BIOM-02. LEPTOMENINGEAL DISEASE SECONDARY TO MELANOMA: UPDATES ON THE VALIDITY OF THE VERIDEX CELLSEARCH SYSTEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi10-vi10
Author(s):  
yolanda Pina ◽  
Sepideh Mokhtari ◽  
Youngchul Kim ◽  
Brittany Evernden ◽  
Nam Tran ◽  
...  

Abstract BACKGROUND Leptomeningeal disease (LMD) is devastating with a median survival of 8-10 weeks without treatment. LMD affects approximately 5% to 25% of melanoma patients. Its pathophysiology remains unknown and effective treatments are virtually non-existent. The primary aim of this study was to evaluate the validity of Veridex CellSearch® System (VCS) compared to Gold Standard test (i.e., CSF cytology). MATERIALS AND METHODS A retrospective chart review was performed of subjects with suspected LMD from melanoma enrolled in the MCC 19332/19648 at Moffitt Cancer Center. Patients underwent standard of care with different treatments as deemed appropriate by treating physician. CSF samples were obtained from lumbar punctures, surgeries, and Ommaya reservoir. CSF was evaluated for quantification of CSF circulating tumor cells (CTCs) with the Veridex CellSearch® System (VCS). RESULTS Forty-eight patients were identified with melanoma as primary tumor, ages 29-80. Twenty-seven had LMD (median age 62) with median KPS 70. N=19 (70%) were diagnosed radiographically and n=5 (19%) with CSF cytology; n=14 (54%) had positive cytology on first LP. From 24 patients with LMD who underwent VCS, n=22 (92% patients had positive CSF CTCs. Number of CTCs/mL CSF was significantly higher in patients with LMD versus in patients without LMD (mean SD 227.6 vs. 0.07, p < 0.001). VCS sensitivity and specificity was analyzed. AUC was 0.515, with TPR 0.250 and FPR 0.286. CSF analysis and treatments were described. The median survival of those with LMD was 2.7 months. CONCLUSION These results indicate the potential value of the VCS as an additional tool to the gold standard in the diagnosis of LMD in patients with high suspicion of the disease. Future directions involve doing prospective studies to further validate this method, and to better understand this patient population to enhance diagnostic tools and management of LMD.

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii43-ii43
Author(s):  
Y Pina ◽  
S Mokhtari ◽  
B R Evernden ◽  
N D Tran ◽  
I Smalley ◽  
...  

Abstract BACKGROUND Leptomeningeal disease (LMD) is devastating with a median survival of only 8–10 weeks. LMD affects approximately 5% to 25% of melanoma patients. Its pathophysiology remains unknown and effective treatments are virtually non-existent. The aim was to evaluate demographics, validity of Veridex CellSearch® System (VCS) compared to Gold Standard test (i.e., CSF cytology), risk factors for LMD, and treatment outcomes. MATERIALS AND METHODS A retrospective chart review was performed of subjects with suspected LMD from melanoma enrolled in the MCC 19332/19648 studies between 2013 and 2019 at Moffitt Cancer Center. The patients underwent standard of care with different treatments as deemed appropriate by treating physician. CSF samples were obtained from lumbar punctures, surgeries, and Ommaya reservoir, and sent for analysis. Peripheral blood and CSF were evaluated for detection and quantification of CSF circulating tumor cells (CTCs) with the Veridex CellSearch® System, which is adapted to enumerate CTCs from CSF. RESULTS More than 100 patient charts were reviewed. Only patients with melanoma as primary tumor (N=48) were included in the analysis, with ages 29–80. N=28 (58%) met criteria for LMD (median age 59, M:F ratio of 3:1). Within the LMD group, n=26 patients had cutaneous melanoma as primary tumor; BRAF mutant n=17 (V600E n=14; G469E n=1). At the time of diagnosis, median KPS score was 70, with most prevalent symptoms of headaches, encephalopathy, focal weakness, and nausea/vomiting. N=20 (71%) patients were diagnosed radiographically and n=5 (18%) with CSF cytology; n=14 (52%) had positive cytology on first LP, n=18 (67%) on first two LPs. From 25 patients with LMD who underwent CellSearch® to quantify CTCs, n=22 (88%) patients had positive CSF CTCs; n=18 (72%) on first sample sent for analysis, n=20 (80%) on first two samples. The sensitivity and specificity of the Veridex CellSearch® System compared to the Gold Standard CSF cytology were analyzed. Survival in months plotted against the percentage of CSF-CTCs showed a significant value of p=0.0377. CSF analysis i.e., inflammatory markers, and treatments pre-/post-LMD diagnosis will be described. Most patient were managed with Ommaya reservoir placement, radiation therapy, immunotherapy, BRAF +/- MEK inhibitors, IT thiotepa, or IT topotecan. The median survival of those with LMD was 3.15 months. Two patients outlived their counterparts by 21.1 and 39.0 months after the LMD diagnosis, one of them is still alive but with a very poor functional status. CONCLUSION These results indicate the potential value of the VCS as an additional tool to the gold standard in the diagnosis of LMD in patients with high suspicion of the disease. Future directions involve doing prospective studies to further validate this method, and to better understand this patient population to enhance diagnostic tools and management of LMD.


