Circulating epithelial tumor cell analysis in CSF in patients with leptomeningeal metastases

Neurology ◽  
2020 ◽  
Vol 94 (5) ◽  
pp. e521-e528 ◽  
Author(s):  
Mark T.J. van Bussel ◽  
Dick Pluim ◽  
Bojana Milojkovic Kerklaan ◽  
Mijke Bol ◽  
Karolina Sikorska ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
High Sensitivity ◽  
Primary Objective ◽  
Leptomeningeal Metastases ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Class Iii ◽  
Epithelial Tumor ◽  
Epithelial Tumor Cell ◽  
Droplet Pcr

ObjectiveThe primary objective was to determine the sensitivity and specificity of epithelial cell adhesion molecule (EpCAM) immunoflow cytometry circulating tumor cells (CTC) analysis in CSF in patients with suspected leptomeningeal metastases (LM). The secondary objective was to explore the distribution of driver mutations in the primary tumor, plasma, cell free CSF (cfCSF), and isolated CTC from CSF in non-small cell lung cancer (NSCLC).MethodsWe tested the performance of the CTC assay vs CSF cytology in a prospective study in 81 patients with a clinical suspicion of LM but a nonconfirmatory MRI. In an NSCLC subcohort, we analyzed circulating tumor (ct)DNA of the selected driver mutations by digital droplet PCR (ddPCR).ResultsThe sensitivity of the CTC assay was 94% (95% confidence interval [CI] 80–99) and the specificity was 100% (95% CI 91–100) at the optimal cutoff of 0.9 CTC/mL. The sensitivity of cytology was 76% (95% CI 58–89). Twelve of the 23 patients with NSCLC had mutated epidermal growth factor receptor (EGFR). All 5 tested patients with LM demonstrated the primary EGFR driver mutation in cfCSF. The driver mutation could also be detected in CTC isolated from CSF.ConclusionCTC in CSF are detected with a high sensitivity for the diagnosis of LM. ddPCR can determine EGFR mutations in both cfCSF and isolated CTC from CSF of patients with EGFR-mutated NSCLC and LM.Classification of evidenceThis study provides Class III evidence that EpCAM-based immunoflow cytometry analysis of CSF accurately identifies patients with LM.

scholarly journals High Sensitivity of Plasma Cell-Free DNA Genotyping in Cases With Evidence of Adequate Tumor Content

2021 ◽  
pp. 921-930
Author(s):  
Catherine B. Meador ◽  
Marina S. D. Milan ◽  
Emmy Y. Hu ◽  
Mark M. Awad ◽  
Michael S. Rabin ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Nsclc Patient ◽  
False Negative ◽  
High Sensitivity ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Resistance Mutations ◽  
Assay Sensitivity ◽  
Cell Free Dna ◽  
Free Dna

PURPOSE Plasma cell-free DNA (cfDNA) sequencing is a compelling diagnostic tool in solid tumors and has been shown to have high positive predictive value. However, limited assay sensitivity means that negative plasma genotyping, or the absence of detection of mutation of interest, still requires reflex tumor biopsy. METHODS We analyzed two independent cohorts of patients with advanced non–small-cell lung cancer (NSCLC) with known canonical driver and resistance mutations who underwent plasma cfDNA genotyping. We measured quantitative features, such as maximum allelic frequency (mAF), as clinically available measures of cfDNA tumor content, and studied their relationship with assay sensitivity. RESULTS In patients with EGFR-mutant NSCLC harboring EGFR T790M, detection of driver mutation at > 1% AF conferred a sensitivity of 97% (368/380) for detection of T790M across three cfDNA genotyping platforms. Similarly, in a second cohort of patients with EGFR or KRAS driver mutations, when the mAF of nontarget mutations was > 1%, sensitivity for driver mutation detection was 100% (43/43). Combining the two NSCLC patient cohorts, the presence of nontarget mutations at mAF > 1% predicts for high sensitivity (> 95%) for identifying the presence of the known driver mutation, whereas mAF of ≤ 1% confers sensitivity of only 26%-54% across platforms. Focusing on 21 false-negative cases where the driver mutation was not detected on plasma next-generation sequencing, other mutations (presumably clonal hematopoiesis) were detected at ≤ 1% AF in 14 (67%). CONCLUSION Plasma cfDNA genotyping is highly sensitive when adequate tumor DNA content is present. The likelihood of a false-negative cfDNA genotyping result is low in a sample with evidence of > 1% tumor content. Bioinformatic approaches are needed to further optimize the assessment of cfDNA tumor content in plasma genotyping assays.

