Fengying Wu

The role of endobronchial ultrasound elastography in the diagnosis of mediastinal and hilar lymph nodes

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used for diagnosis and mediastinal lymph nodes staging in patients with suspicious lung cancer. Ultrasound elastography is a novel sonographical technique that can evaluate tissue compressibility. The aim of the present study was to investigate the diagnostic yield of elastography for differentiating malignant and benign mediastinal lymph nodes. Conventional EBUS B-mode features, including size, shape, border distinction, echogenicity, central hilar structure with central blood vessel and coagulation necrosis were also evaluated. The ultrasonic features were compared with the pathological results from EBUS-TBNA. 133 lymph nodes in 60 patients were assessed. Elastography displayed the highest area under the curve (AUC) (type 3 versus type 1: AUC, 0.825; 95% confidence interval [CI], 0.707-0.910) with an impressive sensitivity (100%) and an acceptable specificity (65%). The combined model covering the four positive criteria (elastography, heterogeneity, size, and shape) showed that the odds ratio for malignance is 9.44 with a 95% CI of 3.99 to 22.32 (p <0.0001). The combined model was superior to elastography alone (AUC, 0.851; sensitivity, 89.89%; specificity, 72.73%; p <0.0001). This prospective study showed that elastography is a feasible technique for classifying mediastinal lymph nodes, especially in combination with conventional EBUS imaging.Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used for diagnosis and mediastinal lymph nodes staging in patients with suspicious lung cancer. Ultrasound elastography is a novel sonographical technique that can evaluate tissue compressibility. The aim of the present study was to investigate the diagnostic yield of elastography for differentiating malignant and benign mediastinal lymph nodes. Conventional EBUS B-mode features, including size, shape, border distinction, echogenicity, central hilar structure with central blood vessel and coagulation necrosis were also evaluated. The ultrasonic features were compared with the pathological results from EBUS-TBNA. 133 lymph nodes in 60 patients were assessed. Elastography displayed the highest area under the curve (AUC) (type 3 versus type 1: AUC, 0.825; 95% confidence interval [CI], 0.707-0.910) with an impressive sensitivity (100%) and an acceptable specificity (65%). The combined model covering the four positive criteria (elastography, heterogeneity, size, and shape) showed that the odds ratio for malignance is 9.44 with a 95% CI of 3.99 to 22.32 (p <0.0001). The combined model was superior to elastography alone (AUC, 0.851; sensitivity, 89.89%; specificity, 72.73%; p <0.0001). This prospective study showed that elastography is a feasible technique for classifying mediastinal lymph nodes, especially in combination with conventional EBUS imaging.

Feasibility of cytological specimens for ALK fusion detection in patients with advanced NSCLC using the method of RT-PCR.

OBJECTIVESnHistological tissues are preferred for anaplastic lymphoma kinase (ALK) fusion detection in non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the feasibility of cytological sample as an alternative specimen for ALK fusion testing in patients with advanced NSCLC.nnnMATERIALS AND METHODSnAdvanced NSCLC patients with cytological specimens or tumor tissue who had their ALK fusion status detected by the method of reverse transcriptase polymerase chain reaction (RT-PCR) in Shanghai Pulmonary Hospital, Tongji University were included into this study. The efficacy was evaluated in those with ALK fusion positive and received the therapy of crizotinib.nnnRESULTSn1274 patients were included in this study. Among them, 108 patients were ALK RT-PCR positive and 69 of them received crizotinib treatment. Among 1002 patients with cytological specimens, the average concentration of RNA extracted from cytological specimens was 60.99 ng/μl (95% confidence interval [CI], 55.56-66.60) and the incidence rate of ALK fusion was 8.3% (83/1002), which were similar to 63.16 ng/μl (95% CI, 51.88-76.34) (p=0.727) and 9.2% (25/272, p=0.624) in 272 patients with tumor tissue. Also, there were no statistically significant differences regarding to the objective response rate (ORR) (62.0% vs. 42.1%, p=0.177) and the median progression free survival (mPFS) [8.6 months (95% CI 7.30-9.84) vs. 7.0 months (95% CI 4.54-9.47), p=0.736] in patients of cytological group and tissue group after the treatment of crizotinib.nnnCONCLUSIONnCytological specimens showed a high feasibility to detect ALK fusion status, which could be regarded as alternative samples for ALK fusion detection by the method of RT-PCR in patients with advanced NSCLC.

Distinct clinicopathologic features, genomic characteristics and survival of central and peripheral pulmonary large cell neuroendocrine carcinoma: From different origin cells?