2019 ◽  
Vol 37 (31_suppl) ◽  
pp. 113-113
Author(s):  
Lauren Boreta ◽  
Emily Yee ◽  
Susan Y. Wu ◽  
Steve E. Braunstein

113 Background: Whole brain radiation (WBRT) is standard therapy used for palliation of brain metastases (BM). SRS is also used as primary treatment in patients with multiple BM, with WBRT reserved for salvage. We sought to describe WBRT practice patterns at a tertiary cancer center with a high-volume radiosurgical practice, and hypothesized that patients treated with WBRT at our institution had limited survival. Methods: Retrospective chart review was performed for patients treated with WBRT for BM from January 2013-Jan 2019. Patients with complete records were included in the analysis. Mann-Whitney U and chi-squared tests were for comparison of clinical factors. Results: Data for 100 patients receiving WBRT were available for analysis. Patients had NSCLC (32%) breast cancer (30%) and melanoma (9%). Median age was 52 (IQR 23). 43% of patients had SRS prior to WBRT, and 41% had 2+ SRS treatments prior to WBRT. 44% of patients had WBRT only. Median survival from diagnosis of BM was 9.3 months (IQR 17.9) and median survival from WBRT was 2.7 months (IQR 11.3). 35% of patients died within 30 days of WBRT, and 3% of patients died on treatment. 77% of patients had uncontrolled extracranial metastases and 43% of patients had imaging evidence of leptomeningeal disease (LMD). Of those with documented cause of death, 65% of patients with LMD died of neurologic causes, compared with 22% of those without LMD (p < 0.001). Patients with KPS < 70 had median survival of 2 months after WBRT, compared with 3.7 months in those with KPS > 70. Patients treated with WBRT alone and those treated with salvage WBRT after SRS had median survival after WBRT of 2.1 months, however median survival from time of brain met diagnosis was 3.3 months in those treated with WBRT alone, versus 12.8 months in those treated with salvage WBRT (p < 0.0001). Conclusions: This study reveals the poor prognosis of patients requiring WBRT at a tertiary cancer center. 35% patients died within 30 days of WBRT, in contrast to a prior study demonstrating 10% 30-day mortality after SRS, owing to differences in patient selection. The potential for poor outcome should be discussed with patients during shared-decision making, balancing toxicity or futility with potential benefits of treatment.


2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi59-vi59 ◽  
Author(s):  
Nicholas Metrus ◽  
Carolos Kamiya ◽  
Shiao-Pei Weathers ◽  
Christa Seligman ◽  
Barbara O’Brien