Therapeutic Approaches for the Treatment of Epidermal Growth Factor Receptor Mutated Lung Cancer

2018 ◽  
Vol 18 (8) ◽  
pp. 773-791
Author(s):  
Dhaval Sanchala ◽  
Lokesh K. Bhatt ◽  
Kedar S. Prabhavalkar
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Driver Mutations ◽  
Therapeutic Approaches ◽  
Epidermal Growth ◽  
Egfr Mutant

Lung cancer surfaces to be the predominant determinant of mortality worldwide constituting 13% and 19% of all new cancer cases and deaths related to cancer respectively. Molecular profiling has now become a regular trend in lung cancer to identify the driver mutations. Epidermal Growth Factor Receptor (EGFR) is the most regular driver mutation encountered in Non-Small Cell Lung Cancer (NSCLC). Targeted therapies are now available for the treatment of EGFR mutant NSCLC. EGFR mutation is more frequently expressed in adenocarcinoma than squamous cell carcinoma. This article presents a detailed molecular insight of the therapeutic approaches for the treatment of EGFR mutant lung cancer. The article delineates molecular mechanism of the drugs that are approved, the drugs that are in clinical trial and the drugs that have not entered a clinical trial but shows promising future in the treatment of EGFR mutant lung cancer. Furthermore, this article provides concise information on relevant combinational or monotherapy clinical trials that have been completed for various approaches.

Validation of Michigan risk score and D-dimer to predict peripherally inserted central catheter-related thrombosis: A study of 206,132 catheter days

2021 ◽  
pp. 112972982110087
Author(s):  
Junren Kang ◽  
Wenyan Sun ◽  
Hailong Li ◽  
En ling Ma ◽  
Wei Chen
Keyword(s):  
Sensitivity And Specificity ◽  
Risk Score ◽  
Primary Objective ◽  
Class Iii ◽  
Operating Characteristics ◽  
Central Venous ◽  
Sensitivity Specificity ◽  
Catheter Related Thrombosis ◽  
D Dimer ◽  
Independent Cohort

Background: The Michigan Risk Score (MRS) was the only predicted score for peripherally inserted central venous catheters (PICC) associated upper extremity venous thrombosis (UEVT). Age-adjusted D-dimer increased the efficiency for UEVT. There were no external validations in an independent cohort. Method: A retrospective study of adult patients with PICC insertion was performed. The primary objective was to evaluate the performance of the MRS and age-adjusted D-dimer in estimating risk of PICC-related symptomatic UEVT. The sensitivity, specificity and areas under the receiver operating characteristics (ROC) of MRS and age-adjusted D-dimer were calculated. Results: Two thousand one hundred sixty-three patients were included for a total of 206,132 catheter days. Fifty-six (2.6%) developed PICC-UEVT. The incidences of PICC-UEVT were 4.9% for class I, 7.5% for class II, 2.2% for class III, 0% for class IV of MRS ( p = 0.011). The incidences of PICC-UEVT were 4.5% for D-dimer above the age-adjusted threshold and 1.5% for below the threshold ( p = 0.001). The areas under ROC of MRS and age-adjusted D-dimer were 0.405 (95% confidence interval (CI) 0.303–0.508) and 0.639 (95% CI 0.547–0.731). The sensitivity and specificity of MRS were 0.82 (95% CI, 0.69–0.91), 0.09 (95% CI, 0.08–0.11), respectively. The sensitivity and specificity of age-adjusted D-dimer were 0.64 (95% CI, 0.46–0.79) and 0.64 (95% CI, 0.61–0.66), respectively. Conclusions: MRS and age-adjusted D-dimer have low accuracy to predict PICC-UEVT. Further studies are needed.

scholarly journals High sensitivity sanger sequencing detection of BRAF mutations in metastatic melanoma FFPE tissue specimens

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lauren Y. Cheng ◽  
Lauren E. Haydu ◽  
Ping Song ◽  
Jianyi Nie ◽  
Michael T. Tetzlaff ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Limit Of Detection ◽  
False Negative ◽  
High Sensitivity ◽  
Ffpe Tissue ◽  
Braf Mutations ◽  
Tissue Samples ◽  
Ffpe Samples ◽  
Droplet Pcr ◽  
Tissue Specimens

