Brain Metastases Of Carcinoma Research Articles

Single-cell atlas profiling revealed cellular characteristics and dynamic changes after PD-1 blockade therapy of brain metastases from laryngeal squamous cell carcinoma.

Brain metastasis (BM) in laryngeal squamous cell carcinoma (LSCC) is uncommon but prognosis is poor. Anti-PD-1 immunotherapy benefits some advanced LSCC cases, yet its efficiency is limited by tumor complexity. We analyzed paired metastatic tumor samples from before and after immunotherapy using single-cell RNA sequencing (scRNA-seq), along with a primary LSCC dataset and bulk RNA sequencing. This identified changes post-immunotherapy and revealed differences in single-cell transcriptomes among LSCC, primBM, and neoBM. Our findings show that anti-PD-1 treatment suppresses metastasis-promoting pathways like VEGF and EMT in cancer cells, and alters immune cell functions. Notably, it upregulates T cell activation, leading to CD8 T cell exhaustion from excess heat shock proteins, notably HSPA8. However, CD8 T cell cytotoxic functions improve post-treatment. In myeloid cells, anti-PD-1 therapy enhances antigen presentation and promotes a proinflammatory shift post-metastasis. Additionally, NUPR1 is linked to BM in LSCC, and NEAT1 is a potential metastatic cancer cell cycle participant. Our study provides insights into cancer heterogeneity and the impact of PD-1 immunotherapy on metastasis, aiding precise diagnosis and prognosis.

The landscape of cancer-associated transcript fusions in adult brain tumors: a longitudinal assessment in 140 patients with cerebral gliomas and brain metastases.

Oncogenic fusions of neurotrophic receptor tyrosine kinase NTRK1, NTRK2, or NTRK3 genes have been found in different types of solid tumors. The treatment of patients with TRK fusion cancer with a first-generation TRK inhibitor (such as larotrectinib or entrectinib) is associated with high response rates (>75%), regardless of tumor histology and presence of metastases. Due to the efficacy of TRK inhibitor therapy of larotrectinib and entrectinib, it is clinically important to identify patients accurately and efficiently with TRK fusion cancer. In this retrospective study, we provide unique data on the incidence of oncogenic NTRK gene fusions in patients with brain metastases (BM) and gliomas. 140 samples fixed and paraffin-embedded tissue (FFPE) of adult patients (59 of gliomas [17 of WHO grade II, 20 of WHO grade III and 22 glioblastomas] and 81 of brain metastasis (BM) of different primary tumors) are analyzed. Identification of NTRK gene fusions is performed using next-generation sequencing (NGS) technology using Focus RNA assay kit (Thermo Fisher Scientific). We identified an ETV6 (5)::NTRK3 (15) fusion event using targeted next-generation sequencing (NGS) in one of 59 glioma patient with oligodendroglioma-grade II, IDH-mutated and 1p19q co-deleted at incidence of 1.69%. Five additional patients harboring TMPRSS (2)::ERG (4) were identified in pancreatic carcinoma brain metastasis (BM), prostatic carcinoma BM, endometrium BM and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted. A FGFR3 (17)::TACC3 (11) fusion was identified in one carcinoma breast BM. Aberrant splicing to produce EGFR exons 2-7 skipping mRNA, and MET exon 14 skipping mRNA were identified in glioblastoma and pancreas carcinoma BM, respectively. This study provides data on the incidence of NTRK gene fusions in brain tumors, which could strongly support the relevance of innovative clinical trials with specific targeted therapies (larotrectinib, entrectinib) in this population of patients. FGFR3 (17)::TACC3 (11) rearrangement was detected in breast carcinoma BM with the possibility of using some specific targeted therapies and TMPRSS (2)::ERG (4) rearrangements occur in a subset of patients with, prostatic carcinoma BM, endometrium BM, and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted, where there are yet no approved ERG-directed therapies.