Abstract INTRODUCTION The incidence of leptomeningeal disease (LMD) is increasing, due to better imaging, earlier diagnosis and improved systemic disease control. However, many of the systemic therapies do not cross the blood brain barrier (BBB) and, despite treatment with radiation and/or intrathecal (IT) chemotherapy, median survival is approximately 4-6months in solid tumors complicated by LMD. Repeated IT injections increase the risk of CNS infection. Preclinical models have shown that infectious meningitis transiently modifies the BBB. METHODS Our series consisted of 6 LMD patients (5 breast cancer primary, 1 lung cancer primary) treated on IT chemotherapy at MD Anderson Cancer Center between 2013 and 2018, who subsequently developed infectious meningitis. Three patients had history of parenchymal metastases in addition to LMD and four had history of radiation to brain and/or spine. LMD was confirmed by cytology and/or imaging. All were treated with IT topotecan. RESULTS CSF cultures were positive for Proprionobacterium acnes in three patients, Pseudomonas aeruginosa in two, and Raoultella ornithinolytica in one, who died shortly thereafter. Antibiotic regimens were variable. Three patients went on to receive IT chemotherapy post-infection (two never discontinued IT chemotherapy throughout infection). Those that had IT chemotherapy post-infection cleared CSF and imaging findings of LMD or maintained stability of radiographic LMD burden until death. No patients died directly from LMD. One patient, who developed infection after Ommaya placement and was never initiated on IT chemotherapy, still cleared his CSF of malignant cells. Excluding the patient who died shortly after meningitis diagnosis, the average time from meningitis diagnosis to death was 8.8 months and the average median survival from LMD diagnosis to death was 14 months. CONCLUSION Our findings support further evaluating the safety and timing of IT chemotherapy with active infectious meningitis and the potential synergistic benefit of increased immunogenicity and chemotherapy in LMD.


2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii4-ii4
Author(s):  
Yolanda Pina ◽  
Brittany Evernden ◽  
Keiran Smalley ◽  
Peter Forsyth

Abstract BACKGROUND Nearly 5–8% of solid cancers present with leptomeningeal disease (LMD). Patients with LMD have a dismal prognosis with survival measured in weeks-to-months. The pathophysiology of this devastating disease remains unknown. METHODS A retrospective chart review was performed of twenty-five adult patients with LMD due to melanoma who were enrolled in the MCC 50172 clinical trial between 05/26/2015 and 07/17/2018. RESULTS Patients had a median age 63 years (31–80) at diagnosis with LMD. Sixteen had confirmed LMD and five did not meet criteria for LMD, but had positive cerebrospinal fluid (CSF)-circulating tumor cells (CTC’s). Those with LMD had a median KPS of 70 (30–90) at presentation, and symptoms most commonly included altered mentation n=6 (37%), headaches n=4 (25%), focal weakness n=3 (19%), and paresthesia n=2 (12%). Eleven patients were diagnosed by MRI. Ten patients (62%) had positive CSF cytology on first attempt and fourteen (87%) on first-two attempts. Lumbar puncture mean OP was 29.4 cmH2O (18–65), with CSF WBC 21.8/cumm (SD 25.6), RBC 2942.5/cumm (SD 9056.1), and protein 187.6 mg/dL (SD 166.1). CSF-CTC’s CellSearch analysis had a sensitivity of 0.75 (12[12 + 4]) and specificity of 0.44 (4[4 + 5]); PPV 0.71 and NPV 0.50. Twelve patients with LMD had positive CSF-CTC’s. Prior to LMD diagnosis, patients were treated with immune checkpoint inhibitors (ICI’s) n=9 (56%), BRAF+/-MEK inhibitors n=5 (31%), and/or RT n=5 (31%). Patients with LMD were treated with Ommaya n=13 +VPS n=3, WBRT n=7, ICI’s n=5, BRAF+MEK inhibitors n=4, and IT topotecan. LMD patients had a median survival 3.27 months after diagnosis (0.30–39). Two patients outlived their counterparts by 21.1 and 39.0 months. The 2 long-term survivors were treated with WBRT and either ICI, pembrolizumab or ipilimumab+nivolumab. CONCLUSION Clinical studies in LMD can provide critical insights and help to develop improved guidelines and current therapies.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1104-1104
Author(s):  
Y. Kwon ◽  
J. Ro ◽  
K. S. Lee ◽  
I. H. Park