BACKGROUNDnPulmonary large cell neuroendocrine carcinoma (LCNEC) represents a rare entity in lung cancer with dismal prognosis. In the present study, we investigated whether there are significant differences between central and peripheral tumors of LCNEC, in terms of clinicopathologic features, genomic profiles, and survival.nnnMETHODS AND MATERIALSnA total of 126 cases of LCNEC were included. The tumors with invasion of the segmental and/or lobar bronchus were classified as central LCNEC and those without as peripheral LCNEC. EGFR/BRAF/Kras mutations and ALK/ROS1 translocations were detected. Overall survival (OS) was evaluated by the Kaplan-Meier plots.nnnRESULTSnThe majority of LCNEC proved to be of the peripheral type (64.3%, 81/126). Central tumors were associated with smoking habit (pu202f=u202f0.047), higher TNM-stage (pu202f=u202f0.014) and larger tumor size (pu202f<u202f0.001). Expression of neuroendocrine markers (CD56, CGA, and SYN) was not significantly different by tumor location but central tumors had higher serum levels of NSE (pu202f=u202f0.004). Peripheral tumors had a higher incidence of EGFR mutations (18.8% vs. 0%, pu202f=u202f0.023). ROS1 translocation was detected in 1 patient with peripheral LCNEC. RB1 protein was more frequently expressed in peripheral tumor than central tumor. The median OS was 3.71 years in the entire cohort. Peripheral tumors had better survival compared with central tumors (median OS: 4.04 vs. 1.51 years, pu202f<u202f0.001). Multivariate analyses demonstrated tumor location (hazard ratio [HR], 6.07, 95% confidence interval [CI], 1.57-23.44, pu202f=u202f0.009), resection status (HR, 6.58, 95% CI, 1.92-22.51, pu202f=u202f0.003) and EGFR mutational status (HR, 0.18, 95% CI, 0.04-0.75, pu202f=u202f0.018) were independent prognostic factors for OS.nnnCONCLUSIONnPrimary tumor location of LCNEC, divided into central and peripheral type, has distinct clinicopathologic features, genomic characteristics and survival. These differences are likely due to differences in the origin cells and pathogenesis of these tumors.

Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: a case report and literature review

ABSTRACT Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC.

Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers

BackgroundCD73 is one of the critical component in the formation of immunosuppressive microenvironment in cancers. We aimed to provide an overview of the current status of CD73 expression and its relationship with clinicopathlogical features and prognosis in different cancers.MethodsPubMed, Web of Science, EMBASE and Cochrane library were searched to identify the relevant studies. CD73 expression level in distinct cancers and its relationship with clinicopathlogical characteristics and prognosis were investigated using online database. Meta-analyses were conducted using RevMan v5.0 and STATA v12.0.ResultsFourteen publications with 2951 cases were included. The incidence of high CD73 expression was 0.50 (95% CI: 0.36–0.63). Data from Oncomine validated that median CD73 expression level in tumor tissues was markedly higher than that in normal tissues in most kinds of cancers except cecum adenocarcinoma and ovarian cancer (Pu2009<u20090.05). High CD73 expression was significantly correlated with shorter overall survival (OS) in various cancers (high risk [HR]u2009=u20091.48; Pu2009<u20090.05). Subgroup analysis using online database demonstrated that high CD73 expression was significantly correlated with poor OS in breast (HRu2009=u20091.23; Pu2009<u20090.05) and ovarian cancer (HRu2009=u20091.14; Pu2009<u20090.05), but favorable OS in lung (HRu2009=u20090.80; Pu2009<u20090.05) and gastric cancer (HRu2009=u20090.71; Pu2009<u20090.05). High CD73 expression was dramatically associated with lymph node metastases (ORu2009=u20092.61; Pu2009=u20090.05).ConclusionHigh CD73 expression was significantly associated with lymph node metastases and a promising prognostic factor in different types of cancers.

EGFR-TKIs plus chemotherapy demonstrated superior efficacy than EGFR-TKIs alone as first-line setting in advanced NSCLC patients with EGFR mutation and BIM deletion polymorphism