Endometrioid Karsinomanın Çoklu Beyin Metastazında Eşzamanlı Tümöriçi Kanama: Nadir Bir Metastazın Nadir Bir Bulgusu

Metastasis of endometrioid carcinomas to the brain is rare, usually solitary, and has a poor prognosis. Intratumoral bleeding is also a poor prognostic factor for metastatic brain tumors but rarely occurs in gynecological cancers. A female patient who was under chemotherapy for endometrioid carcinoma was admitted to the emergency department for recent deterioration and seizures. She had confusion and left hemiparesis, along with an elevated systolic blood pressure and platelet count of 45,000 /mL. An emergent computerized tomography and subsequent magnetic resonance imaging revealed multiple hemorrhagic metastatic lesions in both hemispheres and cerebellum. Brain metastasis of endometrioid carcinoma is rare and can present with intratumoral hemorrhage, which is associated with a poor prognosis and is more likely to occur in the setting of low platelet counts. This case highlights the importance of monitoring brain metastasis in patients with endometrioid carcinoma and considering the possibility of intratumoral hemorrhage.

Brain-Tumor Interface-Based MRI Radiomics Models to Determine EGFR Mutation, Response to EGFR-TKI and T790M Resistance Mutation in Non-Small Cell Lung Carcinoma Brain Metastasis.

Preoperative assessment of epidermal growth factor receptor (EGFR) status, response to EGFR-tyrosine kinase inhibitors (TKI) and development of T790M mutation in non-small cell lung carcinoma (NSCLC) patients with brain metastases (BM) is important for clinical decision-making, while previous studies were only based on the whole BM. To investigate values of brain-to-tumor interface (BTI) for determining the EGFR mutation, response to EGFR-TKI and T790M mutation. Retrospective. Two hundred thirty patients from Hospital 1 (primary cohort) and 80 patients from Hospital 2 (external validation cohort) with BM and histological diagnosis of primary NSCLC, and with known EGFR status (biopsy) and T790M mutation status (gene sequencing). Contrast-enhanced T1-weighted (T1CE) and T2-weighted (T2W) fast spin echo sequences at 3.0T MRI. Treatment response to EGFR-TKI therapy was determined by the Response Evaluation Criteria in Solid Tumors. Radiomics features were extracted from the 4 mm thickness BTI and selected by least shrinkage and selection operator regression. The selected BTI features and volume of peritumoral edema (VPE) were combined to construct models using logistic regression. The performance of each radiomics model was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). A total of 7, 3, and 3 features were strongly associated with the EGFR mutation status, response to EGFR-TKI and T790M mutation status, respectively. The developed models combining BTI features and VPE can improve the performance than those based on BTI features alone, generating AUCs of 0.814, 0.730, and 0.774 for determining the EGFR mutation, response to EGFR-TKI and T790M mutation, respectively, in the external validation cohort. BTI features and VPE were associated with the EGFR mutation status, response to EGFR-TKI and T790M mutation status in NSCLC patients with BM. 3 Technical Efficacy: Stage 2.

Complete response with combined therapy in a patient with brain metastasis from nasopharyngeal carcinoma: case report and literature review

Brain metastasis of nasopharyngeal carcinoma (NPC) is a rare event with limited research. In this report, we discuss the details of a case of brain metastasis from NPC that presented with a solitary, cystic lesion in the frontal lobe. We also reviewed the related literature published in the last 20 years. We analyzed the patient's clinical characteristics, which indirectly suggested hematogenous spread rather than a cerebrospinal fluid route. Although there are no standard treatments for brain metastasis of NPC, previous studies reported that combined surgery and radiotherapy was a good treatment option, with long survival. Our patient achieved intracranial complete response after the combination of conventional chemoradiotherapy and novel immunotherapy. This treatment option could be useful in future similar cases.

Retracted: Risk Factors for Brain Metastasis of Hepatocellular Carcinoma.

[This retracts the article DOI: 10.1155/2022/7848143.].

Risk factors and prognostic factors for pulmonary large cell neuroendocrine carcinoma with brain metastasis.

