Extracranial Research Articles

Survival and relapse patterns in patients of cranial versus extra-cranial oligometastases treated with stereotactic radiosurgery/stereotactic body radiation therapy and systemic therapy

Abstract Objectives To evaluate the outcome of patients with cranial (C) and extra cranial (EC) oligometastases treated with stereotactic radiosurgery (SRS)/stereotactic body radiotherapy (SBRT) and standard of care systemic therapy. Methods During the period 2018-2022, patients who received SBRT or SRS for oligometastases (≤5 lesions) in addition to systemic therapy were evaluated. PET-CT was done to categorize them as C or EC oligometastases. Local control, distant progression, progression free (PFS), overall survival (OS) and toxicity of the treatment were recorded. Results 43 patients received SBRT/SRS to 88 oligometastatic lesions. Eighteen patients had C metastases, 23 had EC metastases and 2 patients had both. 40/43 patients had received systemic therapy. At a median follow up of 13 months, median PFS was 14 months and 1 and 2 years OS was 83.2% and 67.4%. Local control with SRS was 92.8% and with SBRT was 86.3%. Distant failure in C Vs EC oligometastases was seen in 12/14 Vs 7/20 patients (p = 0.03). Median PFS was 30 months for EC and 6 months for C oligometastases (p = 0.003). 1 and 2 years OS was 89.6% and 82.7% for EC and 77.6% and 48.5% for C oligometastases (p = 0.21). One patient had grade 3 and 3 patients had grade 1 toxicity. Conclusions SRS and SBRT yielded high rates of local control with low toxicity. Compared to EC, patients with cranial oligometastases had higher distant relapses, poorer PFS and a trend towards worse survival. More studies with separate enrolment of patients with C and EC oligometastases are needed. Advances in knowledge Outcome of patients with cranial oligometastases is poorer than extra cranial metastases and hence the studies should be separately done in these two groups to assess the benefit of SRS/SBRT.

Intracranial Efficacy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel in Real-World Patients with Non-Small-Cell Lung Cancer and EGFR or ALK Alterations.

Contrary to Pemetrexed-containing chemo-immunotherapy studies, Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel (ABCP) treatment has consistently shown clinical benefit in prospective studies in patients with lung cancer and actionable mutations, where intracranial metastases are common. Here, we aimed to describe the real-life population of patients fit to receive ABCP after targeted therapy and quantify its clinical effect in patients with brain metastases. Patients treated in Cheshire and Merseyside between 2019 and 2022 were identified. Data were collected retrospectively. A total of 34 patients with actionable EGFR or ALK alterations had treatment with a median age of 59 years (range 32-77). The disease control rate was 100% in patients with PDL1 ≥ 1% (n = 10). In total, 19 patients (56%) had brain metastases before starting ABCP, 17 (50%) had untreated CNS disease, and 4 (22%) had PDL1 ≥ 1%. The median time to symptom improvement was 12.5 days (range 4-21 days), with 74% intracranial disease control rates and 89.5% synchronous intracranial (IC) and extracranial (EC) responses. IC median Progression Free Survival (mPFS) was 6.48 months, EC mPFS was 10.75 months, and median Overall Survival 11.47 months. ABCP in real-life patients with brain metastases (treated or untreated) was feasible and showed similar efficacy to that described in patients without actionable mutations treated with upfront chemo-immunotherapy.

Clinical Outcomes After Traumatic Brain Injury and Exposure to Extracranial Surgery

