Role of aneuploid circulating tumor cells and CD31+ circulating tumor endothelial cells in predicting and monitoring anti-angiogenic therapy efficacy in advanced NSCLC.

Prognosticating the efficacy of anti-angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co-detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non-small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell-based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post-therapeutic platelet endothelial cell adhesion molecule-1 (CD31)- CTCs and CD31+ CTECs exhibited a significantly reduced median progression-free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)+ CTECs (mesenchymal M-type) at baseline revealed a significantly shortened mPFS compared with patients with Vim- CTECs. Post-therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)+ CTCs and CTECs (epithelial E-type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post-therapeutic patients possessing de novo EpCAM+ /Vim+ (hybrid E/M-type) CTECs displayed the shortest mPFS. Patients harboring either pre- or post-therapeutic EpCAM- /Vim- null CTECs (N-type) exhibited a better response to therapy compared to patients harboring EpCAM+ and/or Vim+ CTECs. The presented results support the notion that baseline Vim+ CTECs and post-therapeutic EpCAM+ CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti-angiogenesis combination regimens in NSCLC patients.

[Expression of CD44 in Tumor Tissue and Serum of Small Cell Lung Cancer and Its Clinical Prognostic Significance].

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid growth, early metastasis and acquired therapeutic resistance, and the prognosis is extremely poor. Studies have proved that the stem cell marker CD44 is correlated with tumor recurrence and treatment resistance, however, there are limited reports yet concerning on the CD44 expression and its clinical prognostic significance in SCLC patients. The purpose of this study is to investigate the expression of CD44 in tumor tissues as well as serum of SCLC patients and explore its correlation with the clinical characteristics, therapeutic effect and prognosis. METHODS: The tumor tissues and serum samples of 47 newly diagnosed SCLC patients were collected. Immunohistochemistry and enzyme-linked immunosorbent assay were applied to detect CD44. The relationship between CD44 level and the clinical characteristics as well as prognosis of the patients was analyzed. RESULTS: The stem cell marker CD44 was detectable both in serum sample and tumor tissue of SCLC patients. The positive rate of CD44 in tumor tissue was significantly higher in patients with performance status (PS) 2 than that of patients with PS 0-1 (85.71% vs 30%, P=0.017). Patients were divided in to different groups according to the treatment efficacy. The CD44 immunohistochemical score and serum level in the disease progression group were significantly higher than those in the disease control group, and the differences were statistically significant (P=0.006, P=0.034), Univariate analysis depicted that the progression-free survival (PFS) of CD44 positive patients was significantly shorter than that of CD44 negative patients (5.23 mon vs 9.03 mon, P=0.036). CONCLUSIONS: The positive expression of CD44 in tumor tissues of pre-treatment SCLC patients is correlated with poor PFS. The clinical significance of CD44 is worthy to be further studied.

Pretreatment to Posttreatment Hypoxia Inducible Factor-1α Ratios as a Potentially Predictive Marker for First-Line Treatment in Nonsmall Cell Lung Cancer Patients without Known Driver Mutations.

Background: Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) are key angiogenic regulatory factors. The aim of this study was to identify the most useful prognostic angiogenic factors in advanced nonsmall cell lung cancer (NSCLC) without known driver gene mutations. Methods: Eligible patients were pathologically confirmed to have advanced NSCLC without known driver mutations. All patients were treated with standard first-line chemotherapy ± bevacizumab. Serum concentrations of HIF-1α, VEGF, sVEGFR1, sVEGFR2, and endostatin were measured via enzyme-linked immunosorbent assays (ELISAs) prior to and after two cycles of treatment. Area under the curve (AUC) and optimal cutoff values were calculated by receiver operator characteristic curve (ROC) analyses. The parameters that predicted survival were evaluated by univariate and multivariate Cox proportional hazard analyses. Results: A total of 47 patients were included in this study. HIF-1α levels decreased significantly after treatment in the nonprogressing (partial response/stable disease) patient group (707.94 vs. 355.53 pg/mL, p = 0.002), but increased levels were seen in patients with progressive disease, however, the extent of change did not reach significance (173.70 vs. 416.34 pg/mL, p = 0.078). An HIF-1α ratio of 1.18 was chosen as the best point to predict treatment response through ROC analyses. Via univariate and multivariate analyses, we found that patients with a HIF-1α ratio ≥1.18 after treatment were significantly more likely to have a prolonged progression-free survival (PFS, HR 0.303, 95% CI: 0.153-0.603, p = 0.001) and overall survival (OS, HR 0.436, 95% CI: 0.153-0.603, p = 0.025). Conclusions: We identified the pretreatment to posttreatment HIF-1α ratio as a promising predictor for PFS and OS in NSCLC patients without known driver mutations.