AbstractMutations in the BRAF gene at or near the p. V600 locus are informative for therapy selection, but current methods for analyzing FFPE tissue DNA generally have a limit of detection of 5% variant allele frequency (VAF), or are limited to the single variant (V600E). These can result in false negatives for samples with low VAFs due to low tumor content or subclonal heterogeneity, or harbor non-V600 mutations. Here, we show that Sanger sequencing using the NuProbe VarTrace BRAF assay, based on the Blocker Displacement Amplification (BDA) technology, is capable of detecting BRAF V600 mutations down to 0.20% VAF from FFPE lymph node tissue samples. Comparison experiments on adjacent tissue sections using BDA Sanger, immunohistochemistry (IHC), digital droplet PCR (ddPCR), and NGS showed 100% concordance among all 4 methods for samples with BRAF mutations at ≥ 1% VAF, though ddPCR did not distinguish the V600K mutation from the V600E mutation. BDA Sanger, ddPCR, and NGS (with orthogonal confirmation) were also pairwise concordant for lower VAF mutations down to 0.26% VAF, but IHC produced a false negative. Thus, we have shown that Sanger sequencing can be effective for rapid detection and quantitation of multiple low VAF BRAF mutations from FFPE samples. BDA Sanger method also enabled detection and quantitation of less frequent, potentially actionable non-V600 mutations as demonstrated by synthetic samples.

Driver mutations to predict for poorer outcomes in non-small cell lung cancer patients treated with concurrent chemoradiation and consolidation durvalumab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8528-8528
Author(s):  
Yufei Liu ◽  
Zhe Zhang ◽  
Waree Rinsurongkawong ◽  
Xiuning Le ◽  
Carl Michael Gay ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Mutation Status

8528 Background: The use of durvalumab after chemoradiation in locally advanced non-small cell lung cancer (NSCLC) patients significantly improves overall survival. However, it is unclear whether this benefit applies to all genetic subtypes of lung cancer. We hypothesize that patients with driver mutation NSCLC may derive less benefit from consolidation durvalumab. Methods: Using the Genomic Marker-Guided Therapy Initiative (GEMINI) database at MD Anderson, we identified 134 patients who were treated with chemoradiation followed by durvalumab for NSCLC. We segregated patients with driver mutations to targetable (EGFR, ALK translocation, ROS1 fusion, MET exon 14 skipping, RET fusion, and/or BRAF) (N = 24) and those driven by canonical KRAS mutations (N = 26). The rest (N = 84) had none of these mutations. We gathered demographic, treatment, and outcome data and compared progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. We used multivariate regression analysis to account for demographic and treatment variables. Results: For our cohort, median age at diagnosis was 64.8, 52% were female (n = 70), and median follow up was 1.5 years. 86% of patients have a history of smoking (n = 115). 21% had squamous cell histology (n = 28). 2 patients had stage IIA disease, 6 had stage IIB, 48 had stage IIIA, 56 had stage IIIB, 13 had stage IIIC, and 9 had stage IV. 73 patients had progression after durvalumab and 37 patients died. Patients with driver mutations had significantly worse median PFS compared to those without driver mutations (8.9 mo vs 26.6 mo; HR 2.62 p < 0.001). Patients with KRAS mutations had particularly poor PFS (Median 7.9 mo, HR 3.34, p < 0.001), while patients with targetable driver mutations trended to worse PFS (Median 14.5 mo, HR 1.96, p = 0.056). The median OS for the cohort was 4.8 yrs with no significant differences based on driver mutation status. On multivariate analysis, only driver mutation status was associated with PFS, but not OS. For patients with first progression, we found the targetable driver group to have significantly improved time to second objective progression (PFS2) compared to the KRAS (HR 0.28, p = 0.011) or non-mutated group (HR 0.38, p = 0.025). All patients in the targetable driver group received targeted therapy after first progression. Conclusions: Our results suggest that patients with driver mutations have worse PFS compared to patients without these mutations after chemoradiation. However, patients with targetable oncogene driver mutations have significantly improved prognosis after initial progression compared to the other groups, likely due to targeted therapy, suggesting that these therapies, including novel approaches towards KRAS mutants, should be further explored in this setting.

scholarly journals Evaluation of the Elecsys Syphilis Immunoassay for Detection of Syphilis in Populations at Risk of Disease in the US and Argentina

2018 ◽  
Vol 3 (1) ◽  
pp. 89-99 ◽  
Author(s):  
Robert H Christenson ◽  
Marvin Lessig ◽  
Gabrielle Miles ◽  
Silke Luebcke ◽  
Cheryl Stillions ◽  
...  
Keyword(s):  
At Risk ◽  
Sensitivity And Specificity ◽  
Treponema Pallidum ◽  
High Sensitivity ◽  
Primary Objective ◽  
Screening Assay ◽  
Syphilis Infection ◽  
Populations At Risk ◽  
The Us ◽  
Testing Algorithm