Traumatic brain injury (TBI) is associated with persistent functional and cognitive deficits, which may be susceptible to secondary insults. The implications of exposure to surgery and anesthesia after TBI warrant investigation, given that surgery has been associated with neurocognitive disorders. To examine whether exposure to extracranial (EC) surgery and anesthesia is related to worse functional and cognitive outcomes after TBI. This study was a retrospective, secondary analysis of data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study, a prospective cohort study that assessed longitudinal outcomes of participants enrolled at 18 level I US trauma centers between February 1, 2014, and August 31, 2018. Participants were 17 years or older, presented within 24 hours of trauma, were admitted to an inpatient unit from the emergency department, had known Glasgow Coma Scale (GCS) and head computed tomography (CT) status, and did not undergo cranial surgery. This analysis was conducted between January 2, 2020, and August 8, 2023. Participants who underwent EC surgery during the index admission were compared with participants with no surgery in groups with a peripheral orthopedic injury or a TBI and were classified as having uncomplicated mild TBI (GCS score of 13-15 and negative CT results [CT- mTBI]), complicated mild TBI (GCS score of 13-15 and positive CT results [CT+ mTBI]), or moderate to severe TBI (GCS score of 3-12 [m/sTBI]). The primary outcomes were functional limitations quantified by the Glasgow Outcome Scale-Extended for all injuries (GOSE-ALL) and brain injury (GOSE-TBI) and neurocognitive outcomes at 2 weeks and 6 months after injury. A total of 1835 participants (mean [SD] age, 42.2 [17.8] years; 1279 [70%] male; 299 Black, 1412 White, and 96 other) were analyzed, including 1349 nonsurgical participants and 486 participants undergoing EC surgery. The participants undergoing EC surgery across all TBI severities had significantly worse GOSE-ALL scores at 2 weeks and 6 months compared with their nonsurgical counterparts. At 6 months after injury, m/sTBI and CT+ mTBI participants who underwent EC surgery had significantly worse GOSE-TBI scores (B = -1.11 [95% CI, -1.53 to -0.68] in participants with m/sTBI and -0.39 [95% CI, -0.77 to -0.01] in participants with CT+ mTBI) and performed worse on the Trail Making Test Part B (B = 30.1 [95% CI, 11.9-48.2] in participants with m/sTBI and 26.3 [95% CI, 11.3-41.2] in participants with CT+ mTBI). This study found that exposure to EC surgery and anesthesia was associated with adverse functional outcomes and impaired executive function after TBI. This unfavorable association warrants further investigation of the potential mechanisms and clinical implications that could inform decisions regarding the timing of surgical interventions in patients after TBI.

CNS Control after First-Line Osimertinib in Patients with Metastatic EGFR-Mutant NSCLC

Although osimertinib (osi) has excellent intracranial activity in EGFR-mutant metastatic non-small cell lung cancer (NSCLC), there is no consensus regarding whether to continue osi for central nervous system (CNS) control with second-line chemotherapy (chemo) at the time of systemic progression. We aimed to compare CNS outcomes after first-line osi in patients receiving second-line chemo with or without continuation of osi. We retrospectively reviewed patients with EGFR-mutant NSCLC with brain metastases (BrM) at the time of initiating first-line osi who experienced progression and started second-line chemo. Cumulative incidence of local and distant CNS progression, and extracranial (EC) progression was calculated from time of second-line chemo initiation with death as a competing risk. Overall survival (OS) was analyzed using Kaplan-Meier. We included 52 patients with a median follow up of 9.6 months (range 0.4-36.4). Median OS and CNS progression-free survival (PFS) from the time of starting second-line chemo was 12.5 months (95% CI 8.1-16.9), and 5.3 months (95% CI 3.35-7.26), respectively. The 1-year cumulative incidence of local, distant CNS progression, any CNS progression, and EC progression was 14.4% (95% CI 4.5-24.2), 42.8% (95% CI 22.8-56.8), 42.8% (95% CI 22.8-56.8) and 66.8% (95% CI 53.5-80.2), respectively. After progression on first-line osi, 25 (48.1%) and 27 patients (51.9%) continued and discontinued osi, respectively. Patients who continued osi had significantly higher BrM burden than those who did not, with 17 (68%), 3 (12%), and 5 (20%) versus 26 (96%), 0, and 1 (3.7%) patient having <10 or >11 parenchymal brain lesions, or leptomeningeal disease (LMD) at the time of second line therapy, respectively (p<0.01). In those who continued osi vs those who did not, median OS (10.8 vs 12.5 months; p = 0.37), median intracranial PFS (5.3 vs 4.8 months; p = 0.99), 1-year cumulative incidence of local (8.4% versus 20 % p = 0.26), and 1-year distant CNS progression (24.8% vs 60%; p = 0.08) was not significantly different. CNS complications such as symptomatic, hospitalizations, and steroid initiation for CNS disease, and progression of LMD were not significantly different between the two groups. Eventually, 10 patients underwent salvage RT post first-line osi and median time to salvage RT was 7.8 months (range 2-9.4). Of patients who underwent salvage RT, 2 patients (20%) had continued osi with second-line chemo. Twelve patients (44.4%) who did not continue osi eventually re-started osi for progressive disease. Patients who continued osi had significantly higher BrM tumor burden. Despite these patients being at higher risk for CNS progression, time to CNS progression and incidence of CNS complications were not significantly different in the two cohorts. Patients who discontinued osi were more likely to undergo salvage RT. Continuation of osi may allow patients to defer salvage RT.