[A Single Center Analysis of Advanced Non-small Cell Lung Cancer Patients Treated with Immunotherapy in Real-world Practice].

BACKGROUND: In recent years, a number of clinical trials have shown that immunocheckpoint inhibitors (ICI) have brought survival benefits to patients with advanced non-small cell lung cancer (NSCLC), however, such clinical trials comprise cohorts selected based on strict and complex entry and exclusion criteria, and the results cannot fully reflect the real world situation. The purpose of this study was to investigate the clinical efficacy and safety of immunotherapy in the real world, as well as possible prognostic factors. METHODS: Patients with advanced NSCLC receiving immunotherapy in Beijing Chest Hospital from January 2017 to July 2019 were retrospectively collected, and the following information were collected: curative effect, progression-free surival (PFS) and adverse reactions. The occurrence of adverse reactions and clinical curative effect and prognosis factors that may be relevant were explored. RESULTS: 34 patients were enrolled in this study, median PFS was 5.66 months (95%CI: 4.48-6.84), grade 1-2 and 3-4 incidence of adverse events was 61.71% (22/34) and 14.71% (5/34), there were 3 patients (8.82%) experienced fatal immune related adverse events (irAE), 2 cases were immune associated pneumonia, 1 case was immune related myocarditis. Univariate analysis showed that tumor-node-metastasis (TNM) stage and metastatic site were correlated with median PFS (P<0.05), and multivariate analysis showed that patients with extrapulmonary metastasis (OR=6.42, P=0.029) and pleural metastasis (OR=14.14, P=0.006) had shorter median PFS. CONCLUSIONS: In the real world, immunotherapy has good efficacy in patients with advanced NSCLC, but the incidence of severe irAE is also higher. Distant metastasis and pleural metastasis are poor prognostic factors for advanced NSCLC patients receiving immunotherapy.

Vimentin expression in circulating tumor cells (CTCs) associated with liver metastases predicts poor progression-free survival in patients with advanced lung cancer.

OBJECTIVE: To investigate the presence of vimentin expression in CTCs and its clinical relevance in patients with advanced lung cancer. METHODS: Peripheral blood was obtained from 61 treatment-naive patients with advanced lung cancer. Subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) platform was applied to identify, enumerate and characterize CTCs based on cell size, aneuploidy of chromosome 8 (Chr8) and vimentin expression. Quantification and analysis of CTCs were performed on patients before chemotherapy administration and after two cycles of therapy. RESULTS: Before treatment, CTCs were detected in 60 (98.4%) patients, small cell CTCs (≤ 5 µm of WBCs) accounted for 52.8% of the absolute CTCs number, while 12 (19.7%) of the included patients had detectable vimentin-positive CTCs (vim+ CTCs). Liver metastases were reported in 7 (11.5%) patients and were significantly correlated to the presence of Vim+ CTCs (p = 0.002), with a high positivity rate of 71.4% (5/7). Vim+ CTCs were mostly in small cell size and Chr8 aneuploidy (77.0% and 82.05%, respectively). Baseline small cell CTCs ≥ 2/6 ml, triploid CTCs ≥ 2/6 ml, Vim+ CTCs ≥ 1/6 ml were found to significantly correlate with poor progression-free survival (PFS) (p = 0.017, p = 0.009 and p = 0.001, respectively). After adjusting for clinically significant factors, baseline Vim+ CTCs ≥ 1/6 ml was the only independent predictor of poor PFS [hazard ratio (HR):2.756, 95% confidence interval (CI): 1.239-6.131; p = 0.013]. CONCLUSIONS: This study demonstrates an important morphologic, karyotypic and phenotypic CTCs heterogeneity in advanced lung cancer patients. The majority of Vim+ CTCs are in small size and Chr8 aneuploidy. Baseline presence of Vim+ CTCs is correlated with liver metastases and may help predict poor PFS.