As the studies regarding the brain metastasis (BM) of pulmonary large cell neuroendocrine carcinoma (LCNEC) are insufficient, the present research aims to describe the risk factors and prognostic factors that are related to cancer-specific survival (CSS) for LCNEC patients with BM. The data of LCNEC patients between January 2010 and October 2018 were obtained from the SEER database. Binary logistic regression analyses were utilized to screen the possible risk factors related to BM. Prognostic factors for LCNEC patients with BM were indentified by Cox regression analyses. Moreover, a nomogram was established to predict the 6-, 12-, and 18-month CSS rates. The concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves were utilized to assess the discrimination and reliability of the model. Clinical decision curves (DCAs) were used to evaluate the clinical benefits and utility of our model. Totally, 1875 patients were enrolled, with 294 (15.7%) of them having BM at diagnosis. Multivariate logistic regression analyses revealed that patients with age < 65 (odds ratio, OR=1.564) and N2 staging (OR=1.775) had a greater chance of developing BM. Age (≥ 65 vs. < 65: hazard ratio, HR=1.409), T staging (T1 vs. T0: HR=4.580; T2 vs. T0: HR=6.008; T3 vs. T0: HR=7.065; T4 vs. T0: HR=6.821), N staging (N2 vs. N0: HR=1.592; N3 vs. N0: HR=1.654), liver metastasis (HR=1.410), primary site surgery (HR=0.581) and chemotherapy (HR=0.452) were independent prognostic factors for LCNEC patients with BM. A nomogram prediction model was constructed by incorporating these factors. Using the C-index, calibration curves, ROC curves, and DCAs, we found that the clinical prediction model performed well. We described the risk factors and prognostic factors that were associated with CSS for LCNEC patients with BM. The related nomogram was established and validated to help clinicians formulate more rational and effective treatment strategies.

Molecular profile and clinical outcomes of renal cell carcinoma brain metastases treated with stereotactic radiosurgery.

4526 Background: Molecular profiles of renal cell carcinoma (RCC) tumors are associated with systemic treatment (ST) responses and clinical outcomes. However, the molecular profiles of RCC brain metastases (BM) and their correlation with ST response and clinical outcomes are not well characterized. Effective management of BM with locoregional therapies including stereotactic radiosurgery (SRS) is critical as ST advances have improved overall survival (OS). Therefore, we sought to identify the clinical and genomic features of RCC BM in a large cohort of patients treated with SRS. Methods: We performed an institutional retrospective analysis of RCC BM patients treated with SRS and evaluated corresponding genomic next generation sequencing (NGS) data via a targeted sequencing panel (MSK-IMPACT). A comparison cohort of all institutional patients with available NGS data was utilized to investigate genes enriched in our BM cohort using Fisher exact testing. Kaplan Meier analyses were performed for OS and intracranial progression-free survival (iPFS). Clinical factors and genes mutated in ≥ 10% of samples were assessed per patient using Cox proportional hazards models, and per individual BMs using clustered competing risks regression with a competing risk of death. Results: From 2010-2021, 91 RCC BM patients underwent SRS for 212 BMs, including 86% clear cell and 14% non-clear cell RCC. NGS data was available for 76 patients (84%), including 18 resected BMs, 26 extra-cranial metastatic lesions (EM), and 32 primary kidney tumors (Table 1). Median follow-up was 3.2 years with median OS of 21 months (m) and median iPFS of 7.8m. Karnofsky performance status ≥80 and extracranial disease control were significantly associated with improved OS on multivariable analyses (MVA; p=0.049 and 0.01, respectively). No clinical variables were significantly associated with iPFS on MVA. At the BM level, SETD2 alterations approached significance for improved iPFS (HR=0.35; 95%CI 0.11, 1.05; p=0.06). Enrichment in SMARCA4 alterations was seen in the BM cohort as compared to primary kidney and EM samples from patients without BM (17% vs 1% vs 2%, p&lt;0.05). Conclusions: To our knowledge, this is the largest study investigating mutational profiles of RCC BM. SMARCA4 alterations were enriched in BM samples and a trend towards improved iPFS was seen in SETD2 variant BMs, warranting further investigation.[Table: see text]

Safety and Efficacy of Sorafenib and Lenvatinib in Patients Who Underwent Surgery or Whole-Brain Radiotherapy for Brain Metastasis of Hepatocellular Carcinoma.