1039MO CheckMate 204: 3-year outcomes of treatment with combination nivolumab (NIVO) plus ipilimumab (IPI) for patients (pts) with active melanoma brain metastases (MBM)

In CheckMate 204, asymptomatic pts (cohort A) with active, untreated MBM achieved high intracranial (IC) and extracranial (EC) response rates with NIVO + IPI; efficacy was lower in pts with symptomatic and/or steroid-requiring MBM (cohort B). Here, we report 3-y response and survival outcomes in both cohorts, along with first results of the blinded independent central review (BICR) of imaging data.

Real-life data for first-line combination immune-checkpoint inhibition and targeted therapy in patients with melanoma brain metastases

BackgroundMelanoma brain metastases (MBM) have a poor prognosis. Systemic treatments that have improved outcomes in advanced melanoma have been shown to have an intracranial (IC) effect. We studied the efficacy and outcomes of combined immune checkpoint inhibitor ipilimumab/nivolumab (Combi-ICI) or targeted therapy (Combi-TT) as first-line treatment in MBM. MethodsMBM patients treated with Combi-ICI or Combi-TT within 3 months after MBM diagnosis. Endpoints were progression-free survival (PFS) and overall survival (OS). Results53 patients received Combi-ICI, 32% had symptomatic MBM and 33.9% elevated LDH. 71.7% required local treatment. The disease control rate was 60.3%. IC response rate (RR) was 43.8% at 3-months with durable responses at 6- (46.5%) and 12-months (53.1%). Extracranial (EC) RR was 44.7% at 3-months and 50% at 12-months. Median PFS was 9.6 months (95% CI 3.6-NR) and median overall survival (mOS) 44.8 months (95% CI; 26.2-NR).63 patients received Combi-TT, 55.6% of patients had symptomatic MBM, 57.2% of patients had elevated LDH and 68.3% of patients required local treatment. The disease control rate was 60.4%. ICRR was 50% at 3-months, but dropped at 6-months (20.9%). ECRR was 69.2% at 3-months and 17.6% at 12-months. Median PFS was 5.8 months (95% CI 4.2–7.6) and mOS 14.2 months (95% CI 8.99–26.8).In BRAFV600 patients, 26.7% of patients received Combi-ICI and 73.3% Combi-TT with OS (p = 0.0053) and mPFS (p = 0.03) in favour to Combi-ICI. ConclusionCombi-ICI showed prolonged mOS with sustainable IC and EC responses. Despite the initially increased efficacy, Combi-TT responses at 12 months were low. Combi-ICI appeared superior to Combi-TT for OS and PFS in BRAFV600 patients. Other clinical factors are determinants for first-line treatment choice.

Risk Factors Associated with Extra Cranial and Intracranial Atherosclerosis Stroke

Risk Factors Associated with Extra Cranial and Intracranial Atherosclerosis Stroke

Intracranial and extracranial complications of chronic otitis media and their management at a tertiary care center: a descriptive study