BACKGROUNDnNon-small-cell lung cancer (NSCLC) patients with both epidermal growth factor receptor (EGFR) positive mutation and B-cell chronic lymphocytic leukemia/lymphoma-like 11 (BIM) deletion polymorphism had a poor clinical response to EGFR-tyrosine kinase inhibitors (TKIs). The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus chemotherapy versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletion polymorphism.nnnMETHODSnA retrospective, non-randomized analysis was conducted. BIM deletion polymorphism was detected using polymerase chain reaction (PCR) analysis and direct sequencing of DNA from peripheral blood cells. Clinical characteristics, overall survival (OS), progress-free-survival (PFS), objective response rate (ORR) and treatment-related adverse events were compared between EGFR-TKIs alone versus EGFR-TKIs plus chemotherapy group.nnnRESULTSn65 patients were enrolled. 36 of them received EGFR-TKIs and 29 received EGFR-TKIs plus chemotherapy. EGFR-TKIs plus chemotherapy had significantly higher ORR than TKIs alone (65.5% vs. 38.9%, Pu202f=u202f0.046). Median PFS was significantly longer in EGFR-TKIs plus chemotherapy group than in TKIs group (7.2 vs 4.7u202fm; Pu202f=u202f0.008). Median OS was numerically longer in EGFR-TKIs plus chemotherapy group than in TKIs alone (18.5 vs 14.2u202fm; Pu202f=u202f0.107). EGFR-TKIs plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKIs alone.nnnCONCLUSIONnEGFR-TKIs plus chemotherapy conferred a significantly higher ORR, prolonged PFS and numerically longer OS in advanced NSCLC patients with EGFR mutation and BIM deletion polymorphism. Further prospective studies are needed to validate these findings.

Novel antibodies against GPIbα inhibit pulmonary metastasis by affecting vWF-GPIbα interaction

BackgroundPlatelet glycoprotein Ibα (GPIbα) extracellular domain, which is part of the receptor complex GPIb-IX-V, plays an important role in tumor metastasis. However, the mechanism through which GPIbα participates in the metastatic process remains unclear. In addition, potential bleeding complication remains an obstacle for the clinical use of anti-platelet agents in cancer therapy.MethodsWe established a series of screening models and obtained rat anti-mouse GPIbα monoclonal antibodies (mAb) 1D12 and 2B4 that demonstrated potential value in suppressing cancer metastasis. To validate our findings, we further obtained mouse anti-human GPIbα monoclonal antibody YQ3 through the same approach.Results1D12 and 2B4 affected the von Willebrand factor (vWF)-GPIbα interaction via binding to GPIbα aa 41-50 and aa 277-290 respectively, which markedly inhibited the interaction among platelets, tumor cells, and endothelial cells in vitro, and reduced the mean number of surface nodules in the experimental and spontaneous metastasis models in vivo. As expected, YQ3 inhibited lung cancer adhesion and demonstrated similar value in metastasis. More importantly, for all three mAbs in our study, none of their Fabs induced thrombocytopenia.ConclusionOur results therefore supported the hypothesis that GPIbα contributes to tumor metastasis and suggested potential value of using anti-GPIbα mAb to suppress cancer metastasis.

Heterogeneity of PD-L1 Expression Among the Different Histological Components and Metastatic Lymph Nodes in Patients With Resected Lung Adenosquamous Carcinoma.

&NA; In this study, we investigated heterogeneity of programmed death‐ligand 1 (PD‐L1) expression and accordance of metastatic nodes. PD‐L1 expression in 72 resected lung adenosquamous carcinoma and paired metastatic nodes was assessed. We found that PD‐L1 expression was inconsistent in different histologic components within the tumor, and consistent in paired (primary and lymph node) histologic components. Introduction: Programmed death‐ligand 1 (PD‐L1) expression using immunohistochemistry is approved by the US Food and Drug Administration to guide treatment with anti‐programmed death‐1/PD‐L1 monoantibodies. However, intratumoral heterogeneity of PD‐L1 expression and the accordance between primary and metastatic lesions remains unresolved. Materials and Methods: PD‐L1 expression was evaluated in tumor cells and tumor‐infiltrating lymphocytes (TILs) of surgically resected lung adenosquamous carcinoma. Discrepancy of PD‐L1 expression and cluster of differentiation 8‐positive TILs of different histologic components was investigated. PD‐L1 expression was also compared between primary tumor and nodal metastases. Results: The study included a total of 72 lung adenosquamous carcinomas. Fifteen patients (20.8%) and 25 patients (34.7%) were positive for PD‐L1 expression in adenomatous and squamous components respectively, with a cutoff value of 5%. We found that 57.8% of cases showed consistent PD‐L1 expression in tumor cells in the different histological components at a cutoff of 1%, and 48.1% of cases were likewise consistent at a cutoff of 5%. In paired squamous components of metastatic nodes and primary lesions, 90% and 80% of cases of PD‐L1 expression were consistent, at cutoffs of 1% and 5%, respectively. For the adenomatous component of tumor/metastasis pairs, 77.8% of cases at the 1% cutoff and 74.1% of cases at the 5% cutoff were consistent, partially attributed to the difference of predominant histologic patterns. Conclusion: PD‐L1 expression showed discrepancy in different histological components within a tumor and consistency in paired histological type between tumor and metastases. Different pathological features might contribute to the heterogeneous PD‐L1 expression in patients with non–small‐cell lung cancer.