Trichomegaly and scalp hair changes following treatment with erlotinib in pulmonary adenocarcinoma patients: A case report and literature review.

Erlotinib is among the oral EGFR-tyrosine kinase inhibitors used to treat non-small cell lung cancer. The common side effects of erlotinib include acne form rash and diarrhea. Eyelash trichomegaly and alterations of scalp hair are rarely observed symptoms. In the present study, we report changes in eyelash trichomegaly and scalp hair in six cases of pulmonary adenocarcinoma patients that had been administered erlotinib. The symptoms of eyelash trichomegaly include curly, irregular, excessively long and brittle eyelashes, and alterations of scalp hair include curly or straight, brittle, fine or rigid, reduced growth rate and volume. Since these side effects does not substantially impact patient quality of life, no treatments were administered. These changes in eyelashes and scalp hair gradually disappeared after withdrawal of erlotinib.

[Serum CYFRA21-1 is Correlated with the Efficacy of Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor in Non-small Cell Lung Cancer Patients Harboring EGFR Mutations].

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line treatment regimen for EGFR mutated non-small cell lung cancer (NSCLC) patients. However, the efficacy of EGFR-TKIs widely varies. The aim of this study is to determine whether the pretreatment serum cytokeratin-19 fragments (CYFRA21-1) and carcinoembryonic antigen (CEA) are associated with the efficacy of EGFR-TKIs in EGFR-mutated NSCLC patients. METHODS: We retrospectively enrolled 194 NSCLC patients harboring EGFR mutations who received EGFR-TKIs. Clinical characteristics were collected, and the relation between the efficacy of EGFR-TKIs and pretreatment serum CYFRA21-1 and CEA was analyzed. RESULTS: In all cases, progression-free survival (PFS) in patients with high CYFRA21-1 level was significantly shorter than PFS in patients with normal CYFRA21-1 (7.0 vs 11.9 months, P<0.001). Overall survival (OS) in patients with high CYFRA21-1 was significantly shorter than in the normal-CYFRA21-1 group (12.6 vs 28.0 months, P<0.001). In adenocarcinoma patients, PFS in the high-CYFRA21-1 level group was significantly shorter than in patients with normal CYFRA21-1 (7.0 vs 12.0 months, P<0.001). OS in patients with high CYFRA21-1 was significantly shorter than that in the normal-CYFRA21-1 group (13.1 vs 28.1 months, P<0.001). Among squamous carcinoma patients, CYFRA21-1 level did not affect survival. No significant difference in PFS and OS was observed between patients with high CEA and patients with normal CEA. CONCLUSIONS: EGFR-mutated patients with high CYFRA21-1 had significantly shorter PFS and OS than patients with normal CYFRA21-1 after receiving EGFR-TKIs. Pretreatment serum CYFR21-1 level was a predictive marker of EGFR-TKI treatment in EGFR-mutated NSCLC patients.
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High levels of Phosphatase and Tensin Homolog Expression Predict Favorable Prognosis in Patients with Non-small Cell Lung Cancer.