&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;In the pre-antibiotic era complications from otitis media occurred abundantly, accompanied by high morbidity and mortality. With availability of higher antibiotics, morbidity and mortality due to chronic otitis media (COM) has reduced, but still complications due to COM remain a significant problem in developing countries. The aim is to study clinical presentation, management and outcomes of intracranial and extracranial complications of COM. Study design is retrospective case series study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods:&lt;/strong&gt; Patients admitted in department of otorhinolaryngology and head and neck surgery, S. Nijalingappa medical college and H.S.K hospital and research center, Bagalkot from May 2018 to April 2020 with COM associated with intracranial or extracranial complications were included in the study. Data of clinical presentation, associated complications, management, and follow-up were analyzed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; A total of 20 patients were reviewed during study period. Of these seventeen patients had extracranial (EC) complications, while one had intracranial (IC) complications and two had both. Otalgia, otorrhea and fever were the main presenting symptoms. The encountered IC complication were lateral sinus thrombophlebitis, cerebellar abscess. Among the EC complications most common were post-auricular subperiosteal abscess, lateral semicircular canal fistula and facial paralysis. Most commonly isolated organism was staphylococcus. Surgery was main modality of treatment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; COM is still a significant problem in developing countries in spite of availability of antibiotics and early diagnosis is crucial in the management of complications associated. This study emphasizes the importance of early diagnosis and prompt treatment to limit the morbidity.&lt;/p&gt;

The Intra and Extra Cranial Veins in Relationship with Chronic Migraine: Electroencephalogram Modifications Induced by Balloon Venoplasty

The Intra and Extra Cranial Veins in Relationship with Chronic Migraine: Electroencephalogram Modifications Induced by Balloon Venoplasty

Blood Neutrophil/Lymphocyte Ratio Is Associated With Cerebral Large-Artery Atherosclerosis but Not With Cerebral Small-Vessel Disease

Background and Objective: The blood neutrophil/lymphocyte ratio (NLR) is a marker of peripheral inflammation, with a high NLR associated with an increased risk of cardiovascular events and poor prognosis in ischemic stroke. However, few data are available on the differential impact of the blood NLR on different silent cerebral vascular pathologies, including cerebral large-artery atherosclerosis (LAA) and cerebral small-vessel disease (CSVD), in neurologically healthy individuals.Methods: We evaluated cardiovascular risk factors, brain magnetic resonance imaging (MRI), and MR angiography of 950 individuals without any neurological diseases. The study participants were divided into three groups according to NLR tertile (low, middle, and high). The presences of extracranial (EC) and intracranial (IC) atherosclerosis were considered to indicate LAA on brain MR angiography. The presences of silent lacunar infarction (SLI) and cerebral white matter hyperintensities (WMHs) were analyzed as indices of CSVD on brain MRI.Results: In univariate analysis, the high NLR tertile group showed a high prevalence of old age, hyperlipidemia, and renal dysfunction and higher fasting glucose. Multivariable logistic regression analysis revealed that indices of LAA (EC atherosclerosis [odds ratio: 1.88; 95% confidence interval: 1.14–3.09; p = 0.01] and IC atherosclerosis [odds ratio: 1.87; 95% confidence interval: 1.15–3.06; p = 0.01]) were more prevalent in the highest NLR tertile group than in the lowest NLR tertile group after adjustment for cardiovascular risk factors. However, no significant differences were found in the prevalence of CSVD indices (SLI and WMHs) among the three NLR tertile groups.Conclusions: A high NLR is associated with the development of cerebral LAA but not CSVD.

GLASS: Global Lorlatinib for ALK(+) and ROS1(+) retrospective Study: real world data of 123 NSCLC patients