1104 Background: Leptomeningeal diseases (LMD) from breast cancer are detected in up to 19% of patients with brain metastasis and their prognosis is extremely poor. Diagnosis of leptomeningeal disease requires positive cerebrospinal fluid (CSF) cytology. However, it is not known whether HER2 status of malignant CSF cells coincides with that of original breast carcinoma cells. We intended to determine whether CSF cytology specimen is suitable for evaluating HER2 status by fluorescence in situ hybridization (FISH) in LMD to provide the basis for HER2 targeted intrathecal therapy. Methods: Both formalin-fixed paraffin-embedded (FFPE) breast carcinoma tissue and liquid based CSF cytology specimen were tested for HER2 status in 16 patients who developed LMD at National Cancer Center between Dec 2004 and Jul 2008. We evaluated HER2 gene amplification by FISH on destained CSF cytology slides which contained minimum 20 malignant cells per slide, and compared with HER2 status by immunohistochemistry (IHC) in FFPE breast carcinoma tissue. HER2 was determined positive when FISH ratio > 2.2 or IHC 3+ according to ASCO/CAP guideline. Results: Concordance rate of HER2 status between CSF cytology by FISH and FFPE tissue by IHC was 100% as shown in the table. Conclusions: When CSF cytology specimen was appropriately prepared yielding adequate cellularity without dry artifact, CSF cytology was suitable for evaluating HER2 status by FISH in LMD. Intrathecal HER2 targeted therapy could be attempted when FFPE breast carcinoma tissue is HER2 positive in view of highly concordant HER2 status by our data. Supported by NCC Grant No 0610240- 3. [Table: see text] No significant financial relationships to disclose.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi24-vi24
Author(s):  
Anthony Sloan ◽  
Harry Hoffman ◽  
Peggy Harris ◽  
Christine Lee-Poturalski ◽  
Theresa Elder ◽  
...  

Abstract The effect of platelets on oncogenesis has been studied extensively in cancer metastasis, but not in glioblastoma (GBM), where metastasis is rare. Here we identify the unique crosstalk between glioma stem cells (GSCs) and platelets within GBM solid tumors that enhance disease progression. Targeting GSCs is considered a promising therapeutic approach; however, no clear method has been identified. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Immunofluorescence, qPCR, and western blot were used to evaluate the presence of GSCs and platelets and their colocalization in GBM patient tissue at University Hospitals-Seidman Cancer Center. Functional assays followed by RNA sequencing were conducted to determine the functional effect of healthy and GBM platelets on growth of patient derived, autologous GSCs. Our clinical studies suggest elevated platelet counts positively correlate with GSC proliferation and negatively correlate with overall survival in patients with GBM. Patients with high platelet counts ( &gt;350k/µl) had a median survival time of 9 months compared to 16 months median survival for patients with normal platelet count (150-350/µl) (p&lt;0.05). We demonstrate platelet and GSC co-localization in GBM solid tissue and platelet exposure to patient derived GSCs cell lines results in a ≥ 3-fold increase in GSC proliferation compared to GSCs not exposed to platelets (p&lt;0.0005). Similarly we found that platelets increased the self-renewing capacity by enhancing the average sphere size (p &lt; 0.005), and increasing the GSC “Stem-like” transcriptional pattern (P&lt; 0.05). Conversely, pharmacologic inhibition of platelet activation reversed the effect of platelets on GSC proliferation (p ranging from 0.05-0.005). These studies suggests the platelet-GSC interactions appear to stimulate GBM oncogenesis, identifying a potential therapeutic target for the treatment of GBM.


2013 ◽  
Vol 71 (9B) ◽  
pp. 677-680 ◽  
Author(s):  
Helio Rodrigues Gomes

Central nervous system (CNS) involvement is a major complication of haematological and solid tumors with an incidence that ranges from 10% in solid malignances up to 25% in specific leukaemia or lymphoma subtypes. Cerebrospinal fluid (CSF) patterns are unspecific. Though CSF cytology has a high specificity (up to 95%), its sensitivity is generally less than 50% and no diagnostic gold standard marker is available, yet. New technologies such as flow cytometry, molecular genetics and newer biomarkers may improve diagnostic sensitivity and specificity, leading to the CNS involvement diagnosis, and consequently, to an effective prophylaxis and successful treatment.