Surgery or whole-brain radiotherapy (WBRT) for the management of brain metastasis of hepatocellular carcinoma (HCC) is associated with improved survival. However, the efficacy of multi-tyrosine kinase inhibitors (TKIs) and possible bleeding complications have not been studied in these patients. Therefore, this study aimed at investigating TKI safety and efficacy in these patients. We retrospectively reviewed 39 patients who underwent surgery or WBRT for brain metastasis of HCC. Intracranial tumor bleeding rates were compared between patients who did and did not receive TKIs. Survival outcomes were analyzed using the log-rank and Cox regression tests. A total of 22 and 7 patients received sorafenib and lenvatinib, respectively. The intracranial tumor bleeding rates were 61.5% and 70% in patients who did and did not receive TKIs, respectively (p > 0.99). Survival analysis revealed craniotomy (adjusted odds ratio [AOR]: 0.45, p = 0.04), a higher Karnofsky Performance Score (AOR: 0.97, p < 0.01), and TKI use (AOR: 0.26, p < 0.01) were positive prognostic factors for overall survival. TKIs were associated with better survival outcomes in patients who underwent surgery or WBRT for brain metastasis of HCC and did not increase intracranial bleeding. Therefore, TKIs are efficacious and safe for treating brain metastasis of HCC.

Merkel cell carcinoma brain metastasis with radiological findings mimicking primary CNS lymphoma: illustrative case.

BACKGROUNDMerkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor with a high likelihood of distant metastasis. Approximately 30 cases of MCC brain metastasis have been reported. The authors report a case of MCC brain metastasis with imaging findings mimicking primary central nervous system lymphoma.OBSERVATIONSA 69-year-old asymptomatic White female with a past medical history of rheumatoid arthritis and MCC of the right cheek with no known regional or distant spread presented with a right frontal lobe lesion discovered incidentally on a surveillance scan. Brain magnetic resonance imaging revealed a vividly enhancing homogeneous lesion with restricted diffusion on diffusion-weighted imaging and corresponding apparent diffusion coefficient maps. Imaging characteristics suggested a highly cellular mass consistent with primary central nervous system lymphoma; however, given the likelihood of metastasis, resection was recommended. An intraoperative frozen section suggested lymphoma. However, further examination revealed positive cytokeratin 20 staining for a tumor, and a final diagnosis of MCC brain metastasis was made.LESSONSImaging characteristics of MCC brain metastasis can vary widely. A high level of suspicion should be maintained in a patient with a known history of MCC. Aggressive resection is recommended, regardless of appearance on scans or pathology of frozen sections, because MCC can mimic other intracranial pathologies.

The Effect of Local Therapy on Brain Metastasis of Renal Cell Carcinoma

We compared brain metastasis of renal cell carcinoma (RCC) in patients who received tyrosine kinase inhibitors (TKIs) ; 17 received local therapy, while 16 did not. The median survival rate was 19 months in the local therapy group and 11 months in the tyrosine kinase inhibitor alone group, showing no significant difference (p＝0.52). Symptoms such as paralysis, headache, and dysarthria occurred due to brain metastasis. These symptoms improved in 8 out of 10 patients in the local therapy group. There were no cases of grade 3 or higher complications due to local therapy. Although local therapy did not prolong the overall survival, an improvement in symptoms was observed, suggesting that it is acceptable as palliative treatment.

Outcomes of Immunotherapy (ICI) Alone vs. Stereotactic Radiosurgery (SRS) Alone vs. ICI and SRS Combined in Renal Cell Carcinoma Brain Metastasis