Lorlatinib is a third-generation tyrosine-kinases inhibitor (TKI) targeting ALK/ROS1 fusions. The FDA has approved lorlatinib for TKI-pretreated ALK(+) NSCLC, while its approval for ROS1(+) is still pending. Here we present the largest real-world data of NSCLC patients harboring ALK/ROS1 rearrangements treated with lorlatinib. Methods123 patients were enrolled retrospectively (data cut-off 1/1/2019). Lorlatinib was administered through an early access program for patients with no other available therapy. Outcome and response were defined by each investigator upon RECIST 1.1 criteria. Results106 ALK(+) and 17 ROS1(+) patients recruited from 8 different countries. The ALK(+) cohort included 50 % males, 73 % never-smokers and 68 % with brain metastases. Extracranial (EC) and intracranial (IC) response rates (RR) were 60 % and 62 %, with disease control rates (DCR) of 91 % and 88 % respectively. Mean duration of therapy (DoT) was 23.9 ± 1.6 months and median overall survival (mOS) was 89.1 ± 19.6 months. ROS1 cohort enrolled 53 % males, 65 % never-smokers and 65 % had brain metastases. EC and IC RR were 62 % and 67 % with DCR of 92 % and 78 % respectively. Median DoT was 18.1 ± 2.5 months and mOS of 90.3 ± 24.4 months. OS and DoT in both cohorts were not significantly correlated with line of therapy nor other parameters.The most common adverse events of any grade were peripheral edema (48 %), hyperlipidemia (47 %), weight gain (25 %) and fatigue (30 %). CNS adverse events such as cognitive effect of grade 1–2 were reported in 18 % of patients. ConclusionLorlatinib shows outstanding EC/IC efficacy in ALK/ROS1(+) NSCLC. The observed mOS of 89 ± 19 months in ALK(+) NSCLC supports previous reports, while mOS from of 90 ± 24 months is unprecedented for ROS1(+) NSCLC.

Prognostic Value of Serially Estimated Serum Procalcitonin Levels in Traumatic Brain Injury Patients With or Without Extra Cranial Injury on Early In-hospital Mortality: A Longitudinal Observational Study.

BackgroundTraumatic brain injury (TBI) is associated with majority of trauma deaths, and objective tools are required to understand the severity of injury. The application of a biomarker like procalcitonin (PCT) in TBI may allow for assessment of severity and thus aid in prognostication and correlation with mortality and outcome.AimsThe primary objective is to determine the correlation between PCT concentrations with TBI outcomes (mainly in terms of mortality) at intensive care unit (ICU)/hospital discharge. Secondary objectives are to evaluate correlation with associated extra cranial injuries and complications during hospital stay.MethodsIn total, 186 TBI patients aged > 18 years with minimum survival for at least 12 h admitted to the ICU at the level 1 trauma center were prospectively included in the study and divided into two groups: TBI with and without extra cranial injuries. All admitted patients were treated according to the standard institutional protocol. The PCT levels were obtained on admission, on day 2, and 5. Clinical, laboratory, diagnostic, and therapeutic data were also collected. Primary mortality is defined as death related to central nervous system (CNS) injury, while secondary mortality defined as death related to sepsis or extracranial cause.ResultsMedian PCT levels at admission, day 2, and day 5 in TBI patients with extracranial injuries were 3.0, 0.83, and 0.69 ng/ml. In total, primary mortality was observed in 18 (9.7%) patients, while secondary causes were attributable in 20 (12.3%) patients. Regression analysis for primarily CNS cause of mortality showed PCT cutoff level at admission more than 5.5 ng/ml carried sensitivity and specificity of 75%, but for secondary cause (sepsis) of mortality, PCT cutoff values on day 2 > 1.15 ng/ml were derived significant with sensitivity of 70% and specificity of 66%. No significant association of parameters like length of ICU stay, Glasgow outcome scale (GOS), and primary/secondary mortality with the presence of extracranial injuries in TBI patients as compared with TBI alone was noted.ConclusionThis observational study demonstrates the poor correlation between PCT concentrations with outcome at days 1, 2, and 5 post-injury. The predicted relationship between PCT levels and outcome was not confirmed, and that these results do not support the prognostic utility of PCT biomarker in this population for outcome (mortality) assessment in TBI patients with or without extracranial injuries.

Genomic profiling of breast cancer brain metastases reveals targetable alterations.

