CSF biomarkers affecting BBB disruption are valuable in mirroring the risk of lymphoma CNS metastasis. Further study with a larger sample size is needed to verify these biomarkers in predicting lymphoma CNS involvement.Keywords: lymphoma, CNS metastasis, cytokines, tight junction protein