We analyzed the number of circulating tumor cells (CTCs) and Epstein–Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The ...levels of CTCs and EBV DNA were measured at baseline and after first‐line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non‐mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first‐line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first‐line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first‐line chemotherapy was associated with significantly longer progression‐free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first‐line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first‐line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
What's new?
Endemic nasopharyngeal carcinoma (NPC) is associated with latent infection of the oncogenic Epstein‐Barr virus (EBV) and frequently metastasizes to distant lymph nodes and organs. Metastatic NPC is treated by serial administration of cytotoxic or targeted therapies and treatment response is generally assessed with serial imaging, which often fails to detect changes in tumor burden. Here, the authors show that the number of circulating tumor cells (CTCs) and EBV DNA levels before, after, and during first‐line chemotherapy are strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
An asymmetric approach to access 2‐substituted isoindolin‐1‐ones 9–11 was developed through TiCl4‐mediated addition‐chlorination of N,O‐acetals 7 a–7 c with terminal alkynes 8. A range of substrates ...were amenable to this transformation, and the desired substituted isoindolin‐1‐ones were obtained in moderate to good yields with moderate diastereoselectivities.
An efficient method to obtain 2‐substituted isoindolin‐1‐ones have been established by TiCl4‐mediated addition‐chlorination of N,O‐acetals with terminal alkynes. A range of substrates were amenable to this transformation, and a series of desired substituted isoindolin‐1‐ones were obtained in moderate to good yields with moderate diastereoselectivities. Moreover, the one pot chlorination is an additional advantage of this method.
A diastereoselective one-pot approach to access trans-5-hydroxy-6-substituted-2-piperidinones by an addition–cyclization–deprotection process has been developed, in which the stereogenic center at ...the C-6 position was solely controlled by α-OTBS group. The utility of this transformation is demonstrated by the asymmetric synthesis of the enantiomer of (−)-CP-99,994.
A diastereoselective approach to access cis‐pyrido and pyrrolo1,2‐c1,3oxazin‐1‐ones has been developed through a one‐pot BF3.Et2O‐catalyzed 4+2 process starting with N,O‐acetals and terminal alkynes. ...In addition, the utility of this transformation is demonstrated by the scalable synthesis of (+)‐Febrifugine in 7 steps from the N,O‐acetal (15% overall yield).
Leptomeningeal metastases (LMs) indicated a poor prognosis in NSCLC. LMs were more frequent in driver gene–mutated patients, and cerebrospinal fluid (CSF) cell-free DNA has shown unique genetic ...profiles of LM in EGFR-mutated LM. However, studies in patients with ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC with LMs are scarce.
Patients with lung cancer with ALK rearrangement were screened from September 2011 to February 2018 at our institute. CSF and paired plasma were tested by next-generation sequencing.
LMs were diagnosed in 30 (10.3%) of 291 patients with ALK-rearranged lung cancer. A total of 11 paired CSF and plasma samples tested by next-generation sequencing were analyzed. Driver genes were detected in 81.8% of the CSF samples (9 of 11) and 45.5% of the plasma samples (5 of 11) (p = 0.183). The maximum allelic fractions were all higher in CSF than in plasma (p = 0.009). ALK and tumor protein p53 gene (TP53) were the two most frequently mutated genes in CSF. Gatekeeper gene ALK G1202R and C1156F mutations were identified in CSF after resistance to alectinib. Multiple copy number variants were mainly found in CSF, including in EGFR, cyclin D1 gene (CCND1), fibroblast growth factor 3 gene (FGF3), and fibroblast growth factor 4 gene (FGF4). Also found were v-myc avian myelocytomatosis viral oncogene homolog gene (MYC) copy number gains and TP53 and cyclin dependent kinase inhibitor 2A gene (CDKN2A) copy number deletions. Brigatinib seemed to be effective in controlling LM. One case showed that CSF could be used to monitor disease development of LM and longitudinally monitor tumor response.
Liquid biopsy of CSF is more sensitive than liquid biopsy of plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in patients with ALK-rearranged NSCLC with LM. Thus, CSF might be promising as a medium of liquid biopsy in LM.
Leptomeningeal metastases are more common in non-small cell lung cancer (NSCLC) with
mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance ...mechanisms of leptomeningeal metastases.
We compared the CellSearch Assay, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected leptomeningeal metastases. Next-generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTC) of 19 patients.
Twenty-one patients were diagnosed with leptomeningeal metastases, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/7.5 mL; range, 27-14,888). CellSearch had a sensitivity of 95.2% for leptomeningeal metastases diagnosis, which was higher than that of TCT (12/21, 57.1%), MRI (10/21, 47.6%), and MRI plus TCT (19/21, 90.5%), respectively. CTCs were found only in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2-4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene
T790M was detected in 7 of 9 patients with extracranial lesions, but was detected in only 1 of 14 CSFCTC samples. Other potential resistant mutations, such as
amplification and
mutation, were also identified in CSFCTCs.