2525 Background: Genomic characterization of breast cancer brain metastases (BCBMs) has thus far been limited. The objective of this study was to describe the landscape of genomic alterations in patients (pts) with BCBMs. Methods: Targeted next-generation DNA sequencing of &gt; 300 cancer-related genes (OncoPanel) was prospectively performed on primary and metastatic (met) tumors in 321 pts with a diagnosis of BCBM between August 2016 and April 2019 at Dana-Farber Cancer Institute (table). Enrichment analysis of genomic alterations was performed using a two-sided Fisher exact test and differences in tumor mutation burden (TMB) between groups were assessed using two-sided Mann-Whitney U test. Multiple comparison correction was performed using the Benjamini-Hochberg procedure. Results: All subtypes were represented in BCBM (25 HR+/HER2-; 24 HR+/HER2+; 27 HR-/HER2+; 18 TNBC; 5 unknown; n = 99) and extracranial (EC) samples: (96 HR+/HER2-; 32 HR+/HER2+; 22 HR-/HER2+; 41 TNBC; 31 unknown; n = 222). BCBMs were found most commonly to have mutations or copy number alterations in TP53, ERBB2, PIK3CA, GATA3, PTEN, ESR1, CDH1, BRCA2, ARID1A, BRCA1 (&gt;5% frequency, table). Two pts acquired ERBB2 amplification (amp) between the matched primary breast sample and brain met. In pair-wise comparisons of BCBMs to unmatched primaries or EC mets, only ERBB2 amp was significantly enriched (table, † = adjusted p &lt; 0.05). There was no significant difference in TMB between BCBM and EC mets (median 9.12 vs 7.26, p = 0.15). In contrast, TMB was significantly higher in BCBMs compared to unmatched primaries (median 9.12 vs 7.26, p=0.005). Conclusions: BCBMs display similar mutations and copy number alterations compared to primary tumors and EC mets in pts with BCBM. These data suggest that BCBMs contain actionable genomic alterations that are most often also reflected in EC disease. Alterations in ERBB2, PIK3CA/PTEN, and BRCA1/2 represent potentially targetable alterations in pts with BCBM. [Table: see text]

A phase II study of lorlatinib in patients (pts) with ALK-positive (ALK+) lung cancer with brain-only progression.

9595 Background: Lorlatinib is a 3rd-generation ALK tyrosine kinase inhibitor (TKI) developed to penetrate the central nervous system (CNS) and overcome resistance to 2nd-generation (2nd-gen) ALK TKIs. In a phase II study, lorlatinib demonstrated significant intracranial (IC) activity after failure of 2nd-gen TKIs. As treatment discontinuation for extracranial (EC) progression can confound assessment of durability of IC response, we performed a phase II study (NCT02927340) to selectively evaluate lorlatinib activity in ALK+ pts with CNS-only disease. Methods: Between 11/2016 and 1/2019, 22 pts with IC progression on an ALK TKI with no other sites of measurable disease were enrolled at 2 institutions. Pts received lorlatinib at a starting dose of 100 mg QD. The primary endpoint was the IC disease control rate (DCR) at 12 weeks per modified RECIST v1.1. Secondary endpoints were IC objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Results: Of the 22 pts enrolled, 21 (95%) had progressed on a 2nd-gen ALK TKI and 14 (64%) had previously received CNS radiation (median 21.1 months between radiation and lorlatinib). Median number of prior ALK TKIs was 2 (range 1-4). As of the data cutoff of 12/15/19, median follow-up was 14 months. At 12 weeks, the IC-DCR was 95%, including 8 pts with stable disease. Best IC ORR was 59% with 6 complete and 7 partial responses. Nine (41%) pts relapsed on study, including 3 IC-only, 5 EC-only, and 1 combined relapse. Four pts continued treatment beyond EC-only progression. Although median IC DOR and PFS were not estimable due to few progression events, the IC progression-free rate at 12 months was 81% (95% CI: 53%-94%). Twelve pts have discontinued study treatment due to progression (n = 6), edema (n = 1), pulmonary hypertension (n = 1), or transition to commercial lorlatinib (n = 4). Conclusions: Lorlatinib induces durable intracranial responses in pts with CNS-only progression on 2nd-gen ALK TKIs, suggesting that CNS-specific relapses are primarily driven by ALK-dependent mechanisms. Further studies are needed to characterize the molecular basis of sensitivity to lorlatinib in this unique subgroup of pts with ALK+ lung cancer. Clinical trial information: NCT02927340 .