Renal cell carcinoma is the fourth most common cause of metastatic brain tumors. Both Immune Checkpoint Inhibitors (ICIs) and Stereotactic Radiosurgery (SRS) have been used as first line treatment for renal cell carcinoma brain metastasis (RCCBM). The efficacy of ICIs alone, SRS alone, or SRS and ICIs combined as treatment is being evaluated. We hypothesize that a combination of SRS and ICIs will lead to an improvement in Overall Survival (OS), when compared to either alone, for patients with RCCBM.Patients with RCCBM treated at our tertiary care center (2010-2020) with either ICIs, SRS, or both were evaluated. Overall Survival (OS) was measured from initiation of immunotherapy or SRS of RCCBM to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS.210 patients with RCCBM were included. Of these, 26 were treated with ICIs alone, 80 were treated with SRS alone, and 104 were treated with a combination. For treatment with ICIs alone, the median age at diagnosis was 61 years (Interquartile range (IQR) 45-82), 63% of the patients were male, and 96% were white. For treatment with SRS alone the median age at diagnosis was 63 years (IQR 37-84), 70% of the patients were male, and 94% were white. For ICIs/SRS combination treatment, the median age at diagnosis was 63 years (IQR 38-79), 72% of the patients were male, and 97% were white. Overall Survival for patients treated with ICIs alone, SRS alone, and ICIs/SRS combined had a median of 25.4, 29.4, and 81.2 months and a 2 year rate of 56%, 53%, and 89%, respectively. With ICI treatment alone as a reference, SRS treatment alone had an OS hazard ratio, HR = 1.13 (95% CI = 0.69 - 1.84, P = 0.62), and ICI/SRS combination treatment had an OS hazard ratio, HR = 0.41 (95% CI = 0.24 - 0.69, P = < 0.001).In patients with RCCBM, combination treatment with both ICIs and SRS was associated with an increase in Overall Survival when compared to treatment with ICIs alone or SRS alone. Further studies need to be done to control for other patient variables such as KPS/ECOG, number of lesions, and extra-cranial metastasis.

Abstract 1007: Patient-derived metastatic renal carcinoma cells are highly sensitive to in vitro Tumor Treating Fields (TTFields)

Abstract Background: Until the advent of checkpoint inhibitor (CI) therapies, renal cell carcinoma (RCC) was clinically challenging to treat given its radio- and chemotherapy resistance. Despite the advances with CIs, patients with brain metastases derived from RCC still face challenges with treatment due to limited brain penetration of CI compounds. Anti-mitotic TTFields therapy is FDA-approved for the treatment of glioblastoma and mesothelioma, and clinical trials are underway for the application of TTFields therapy to primary lung cancer as well as lung cancer brain metastases. In this study, in vitro TTFields were applied to patient-derived brain metastasis RCC cells to determine the potential efficacy of this emerging treatment modality. Methods: This study was approved by the Institutional Review Board. A single-cell suspension was generated from tumor tissues obtained from a patient with newly-diagnosed RCC brain metastasis (male, age 52, mutant p53). Cells were cultured in DMEM/F12 media with 10% fetal bovine serum and gentamicin. Prior to TTFields initiation, cells were plated on plastic coverslips (1×104cells/coverslip; n=8/group) and incubated overnight. Then, TTFields were applied at 200 kHz with a field intensity of ~1.6 V/cm for 14 days, with one group of coverslips maintained as untreated controls. At the conclusion of the experiment, cells were harvested, stained with acridine orange/propidium iodide and counted with a Cellometer K2 (Nexcelom Bioscience, Lawrence, MA) that provides viable cell counts and average cell diameter. Groups were compared with a two-tailed t-test (GraphPad Prism v9, GraphPad Software, San Diego, CA) with significance set at P&amp;lt;0.05. Results: Viable cell count per coverslip for the control group was 149,863 ± 85644 (mean ± SD; n=8) and for the TTFields (200 kHz) group was 1,426 ± 1345 (n=6, 2 coverslips had no cell recovery). Average cell diameter was 9.713 ± 0.6312 for the control group and 16.92 ± 2.903 for the TTFields group. TTFields application significantly reduced cell count (P=0.0012) and increased the average cell diameter (P&amp;lt;0.0001) compared to the controls. Conclusions: TTFields application (200 kHz) demonstrated efficacy by markedly reducing cell proliferation (i.e., decreased cell counts) in RCC. The increase in average cell diameter observed with TTFields is consistent with previously reported findings of other research groups also showing increases in cell volume with TTFields in multiple cancer types (brain, lung, pancreas, breast, ovarian, and cervical). This study is the first to demonstrate the efficacy of in vitro TTFields treatment in patient-derived RCC and suggests that patients with renal carcinoma brain metastases may benefit from TTFields therapy. Citation Format: Sharon K. Michelhaugh, Blake C. Walker, Susan Coombe, Sandeep Mittal. Patient-derived metastatic renal carcinoma cells are highly sensitive to in vitro Tumor Treating Fields (TTFields) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1007.

Clinicopathologic and Genomic Landscape of Breast Carcinoma Brain Metastases.