Abstract Background The Elecsys® syphilis immunoassay is an automated, qualitative immunoassay that uses a double-antigen sandwich format to detect antibodies to Treponema pallidum in human serum and plasma. We aimed to validate performance of the immunoassay in various populations at risk for syphilis infection in the US and Argentina. Methods Samples were obtained for a number of study cohorts, including participants from routine syphilis testing at high or low risk for syphilis, HIV-positive patients, pregnant women, and patients in various stages of syphilis infection. The primary objective was to validate the Elecsys syphilis immunoassay by comparing it with a composite testing algorithm using US Food and Drug Administration (FDA)-approved tests, including the predicate IMMULITE 2000 syphilis screening assay, the rapid plasma reagin, and the T. pallidum particle agglutination assay. Results Complete algorithm testing was performed on all 2660 collected samples. Acceptable precision was demonstrated in all samples. Comparison of the Elecsys syphilis immunoassay with the final syphilis status for all samples yielded a diagnostic sensitivity of 99.5% (95% CI, 98.21–99.94) and a diagnostic specificity of 99.2% (95% CI, 98.69–99.49). Overall, the lower limit of the 95% CIs for sensitivity and specificity met the expected performance of ≥95%. Conclusion This is the first study that confirms the high sensitivity and specificity of the Elecsys syphilis immunoassay in US and Argentinian cohorts and highlights the assay's usefulness as an alternative to current tests for the diagnosis of syphilis infection in a broad range of participant cohorts.

scholarly journals Consensus on management of metastatic colorectal cancer in Central America and the Caribbean: San José, Costa Rica, August 2016

ESMO Open ◽  
2018 ◽  
Vol 3 (3) ◽  
pp. e000315 ◽  
Author(s):  
Roberto Ivan López ◽  
Jenny Lissette Castro ◽  
Heidy Cedeño ◽  
Dagoberto Cisneros ◽  
Luis Corrales ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Primary Objective ◽  
First Line ◽  
Epidermal Growth ◽  
The Caribbean

Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women worldwide. In Latin America and the Caribbean, it has a mortality of 56%. The median overall survival for patients with metastatic colorectal cancer (mCRC) is currently estimated as ~30 months, which has substantially improved through strategic changes in treatment and in the management of patients. As opposed to other metastatic cancers where first-line regimens are often determined, mCRC requires special attention because there is controversy in the possible combinations of the available drugs and the different periods of duration for each patient. Each combination must seek to be effective and to generate the minimum adverse effects as possible. Instead of giving the first-line regimen until the tumour progresses, treatment is often individualised. Furthermore, up to 60% of colorectal tumours are considered non-mutated or wild-type CRC. Not harbouring mutations in the RAS family of genes or mutations in the signalling pathways of the epidermal growth factor receptor causes a null response to anti-epidermal growth factor receptor antibody therapy, which implies even more complex considerations regarding its management. The primary objective of this consensus is to address the main scenarios of mCRC in order to warrant the most appropriate therapeutic intervention for these patients in the Central American and the Caribbean (CAC) region. This can lead to better clinical outcomes as well as quality of life for palliative patients. This document includes the formal expert consensus recommendations for scenarios of mutated and non-mutated mCRC, including synchronous or metachronous disease, management of mCRC with liver and lung metastasis, resectable, potentially resectable or non-resectable tumours and local in the CAC context.

scholarly journals First-Line Therapies for Metastatic Lung Adenocarcinoma Without a Driver Mutation

2018 ◽  
Vol 14 (9) ◽  
pp. 529-535 ◽  
Author(s):  
J. Nicholas Bodor ◽  
Vineela Kasireddy ◽  
Hossein Borghaei
Keyword(s):  
Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Driver Mutation ◽  
Driver Mutations ◽  
First Line ◽  
Histologic Subtype ◽  
First Line Therapy ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Common Histologic Subtype

Lung cancer is the leading cause of cancer-related death worldwide. The majority of these cancers are non–small-cell lung cancer, of which adenocarcinoma is the most common histologic subtype. Most patients are diagnosed at advanced stages when systemic treatment is needed. Whereas prognosis has improved for patients with targetable driver mutations, the majority of patients do not possess tumors with such molecular mutations. Platinum-based chemotherapy has traditionally been the mainstay of treatment, although in recent years immunotherapy has emerged as a treatment option and can result in robust and durable treatment responses in a subset of patients. Recent clinical trials on novel immunotherapy combinations and immunochemotherapy combinations may broaden the number of patients that may benefit from checkpoint inhibitors and elicit responses in those who otherwise may not have experienced a response to monotherapy with an immunotherapy drug. This review will outline the currently available therapies for the first-line treatment of metastatic adenocarcinoma that do not possess a driver mutation and provide a recommended approach and algorithm by which to select the best first-line therapy.

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