A Phase II Clinical Trial of Apatinib in Pretreated Advanced Non-squamous Non–small-cell Lung Cancer

&NA; Apatinib is an oral multi‐tyrosine kinase inhibitor that has been effective in treating many solid tumors. This phase II clinical trial evaluated the efficacy and safety of apatinib in cases of previously heavily treated non‐squamous non–small‐cell lung cancer. Apatinib showed promising efficacy and manageable toxicity, and thus represents a therapeutic option for patients with non‐squamous non–small‐cell lung cancer. Objectives: Apatinib exhibits broad‐spectrum antitumor activities by selectively inhibiting vascular endothelial growth factor receptor‐2. This study evaluated the efficacy and safety of apatinib in patients with advanced non‐squamous non–small‐cell lung cancer who were heavily pretreated or not suitable to receive standard second‐line chemotherapy. Patients and Methods: This was an open‐label, single‐arm phase II clinical trial (ClinicalTrials.gov NCT02515435). Patients received 500 or 750 mg apatinib daily until progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was the objective response rate. The secondary endpoints included disease control rate, progression‐free survival, overall survival, and side effects. Apatinib administration was allowed beyond disease progression. Results: Between March 2015 and August 2016, 40 patients were enrolled. Among them, 6 (15.0%), 16 (40.0%), and 18 (45.0%) received apatinib as the second‐, third‐, and fourth‐line or beyond treatment, respectively. The mean dosage of apatinib was 477.0 ± 85.3 mg/day. Thirty‐eight patients were available for response evaluation; the objective response rate and disease control rate were 13.2% and 63.2%, respectively. The median progression‐free survival was 3.06 months (95% confidence interval [CI], 2.20‐4.14 months). The median overall survival was 7.69 months (95% CI, 5.36 months to not estimable). The most common treatment‐related adverse events were hand‐foot‐skin reaction (30.0%), proteinuria (27.5%), oral mucositis (22.5%), fatigue (20.0%), and hypertension (17.5%). Nine patients received apatinib after progression, and the median duration of apatinib therapy beyond progression was 5.13 months (95% CI, 4.27‐7.82 months). Conclusion: Apatinib shows promising efficacy and manageable toxicity in patients with advanced non‐squamous non–small‐cell lung cancer. Apatinib therapy beyond progression could provide further benefits in specific subpopulations.

Outcomes of Pemetrexed-based chemotherapies in HER2-mutant lung cancers.

BackgroundHER2 mutation has been found to be an oncogenic driver gene in non-small cell lung cancers(NSCLC) and HER2-directed therapies have shown promising results in this unique population, while little is known about its association with outcomes of chemotherapy. The aim of this study was to investigate the efficacy of first line chemotherapy in patients with advanced HER2-mutant lung adenocarcinomas.MethodsPatients with advanced NSCLC(Nu2009=u20091714) initially underwent testing for EGFR, KRAS, BRAF mutations and ALK, ROS1 rearrangements, and negative cases were then assessed for HER2 mutations using the method of amplification refractory mutation system(ARMS). The efficacy of first line pemetrexed-based chemotherapy was investigated in patients with HER2-mutant and those with EGFR-mutant, ALK/ROS1-rearranged and KRAS-mutant advanced adenocarcinomas.ResultsHER2 mutations were detected in 29 of 572(5.1%) specimens from a selected population of EGFR/KRAS/BRAF/ALK/ROS1 negative patients. All of them are adenocarcinomas. Among patients with HER2-mutant lung cancers, 25 received pemetrexed-based first line chemotherapy. The objective response rate(ORR) was 36.0%. Their median progression free survival(PFS) was 5.1xa0months, which was similar with that of KRAS-mutant group (nu2009=u200940,5.0xa0months, pu2009=u20090.971), numerically shorter than that of EGFR-mutant group(nu2009=u200974, 6.5xa0months, pu2009=u20090.247) and statistically significantly shorter than that of ALK/ROS1-rearranged group (nu2009=u200939,9.2xa0months, pu2009=u20090.004). Furthermore, HER2 variants subgroup analysis showed that PFS was inferior in A775_G776insYVMA group compared with other variants (4.2 vs 7.2xa0months, pu2009=u20090.085).ConclusionsPatients with advanced HER2-mutant lung adenocarcinomas showed an inferior outcome of first line pemetrexed-based chemotherapy compared to those with ALK/ROS1 rearrangements, which strengthen the need for effective HER2-targeted drugs in clinical practice.