The prognostic role of phosphatase and tensin homolog (PTEN) in non-small cell lung cancer (NSCLC) has been controversial. In this study, levels of PTEN expression were investigated in NSCLC patients and their prognostic value in NSCLC was assessed. PTEN expression in tumor tissues from 68 NSCLC patients was analyzed using immunohistochemistry and confocal microscopy. Survival analysis was performed using the log-rank test and Cox proportional hazards regression analysis. NSCLC patients classified as expressers of high levels of PTEN (n = 46) had better prognoses than those classified as expressers of low levels (mean survival 17.1 vs. 12.9 months, log rank P = 0.038). In patients with adenocarcinoma (AC), high PTEN expression (n = 9) was associated with significantly longer survival than low PTEN expression (mean survival 23.50 vs. 15.54 months, log rank P = 0.043). High levels of PTEN expression resulted in 43 % reduction in risk for all NSCLC patients (HR 0.57, 95 % CI 0.33-0.98, P = 0.041). PTEN expression and clinical stage remained significantly associated with survival after adjustment for age, sex, and tumor type (HR 0.56, 95 % CI 0.32-0.99; P = 0.048; HR 0.54, 95 % CI 0.36-0.97; P = 0.045). No significant difference in continuous PTEN expression levels was observed among groups with different clinical or pathological characteristics (P > 0.17). When levels of PTEN expression were binarized using the optimal cut-point, higher levels of PTEN expression were observed in patients with T1/T2 than in those with T3/T4 (80 and 58 %, respectively, P = 0.049) and in patients with AC than in those with squamous-cell carcinoma (78 and 58 %, respectively, P = 0.08). No significant difference in binarized PTEN expression levels was found among groups with any other clinical/pathologic characteristic (P > 0.28). Our results suggest that high levels of PTEN expression may be favorable prognostic markers in NSCLC patients.

Favorable response to icotinib in a lung cancer patient with a special mutation at exon 19 of epidermal growth factor receptor.

Many studies have illustrated that two types of mutation - deletions in exon 19 and a point mutation in exon 21 (L858R) - have been reported to comprise up to 90% of all activating epidermal growth factor receptor (EGFR) mutations. A point mutation at exon 19 is a rare mutation, and to date there have been no reports investigating the sensitivities of EGFR-tyrosine kinase inhibitors (TKIs) to the mutation. In this case report, we have demonstrated a special mutation, a point mutation at c.2279T>C (p.L760P) in exon 19 of EGFR, which has responded favorably to icotinib in a lung adenocarcinoma patient with brain metastasis. Icotinib is a new type of oral EGFR-TKI developed in China and is the first EGFR-TKI in Asia. Icotinib has the potential to improve the prognosis of lung adenocarcinoma patients and with less toxic-effect.

[A randomized study of docetaxel plus cisplatin versus paclitaxel plus cisplatin in previously untreated advanced non-small cell lung cancer.].

BACKGROUND: Docetaxel is an active agent in the second-line treatment for non-small cell lung cancer (NSCLC), many clinical trials have demonstrated that it has similar efficacy to common first-line regimens for NSCLC. A randomized study was conducted to compare docetaxel plus cisplatin (DC) versus paclitaxel plus cisplatin (PC) for patients with advanced non-small cell lung cancer as the first-line regimen. METHODS: Ninety patients with previously untreated advanced non-small cell lung cancer were randomly assigned to receive either DC or PC. Patients received docetaxel 75mg/m(2) on day 1 and cisplatin 75mg/m(2) divided into two doses on days 2 to 3 in DC group and paclitaxel 150mg/m(2) on day 1 and cisplatin 75mg/m(2) divided into two doses on days 2 to 3 in PC group. The cycle of two regimens was repeated every 3 weeks. Response and toxicity were evaluated in patients who completed two cycles of chemotherapy at least. RESULTS: Overall survival rate was 31.1% in DC group and 33.3 % in PC group. The median survival time was 10.2 months in DC group and 10.4 months in PC group. Median time to tumor progression was 4.4 months in DC group and 4.9 months in PC group. 1- and 2-year survival rate were 35.6% and 8.9% in DC group and 37.8% and 11.1% in PC group respectively. There were no significant differences in response rate, median survival time, median time to tumor progression and survival rate between two groups (P >0.05). Leucopenia, anemia, nausea and vomiting, and alopecia were the most common grade III and IV toxicities in DC and PC groups, there were no significant differences in grade III and IV toxicities between two groups(P >0.05). There were no treatment-related deaths in both groups. CONCLUSIONS: DC has similar response rate and survivals with PC, and its toxicity is well-tolerated. Docetaxel plus cisplatin is an effective first-line treatment of non-small cell lung cancer.