Among patients with breast carcinoma who have metastatic disease, 15%-30% will eventually develop brain metastases. We examined the genomic landscape of a large cohort of patients with breast carcinoma brain metastases (BCBMs) and compared it with a cohort of patients with primary breast carcinomas (BCs). We retrospectively analyzed 733 BCBMs tested with comprehensive genomic profiling (CGP) and compared them with 10,772 primary breast carcinomas (not-paired) specimens. For a subset of 16 triple-negative breast carcinoma (TNBC)-brain metastasis samples, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) was performed concurrently. A total of 733 consecutive BCBMs were analyzed. Compared with primary BCs, BCBMs were enriched for genomic alterations in TP53 (72.0%, 528/733), ERBB2 (25.6%, 188/733), RAD21 (14.1%, 103/733), NF1 (9.0%, 66/733), BRCA1 (7.8%, 57/733), and ESR1 (6.3%,46/733) (p<.05 for all comparisons). Immune checkpoint inhibitor biomarkers such as high tumor mutational burden (TMB-high; 16.2%, 119/733); high microsatellite instability (1.9%, 14/733); CD274 amplification (3.6%, 27/733); and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutational signature (5.9%, 43/733) were significantly higher in the BCBM cohort compared with the primary BC cohort (p<.05 for all comparisons). When using both CGP and PD-L1 IHC, 37.5% (6/16) of patients with TNBC brain metastasis were eligible for atezolizumab based on PD-L1 IHC, and 18.8% (3/16) were eligible for pembrolizumab based on TMB-high status. We found a high prevalence of clinically relevant genomic alterations in patients with BCBM, suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for CGP in addition to CGP of the primary tumor may be clinically warranted. This study found a high prevalence of clinically relevant genomic alterations in patients with breast carcinoma brain metastasis (BCBM), suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for comprehensive genomic profiling (CGP) in addition to CGP of the primary tumor may be clinically warranted. In addition, this study identified higher positive rates for FDA-approved immunotherapy biomarkers detected by CGP in patients with BCBM, opening a possibility of new on-label treatments. Last, this study noted limited correlation between tumor mutational burden and PD-L1 immunohistochemistry (IHC), which shows the importance of testing patients with triple-negative BCBM for immune checkpoint inhibitor eligibility with both PD-L1 IHC and CGP.

Outcomes of immunotherapy (ICI) alone vs tyrosine kinase inhibitors (TKI) alone versus ICI and TKI combined in renal cell carcinoma brain metastasis.

2030 Background: Renal cancer is the fourth most common cause of metastatic tumors to the brain. Tyrosine kinase inhibitors (TKIs) targeting VEGFR and other receptors, such as sunitinib, pazopanib, etc., have been used as first line for renal cell carcinoma brain metastasis (RCCBM). Immune Checkpoint Inhibitors (ICIs) targeting PD-L1 and CTLA-4 interactions, such as nivolumab and ipilimumab respectively, have also been used as first line treatment for RCCBM. However, the efficacy of TKIs alone, ICIs alone, or TKIs and ICIs combined as first line treatment has emerged as a topic of interest. Methods: Patients with RCCBM treated with either TKIs, ICIs, or both at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from initiation of either TKI or ICI therapy to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS. Results: 218 patients with RCCBM were included. Of these, 32 were treated with ICIs alone, 112 were treated with TKIs alone, and 76 were treated with a combination of ICIs and TKIs. For ICI treatment alone the median age at diagnosis was 61 years (Interquartile range (IQR) 38-82), 72% of the patients were male, and 97% were white. For TKI treatment alone the median age at diagnosis was 58 years (IQR 37-82), 70% of the patients were male, and 92% were white. For the combination cohort the median age at diagnosis was 63 years (IQR 45-79), 69% of the patients were male, and 97% were white. OS for patients receiving ICI, TKI, and combination treatment had a median of 69.1, 42.7, and 126.0 months and a 2-year rate of 77%, 69%, and 93%, respectively. With ICI treatment as a reference, TKI treated patients had an OS hazard ratio of 1.32 (95% CI = 0.78 - 2.21, p = 0.30) and ICI/TKI combination had an OS hazard ratio of 0.52 (95% CI = 0.30 - 0.92, p = 0.024). Conclusions: A combination treatment of ICIs and TKIs was associated with an increase in OS when compared to treatment with either TKIs or ICIs alone in patients with RCCBM. These results should be interpreted cautiously due to treatment selection bias. Further studies need to be done to control for other patient variables such as performance status, number of intracranial lesions, and extra-cranial metastasis.[Table: see text]