CSFCTCs captured by CellSearch may be a more sensitive and effective way to diagnose leptomeningeal metastases, and may serve as a liquid biopsy medium for gene profiles in NSCLC patients with leptomeningeal metastases.
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An efficient approach to (2R,3S)‐3‐siloxy‐2‐phenylethynyl substituted pyrrolidines was developed through Y(OTf)3‐CuI catalyzed N‐α alkynylation of cyclic imines (1 a and 1 e) with alkynes 2 a–s. As a ...result, a number of trans‐2‐phenyl acetylene substituted‐3‐siloxy pyrrolidine derivatives 4 aa–as, 4 ea–ef and 4 es were synthesized in moderate to good yields with excellent diastereoselectivities (dr up to 99 : 1).
A convenient method to (2R,3S)‐3‐siloxy‐2‐phenylethynyl substituted pyrrolidines through Y(OTf)3‐CuI catalyzed addition process from chiral cyclic imines and alkynes was established. Accordingly, a series of trans‐2‐ethynyl substituted‐3‐siloxy pyrrolidine derivatives were synthesized in moderate yields and with dr up to 99 : 1.
Crizotinib can target against mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK), which has been considered as a multi-targeted tyrosine kinase inhibitor (TKI). The ...objective of this study was to explore the efficacy of crizotinib in advanced non-small-cell lung cancer (NSCLC) with concomitant ALK rearrangement and c-Met overexpression.
Totally, 4622 advanced NSCLC patients from two institutes (3762 patients at the Guangdong Lung Cancer Institute from January 2011 to December 2016 and 860 cases at the Perking Cancer Hospital from January 2015 to December 2016) were screened for ALK rearrangement with any method of IHC, RACE-coupled PCR or FISH. C-Met expression was performed by IHC in ALK-rearranged patients, and more than 50% of cells with high staining were defined as c-Met overexpression. The efficacy of crizotinib was explored in the ALK-rearranged patients with or without c-Met overexpression.
Sixteen patients were identified with c-Met overexpression in 160 ALK-rearranged cases, with the incidence of 10.0% (16/160). A total of 116 ALK-rearranged patients received the treatment of crizotinib. Objective response rate (ORR) was 86.7% (13/15) in ALK-rearranged patients with c-Met overexpression and 59.4% (60/101)in those without c-Met overexpression, P = 0.041. Median PFS showed a trend of superiority in c-Met overexpression group (15.2 versus 11.0 months, P = 0.263). Median overall survival (OS) showed a significant difference for ALK-rearranged patients with c-Met overexpression group of 33.5 months with the hazard ratio (HR) of 3.2.
C-Met overexpression co-exists with ALK rearrangement in a small population of advanced NSCLC. There may be a trend of favorable efficacy of crizotinib in such co-altered patients.
An efficient approach to access functionalized indole derivatives has been developed through Cu(OTf)
-catalyzed C3 aza-Friedel-Crafts alkylation of substituted indoles 5a-5m,
-methyl-pyrrole with ...linear
,
-acetals 4a-4l. As a result, a series of C3 amide aza-alkylated indole derivatives 6a-6ag and 7 were synthesized in moderate to excellent yields.
Background:
Circulating tumor cells (CTCs) are prognostic biomarker in non-small-cell lung cancer (NSCLC). CTCs could also be used as predictor of efficacy of systemic treatments in advanced NSCLC.
...Objectives:
We described the dynamic changes of CTCs during first-line platinum-based chemotherapy in advanced NSCLC and clarified the correlation between CTC counts and efficacy of chemotherapy.
Design:
Chemotherapy is administered and blood specimens are collected at four time points from baseline to disease progression for CTC detection.
Methods:
This multicenter prospective study enrolled patients with previously untreated stage III or IV NSCLC fit for standard platinum-based chemotherapy. Bloods were sampled as per standard operating procedures at baseline, cycle 1 and cycle 4 of chemotherapy, and at disease progression for CTC analysis using the CellSearch system.
Results:
Among 150 patients enrolled, median overall survival (OS) was 13.8, 8.4, and 7.9 months in patients with CTC−, KIT−CTC, and KIT+CTC at baseline (p = 0.002). Patients with persistent negative CTC (46.0%) had longer progression-free survival 5.7 months, 95% confidence interval (CI): 5.0–6.5 versus 3.0 months, 0.6–5.4; hazard ratio (HR): 0.34, 95% CI: 0.18–0.67) and OS (13.1 months, 10.9–15.3 versus 5.6 months, 4.1–7.1; HR: 0.17, 0.08–0.36) compared with patients with persistent positive CTC (10.7%), which was not impacted by chemotherapy. Chemotherapy decreased CTC from 36.0% (54/150) to 13.7% (13/95).
Conclusions:
CTC persistent presence during treatment represents poor prognosis and resistance to chemotherapy in advanced NSCLC. Chemotherapy could effectively eliminate CTCs. Molecular characterization and the functionalization of CTC will be warranted for further intensive investigation.
Trial registration:
NCT01740804.
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