The Prognostic Value of Reversed Ophthalmic Artery Flow Direction in Acute Stroke Patients with Ipsilateral Extra Cranial Carotid Artery Stenosis

Abstract Background According to the World Health Organization, about 15 million people suffer a stroke each year with roughly one-third resulting in death and another one-third sustaining severe permanent disability. Even in developed nations, stroke is the third leading cause of death. It also costs billions of dollars through lost productivity, premature mortality and care for stroke survivors. The evaluation of hemodynamics, autoregulation and collaterals is cardinal for clinical outcomes. The Use of Transcranial Doppler (TCD) in detecting reversal of blood flow direction especially in anterior communicating and ophthalmic arteries, and flow diversion between anterior and posterior circulation provide critical information on ipsilateral collateral status. The impact of collateral status has been correlated with clinical symptoms, reperfusion success and functional outcome at discharge. A rationale now exists for imaging assessment to guide physicians in the precision medicine of stroke care. Aim of the work This study is performed for evaluation of hemodynamics in ophthalmic artery as a collateral and its value as a prognostic factor in patients with carotid artery extra cranial stenosis in acute cerebrovascular stroke. Patients and Methods 30 patients with acute cerebrovascular stroke were recruited in this cross-sectional study admitted in stroke unit at the department of neurology of Ain Shams University hospitals. Results There was a statistically significant difference between the Modified Rankin Scale on discharge and follow up after 3 months in patients suffering from acute cerebrovascular stroke with ipsilateral severe extra cranial carotid artery stenosis and reversed ophthalmic artery flow direction (p value =0.042), compared to the group with direct ophthalmic artery flow direction where the (p = 0.086). Conclusion Transcranial Duplex is a diagnostic tool that provides a non-invasive, real time, safe technique information data on intracerebral hemodynamics. It was used in this study to detect that there is a significant difference in functional outcome between patients with forward and reversed ophthalmic artery flow direction with acute cerebrovascular stroke and ipsilateral extracranial carotid artery stenosis.

Cumulative Incidence and Predictors of CNS Metastasis for Patients With American Joint Committee on Cancer 8th Edition Stage III Melanoma.

Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma. Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis. At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined. Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.

1487PD - Intracranial and extracranial efficacy of lorlatinib in the post second-generation ALK tyrosine kinase inhibitor (TKI) setting

1487PD - Intracranial and extracranial efficacy of lorlatinib in the post second-generation ALK tyrosine kinase inhibitor (TKI) setting

THER-08. BRAIN METASTASES AS A FIRST SITE OF RECURRENCE IN PATIENTS RECEIVING CHEMOTHERAPY WITH CONTROLLED SYSTEMIC CANCER: A CRITICAL BUT UNDER-RECOGNIZED CLINICAL SCENARIO

BACKGROUND: As the treatment of non-central nervous system (CNS) malignancies has improved, brain metastases (BM) have been observed as a site of first recurrence in patients with controlled or responding systemic cancers. This suggests that while chemotherapy is effective for the systemic disease, drug concentrations in the CNS are likely subtherapeutic. These findings are in accord with data suggesting that over 98% of FDA-approved drugs are unable to penetrate the blood brain barrier (BBB). METHODS: A literature review was conducted to estimate the proportion of patients with non-small lung cancer (NSCLC), breast cancer, and melanoma with controlled systemic cancers who developed BM as initial site of recurrence. Only studies explicitly reporting BM with controlled extra-cranial (EC) disease or reporting the first site of recurrence after chemotherapy were included. RESULTS: Of 262 studies screened,13 contained adequate data regarding the status of systemic cancer and initial site of recurrence. These reported on 1,024 patients. Four studies in patients with NSCLC revealed that 11–43% developed BM as initial site of recurrence. Similar data was seen in patients with breast cancer (6 studies, 4–19%) and metastatic melanoma (3 studies, 4–25%). Approximately 15% of patients on chemotherapy with stable or responding systemic NSCLC, breast cancer, and melanoma developed isolated BM as initial site of relapse. CONCLUSIONS: This literature review included 1,024 patients with common and treatable metastatic cancers whose disease was controlled with chemotherapy. First recurrence in the brain was noted in 23% of those with NSCLC, 12% with breast cancer, and 12% with melanoma. These findings strongly suggest that, while systemic antineoplastic therapy controlled their systemic cancer, concentration of these drugs within the CNS was low, allowing disease progression in the CNS. Reducing the incidence of BM requires novel therapeutic approaches designed to facilitate drug entry through an intact BBB early in treatment.