EXTH-05. NON-CYTOTOXIC RADIATION ENHANCES DELIVERY OF ANTISENSE OLIGONUCLEOTIDES AND IMPROVES CHEMO-RADIATION EFFICACY IN BRAIN TUMOR XENOGRAFTS

Abstract Overexpression of O6-methylguanine DNA methyltransferase (MGMT) contributes to brain tumor chemo-resistance. Previously we found that non-cytotoxic radiation improved anti-MGMT Morpholino Oligonucleotides (AMONs) delivery to reduce MGMT levels in subcutaneous tumor xenografts. Here we evaluated if radiation enhanced the delivery of intravenous (IV) AMONs to rat brain and improved chemo-radiation therapy (CRT) efficacy using rat models of human brain tumors. Athymic nude rats bearing orthotopic cerebellar D283 medulloblastoma or intracerebral H460 non-small cell lung carcinoma (NSCLC) brain metastasis xenografts were used. The impact of cranial radiation on delivery of IV 3’-carboxyfluorescein labeled oligonucleotides across the neurovascular unit was evaluated using confocal microscopy. We found that high brain parencymal fluorescence in radiated compared to non-radiated rats. MGMT protein silencing was assessed by immunoblot in tumor-bearing rats 3 d after 2 Gy cranial radiation alone or followed in 1 d by IV AMONs (10.5 mg/kg). Radiation followed by AMONs reduced MGMT expression by 50% in both xenograft models. To evaluate efficacy, tumor-bearing rats received one dose of 2 Gy radiation plus oral temozolomide (20 mg/kg x 4d) with or without IV AMONs. AMONs concurrent with CRT reduced tumor volumes in the medulloblastoma model (p=0.012), and a similar trend was found in the NSCLC brain metastasis model. In conclusion, we demonstrate the use of a single clinically relevant radiation dose fraction to guide and enhance the delivery of oligonucleotides into brain tumor xenograft models to reduce MGMT levels and improve CRT efficacy.

Current Multimodality Treatments Against Brain Metastases from Renal Cell Carcinoma.

Simple SummaryBrain metastasis (BM) is generally one of poor prognostic factors in patients with advanced renal cell carcinoma. However, because of longer control of extra-cranial disease by the recent introduction of molecular target therapy and immune checkpoint inhibitor, the incidence of BM has been recently increasing and to progress the treatment of BM is one of urgent medical unmet needs. Although the pivotal clinical trials usually excluded patients with BM, BM subgroup data from the prospective and retrospective series have been gradually accumulated. To select the appropriate strategy, individual patient and tumor characteristics (e.g., Karnofsky Performance Status (KPS), systemic cancer burden, the number/size/location of BM) are important information. Among the local treatments, the technology of stereotactic radiosurgery (SRT) has been especially advanced and its adaptation has been expanded. The combination of SRT with molecular target therapy and/or immune checkpoint inhibitor would be promising to further enhance the efficacy without increased toxicity.In patients with renal cell carcinoma, brain metastasis is generally one of the poor prognostic factors. However, the recent introduction of molecular target therapy and immune checkpoint inhibitor has remarkably advanced the systemic treatment of metastatic renal cell carcinoma and prolonged the patients’ survival. The pivotal clinical trials of those agents usually excluded patients with brain metastasis. The incidence of brain metastasis has been increasing in the actual clinical setting because of longer control of extra-cranial disease. Brain metastasis subgroup data from the prospective and retrospective series have been gradually accumulated about the risk classification of brain metastasis and the efficacy and safety of those new agents for brain metastasis. While the local treatment against brain metastasis includes neurosurgery, stereotactic radiosurgery, and conventional whole brain radiation therapy, the technology of stereotactic radiosurgery has been especially advanced, and the combination with systemic therapy such as molecular target therapy and immune checkpoint inhibitor is considered promising. This review summarizes recent progression of multimodality treatment of brain metastasis of renal cell carcinoma from literature data and explores the future direction of the treatment.