[A randomized study comparing topotecan plus cisplatin versus etoposide plus carboplatin for previously untreated small cell lung cancer].

BACKGROUND: Topotecan is one of active agents for relapsed small cell lung can-cer (SCLC), some studies have shown that it is effective against SCLC as the first-line drug. This study is to assess the efficacy, toxicity and survival rate of topotecan plus cisplatin (TP) versus etoposide plus carboplatin (CE) in patients with previously untreated SCLC. METHODS: Sixty-four patients with previously untreated SCLC were randomly assigned to receive either TP or CE. Topotecan 0.75 mg/(m²×d) via a 30-min intravenous infusion on days 1 to 5 and cisplatin 25 mg/(m²×d) on days 1 to 3 with hydration were given to patients in TP group. Carboplatin 300 mg/m² on day 1 and etoposide 100 mg/d on days 1 to 5 were given to patients in CE group. Treatment was repeated every 21 days. Responses and toxicities were evaluated in patients who received two cycles of chemotherapy. Patients with limited disease SCLC received thoracic irradiation or operation after the completion of chemotherapy. RESULTS: Overall response rate was 75.0% in TP group and 68.8% in CE group. The median survival time was 10.5 months in TP group and 9.6 months in CE group. 1-, 2- and 3-year survival rate were 40.6%, 18.8% and 9.4% in TP group and 34.4%, 15.6% and 9.4% in CE group respectively. There were no significant differences in response rate, median survival time and survival rate between two groups (P > 0.05). Myelosuppression, nausea and vomiting, and alopecia were the most common toxicities, there was no significant difference in grade III and IV toxicities between two groups (P > 0.05). CONCLUSIONS: TP has similar response rate and survivals with CE, and its toxicities are acceptable. TP regimen is an effective first-line treatment for SCLC.

[Clinical study of combined chemotherapy of domestic paclitaxel and vinorelbine plus platinum for advanced non-small cell lung cancer].

BACKGROUND: To evaluate the efficacy and toxicity of combined chemotherapy of domestic paclitaxel and vinorelbine plus cisplatin and carboplatin in the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: A total of 181 initially treated patients with advanced NSCLC were enrolled in this study and treated by NP (vinorelbine plus cisplatin), TC (domestic paclitaxel plus carboplatin) and TP (domestic paclitaxel plus cisplatin). The efficacy and side effects were analysed after at least two cycles of chemotherapy. RESULTS: The overall response rates (CR+PR) were 42.4% in the NP arm, 40.3% in the TC arm and 43.3% in the TP arm respectively. No significant statistical difference was found among the three groups ( Chi-square= 0.108 6 , P > 0.05). The median survival times were 8.4 months, 9.4 months and 8.9 months respectively in the NP, TC and TP groups ( P > 0.05). The 1-, 2-, 3-year survival rates were 39.0%, 16.9%, 5.1% in the NP group and 41.9%, 21.0%, 6.5% in the TC group and 40.0%, 18.3%, 5.0% in the TP group respectively. No significant statistical difference was found among the three groups ( Chi-square=0.140 4, P > 0.05). The major side effects were myelosuppression, alopecia and nausea/vomiting in the three groups. There were no chemotherapy-related death among the three groups. CONCLUSIONS: The combined regimens of NP, TC and TP are effective and well-tolerated regimens for advanced NSCLC.