Complications of chronic suppurative otitis media and their management: five year study at tertiary care centre

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Chronic suppurative otitis media is a disease that can end up in complications when treatment is delayed. The present prospective study was conducted at our tertiary care hospital and teaching centre to evaluate the incidence of complications of CSOM and their management.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; We analysed the clinical and intra operative findings, type of medical and surgical management and recovery of the patient. &lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; Total 20 cases of CSOM with complications were reviewed in study period of 5 years. Of these 20 cases, 14 cases had extracranial (EC) while 6 cases had intracranial (IC) complications. The encountered IC complications were brain abscess ie temporal lobe abscess, pyogenic meningitis, lateral sinus thrombophlebitis and extradural abscess. Among the EC complications, mastoid abscess, Bezolds abscess, zygomatic abscess and labyrinthitis were encountered. The IC complications presented with fever, headache, and signs of meningeal irritation. &lt;em&gt;Pseudomonas aeruginosa&lt;/em&gt;, &lt;em&gt;Proteus&lt;/em&gt;, &lt;em&gt;Staphylococcus epidermidis&lt;/em&gt; and &lt;em&gt;E. coli&lt;/em&gt; were the common organisms isolated. Both groups of patients had cholesteatoma and middle ear granulations. Surgery was the main modality of treatment with zero mortality rate. We reviewed the clinical presentation and management in both groups.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; CSOM complications, inspite of their reduced incidence still pose a great challenge in developing countries. When the disease presents late, it lead to difficulty in management and consequently higher mortality. Our study emphasizes the importance of early diagnosis and prompt management.&lt;/p&gt;

Circulating tumor DNA (ctDNA) in metastatic melanoma (MM) patients (pts) with brain metastases (mets).

9581 Background: Brain mets are common in pts with MM, occurring in up 50% of pts. Serial ctDNA levels at baseline and early on therapy predict objective response (OR) and overall survival (OS) in MM pts without brain mets receiving immune checkpoint inhibitors (ICI). The predictive utility in pts with brain mets is unknown. Methods: BRAF/NRAS ctDNA at baseline and early on ICI therapy (week 3-8) was analysed using mutation specific digital droplet PCR (detection threshold 2.5 copies/ml plasma) in MM pts with brain mets. Intracranial (IC) and extracranial (EC) disease volume (sum of product of diameters of ALL mets [SPD]) and OR, progression-free survival (PFS) and OS were analyzed. Results: 48 pts with brain mets were studied, 40 with concurrent EC disease (SPD EC med 892mm2 [25-22417mm2], IC med 200mm2 [9-1487mm2]) and 8 with isolated IC mets (SPD med 150mm2 [66-1035mm2]). At baseline, ctDNA was detectable in 28 (58%) pts, 28/40 (70%) with IC + EC mets and 0/8 with isolated IC mets. Baseline ctDNA reflected EC disease volume (Pearson’s r = 0.4, p = 0.01) but not IC volume (r = 0.1, p = 0.5). Baseline ctDNA did not associate with IC or EC OR or PFS, however, undetectable ctDNA was associated with superior OS (HR 0.4, p = 0.01). Early on therapy, ctDNA predicted EC response but not IC response; EC OR was 65% if ctDNA undetectable and 6% if detectable (p &lt; 0.01), IC OR was 35% if undetectable and 12% if detectable (p = 0.1). Nevertheless, undetectable ctDNA early on therapy was associated with a superior PFS (HR 0.3, p &lt; 0.01) and OS (HR 0.2, p &lt; 0.01), indicating survival is largely determined by extracranial disease activity. In the 8 pts with IC disease only, 7/8 had disease progressive disease as best response. 1/8 subsequently developed detectable ctDNA at week 12, with multiple new EC mets seen at first restaging scan at this time. Conclusions: ctDNA does not appear to be a useful biomarker for detecting brain mets nor monitoring brain response in melanoma pts receiving ICI. This has important implications when using ctDNA in the setting of surveillance in the metastatic and adjuvant setting.