Central Nervous System–Invading Eccrine Gland Carcinoma: A Clinicopathologic Case Series and Literature Review

Eccrine carcinoma involvement of the central nervous system (CNS) is exceedingly rare. The prognosis and response to treatment of this pathology remain poorly characterized. A retrospective case series and literature review were conducted. CNS-invading eccrine carcinoma was diagnosed in 3 patients (2 male and 1 female; age range, 60-79 years), including 2 cases of brain metastases and 1 case of brain-invading skull metastasis with subsequent spinal metastasis. The interval from primary tumor to CNS invasion was 18-51 months. All patients received multimodal therapy following diagnosis of CNS involvement. One patient who harbored a NOTCH1 mutation demonstrated a durable oncologic response after treatment with the immune checkpoint inhibitor pembrolizumab and lived 39 months after CNS invasion. The other 2 patients were discharged to hospice care within 1 month after the diagnosis of eccrine carcinoma brain metastasis. Including this case series, 23 cases of eccrine carcinoma invasion or metastasis to the CNS have been reported, with survival after diagnosis of CNS involvement ranging from a few weeks to 4 years. We present 3 cases of eccrine carcinoma metastatic to the CNS, including the first reported case to our knowledge of eccrine carcinoma treated with immunotherapy. This case, harboring a NOTCH1 mutation, demonstrated the longest durable oncologic response reported in this rare disease. Genomic and molecular testing may play increasingly important roles in the evaluation of these metastases.

A systematic review: Role of systemic therapy on treatment and prevention of brain metastasis in renal cell carcinoma.

To define the inclusion/exclusion status of patients with brain metastasis in phase-III clinical trials and the effect of systemic therapies in metastatic renal cell cancer patients with brain metastasis. "kidney neoplasms"[MeSH Terms] OR ("kidney"[All Fields] AND "neoplasms"[All Fields]) OR "kidney neoplasms"[All Fields] OR ("kidney"[All Fields] AND "cancer"[All Fields]) OR "kidney cancer"[All Fields] AND "brain metastasis" were used for searching "PubMed" electronic database and "clinicaltrials.gov" website. Five of 19 landmark phase-III clinical trials included patients with stable or asymptomatic brain metastasis and there was no data about outcomes of brain metastasis. The effect of systemic therapy on prevention of brain metastasis in renal cell cancer was evaluated in four studies. Two studies showed that the incidence of brain metastasis decreased, while the other two studies showed no effect of antiangiogenic agents on the prevention of brain metastasis in patients with renal cell cancer. There were 10 trials regarding systemic therapy of renal cell cancer brain metastasis. The overall response rate improved through a combination of targeted therapies and local treatment. The results of the trials studying the effect of tyrosine kinase inhibitors without local treatment were controversial. None of the ongoing clinical trials included patients with active brain metastasis. In metastatic renal cell cancer patients with brain metastasis, the overall response rate improved with the combination of targeted agents and local treatment. Further trials are needed to evaluate the effect of systemic treatment on the prevention or treatment of brain metastasis in patients with renal cell cancer.

Brain metastasis in epithelial ovarian carcinoma: Case series

The central nervous system (CNS) involvement is an exceptional finding in the management of epithelial ovarian cancer with an incidence between 1% - 2%. Brain metastases from Epithelial ovarian carcinoma (EOC) and that with mucinous adenocarcinoma histology are very rare finding in the gynecological-oncological settings. Ovarian cancer with brain metastases is also a sigil to poor prognosis. Since brain imaging is not a part of the routine follow-up care for ovarian cancer patients, and cancer antigen-125 – one of the standard tools – cannot detect CNS relapse, in a patient suffering from neoplasm that rarely metastasizes to CNS. A careful clinical examination and proper therapeutic approach including chemotherapy and radiotherapy may lead to prolonged survival. Here, presenting our institutional experience in ca ovary, where a total of 610 patients registered in 2009–2018 of ca ovary, of which, only five patients developed brain metastasis and are included in the presented case series.