2009 ◽  
Vol 11 (10) ◽  
pp. 881-884 ◽  
Author(s):  
Annamaria Pratelli ◽  
Kadir Yesilbag ◽  
Marcello Siniscalchi ◽  
Ebru Yalçm ◽  
Zeki Yilmaz

Feline sera from Bursa province (Turkey) were assayed for coronavirus antibody using an enzyme-linked immunosorbent assay (ELISA). The study was performed on 100 sera collected from cats belonging to catteries or community shelters and to households. The serum samples were initially tested with the virus neutralisation (VN) test and the results were then compared with the ELISA. The VN yielded 79 negative and 21 positive sera but the ELISA confirmed only 74 as negative. The ELISA-negative sera were also found to be free of feline coronoviruses-specific antibodies by Western blotting. Using the VN as the gold standard test, ELISA had a sensitivity of 100% and a specificity of 93.6%, with an overall agreement of 95%. The Kappa (κ) test indicated high association between the two tests (κ=0.86, 95% confidence interval (CI) 0.743–0.980). The positive predictive value (PPV) was 0.8, and the negative predictive value (NPV) was 0.93. The prevalence of FCoV II antibodies in the sampled population based on the gold standard was 62% (95% CI 0.44–0.77) among multi-cat environments, and 4% (95% CI 0.01–0.11) among single cat households.


2020 ◽  
Vol 48 (2) ◽  
pp. E4 ◽  
Author(s):  
Evan D. Bander ◽  
Evgeny Shelkov ◽  
Oleg Modik ◽  
Padmaja Kandula ◽  
Steven C. Karceski ◽  
...  

OBJECTIVEIntraoperative cortical and subcortical mapping techniques have become integral for achieving a maximal safe resection of tumors that are in or near regions of eloquent brain. The recent literature has demonstrated successful motor/language mapping with lower rates of stimulation-induced seizures when using monopolar high-frequency stimulation compared to traditional low-frequency bipolar stimulation mapping. However, monopolar stimulation carries with it disadvantages that include more radiant spread of electrical stimulation and a theoretically higher potential for tissue damage. The authors report on the successful use of bipolar stimulation with a high-frequency train-of-five (TOF) pulse physiology for motor mapping.METHODSBetween 2018 and 2019, 13 patients underwent motor mapping with phase-reversal and both low-frequency and high-frequency bipolar stimulation. A retrospective chart review was conducted to determine the success rate of motor mapping and to acquire intraoperative details.RESULTSThirteen patients underwent both high- and low-frequency bipolar motor mapping to aid in tumor resection. Of the lesions treated, 69% were gliomas, and the remainder were metastases. The motor cortex was identified at a significantly greater rate when using high-frequency TOF bipolar stimulation (n = 13) compared to the low-frequency bipolar stimulation (n = 4) (100% vs 31%, respectively; p = 0.0005). Intraoperative seizures and afterdischarges occurred only in the group of patients who underwent low-frequency bipolar stimulation, and none occurred in the TOF group (31% vs 0%, respectively; p = 0.09).CONCLUSIONSUsing a bipolar wand with high-frequency TOF stimulation, the authors achieved a significantly higher rate of successful motor mapping and a low rate of intraoperative seizure compared to traditional low-frequency bipolar stimulation. This preliminary study suggests that high-frequency TOF stimulation provides a reliable additional tool for motor cortex identification in asleep patients.


Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1047
Author(s):  
Justin Z. Amarin ◽  
Razan Mansour ◽  
Sura Al-Ghnimat ◽  
Maysa Al-Hussaini

Women with endometrial carcinomas that express PD-L1 may respond better to immunotherapy. Our aim was to investigate the differential characteristics of PDL1–positive endometrial carcinomas and the prognostic significance of PDL1. We performed a retrospective chart review of 231 women with endometrial carcinomas who were managed at King Hussein Cancer Center (2007–2016) and performed immunohistochemistry for MLH1, PMS2, MSH2, MSH6, p53, and PD-L1. Overall, 89 cases (38.5%) were MMR-deficient. PD-L1 was expressed in 49 cases (21.2%) and its expression was significantly associated with MLH1/PMS2 deficiency (p = 0.044) but not MSH2/MSH6 deficiency (p = 0.59). p53 was mutant in 106 cases (46.5%), and its mutation was significantly associated with MMR proficiency (p < 0.001) but not PDL1 expression (p = 0.78). In women with endometrioid adenocarcinomas, PD-L1 expression was significantly associated with the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) grade (p = 0.008). Overall, PDL1 expression did not significantly predict overall survival in unadjusted or adjusted analyses (p = 0.92 and 0.54, respectively). In conclusion, tumors with MLH1/PMS2 loss and high-grade endometrioid adenocarcinomas were more likely to express PDL1 in tumor cells. Further research is required to investigate whether the presence of either characteristic signals a higher likelihood of a favorable response if immunotherapy is administered.


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