Haihong Yang

The role of NF-E2-related factor 2 in predicting chemoresistance and prognosis in advanced non-small-cell lung cancer.

BACKGROUND NF-E2-related factor 2 (Nrf2) plays an important role in platinum chemoresistance by activating transcription of target genes through binding to the antioxidant response element (ARE) in gene promoters, moreover it could stimulate tumor growth in non-small-cell lung cancer (NSCLC). The objective of this study was to elucidate the correlation between Nrf2 expression and platinum-based chemotherapy response as well as the prognostic significance of Nrf2 levels. PATIENTS AND METHODS Immunohistochemical analysis of Nrf2 in tumor specimens was performed in a total of 60 patients with stage IIIB or IV NSCLC. RESULTS Positive staining for Nrf2 was found in nearly all cases, just at different levels. High Nrf2 expression was noted in 34 of 60 patients (56.7%). The expression of Nrf2 correlated with age (P = .014), stage (P = .017), and performance status (P = .014). The response rate of platinum-based chemotherapy in patients with < 75% positive staining was significantly higher than that in patients with 75%-100% positive staining (P = .003; r = 0.447). Furthermore, a high percentage of Nrf2 staining was the independent prognostic factor in progression survival (P = .000) analysis. CONCLUSION We suggest that the assessment of Nrf2 expression may be useful for evaluating chemoresistance and tumor progression in patients with advanced stage NSCLC.

The expression of p33 ING1 , p53, and autophagy-related gene Beclin1 in patients with non-small cell lung cancer

The purpose of this study was to investigate the expressions of tumor inhibitor of growth (ING1) gene p33ING1, p53, and autophagy-related gene Beclin1 in human non-small cell lung cancer (NSCLC), and the correlation between their expressions with clinical pathological features and clinical significance. The research can provide new ideas and experimental evidence for early diagnosis and biotherapy for NSCLC in the future. The human NSCLC tissues and surrounding non-cancerous tissues were collected from surgical operation. The expressions of mRNA or protein of p33ING1, p53, and Beclin1 were detected by using of reverse transcription polymerase chain reaction or Western blot in these tissues. The results were used to analyze the relationships between these gene expressions with the developing of NSCLC and clinical pathological features. The expressions of mRNA or protein of p33ING1 and Beclin1 in NSCLC tissues were significantly lower than that in surrounding noncancerous tissues (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in well- and middle-differentiated NSCLC tissues were lower than those in poor-differentiated NSCLC tissues (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in presence of lymph nodes metastasis were lower than those in absence of lymph nodes metastasis (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in patients of pathological stage (stages I–II) were higher than those in pathological stage (stages III–IV) (p < 0.05). But the expression of protein of mutant-type p53 in NSCLC tissues was significantly higher than that in surrounding non-cancerous tissues (p < 0.05). The expressions of protein of mutant-type p53 in well- and middle-differentiated NSCLC tissues were higher than those in poor-differentiated NSCLC tissues (p < 0.05). The expressions of protein of mutant-type p53 in presence of lymph nodes metastasis were higher than those in absence of lymph nodes metastasis (p < 0.05). The expressions of protein of mutant-type p53 in patients of pathological stage (stages I–II) were lower than those in pathological stage (stages III–IV) (p < 0.05). These expression changes of p33ING1, p53, and autophagy-related Beclin1 genes were associated with tumor cell differentiation, lymph nodes metastasis, and pathological stage of NSCLC. But these expression changes of these three genes were not associated with gender, age, size of primary carcinoma, histological type of NSCLC (p > 0.05). The expression of mRNA of p53 and Beclin1 were correlated with p33ING1 mRNA expression in NSCLC tissues (p < 0.05). The activity changes of tumor inhibitor of growth, autophagy, and apoptosis may be related to the emergence and the development of NSCLC. The combined detection of p33ING1, p53, and Beclin1 genes and proteins will be helpful for early diagnosis and prognosis judgment for NSCLC, and can provide experimental evidence for biotherapy of NSCLC.

Pulmonary alveolar proteinosis: Quantitative CT and pulmonary functional correlations

OBJECTIVE We assessed the relationship between quantitative computer tomography (qCT) and the pulmonary function test (PFT) or blood gas analysis in pulmonary alveolar proteinosis (PAP) patients, as well as the utility of these analyses to monitor responses to whole lung lavage (WLL) therapy. METHODS Thirty-eight PAP patients simultaneously received a CT scan and PFT. Fifteen of these patients, undergoing sequential WLL for a total of 20 lavages, also underwent chest CT scans and blood gas analysis before and after WLL, and 14 of 15 patients underwent simultaneous PFT analysis. Differences between the qCT and PFT results were analyzed by canonical correlation. RESULTS PAP patients with low predicted values for FVC, FEV1, D(LCO) and D(LCO)/VA indicated small airspace volume and mean lung inflation, low airspace volume/total lung volume ratio and high mean lung density. Correlation and regression analysis revealed a strong correlation between D(LCO) and PaO(2) values with CT results. The qCT results indicated that WLL significantly decreased lung weights and mean lung densities, and improved the total airspace volume/total lung volume ratios and mean lung inflations. CONCLUSION Quantitative CT may be a sensitive tool for measuring the response of PAP patients to medical interventions such as WLL.

High expression levels of class III β‑tubulin in resected non‑small cell lung cancer patients are predictive of improved patient survival after vinorelbine‑based adjuvant chemotherapy

The aim of the present study was to determine the frequency and predictive value of the expression of tumor microtubule components in patients with resected non-small cell lung cancer (R-NSCLC) subsequently treated with vinorelbine-based adjuvant chemotherapy. The expression of the microtubule components was evaluated in 85 R-NSCLC tumor samples using immunohistochemistry. All patients received vinorelbine-based chemotherapy. The predictive value of microtubule protein expression for disease-free survival (DFS) and overall survival (OS) was assessed. The expression of the microtubule components was not associated with any baseline clinicopathological factors in the R-NSCLC patients. High tumor expression levels of class III β-tubulin were correlated with an improved DFS (P=0.033) and a trend towards a longer OS (P=0.226). Class II and IV β-tubulins were not correlated with patient outcome. Multivariate analysis of factors, including gender, age, histology, stage and class II, III and IV β-tubulin expression demonstrated that high levels of class III β-tubulin expression were correlated independently with DFS (P= 0.031). These findings suggest that high class III β-tubulin expression levels in resected tumors are predictive of improved DFS in R-NSCLC patients receiving vinorelbine-based chemotherapy.

Bilateral pneumothorax after bevacizumab-containing chemotherapy in fibrosarcoma

Bevacizumab-containing therapies can improve outcomes in patients with sarcoma. Bevacizumab had several notable adverse effects including bowel perforation but bilateral pneumothorax had never been reported in the available English literature. We reported a 23-year-old male with poorly differentiated fibrosarcoma who had spontaneous bilateral spontaneous pneumothorax (SP) after the third cycle of bevacizumab-containing chemotherapy. His bilateral pneumothorax resolved after closed drainage of pleural cavity with a small caliber catheter. The mechanism of pneumothorax developed after bevacizumab therapy was not clear. In patients who had chest discomfort after bevacizumab-containing therapy, pneumothorax should never be overlooked as one of the differential diagnoses.

Improving Selection Criteria for ALK Inhibitor Therapy in Non-Small Cell Lung Cancer: A Pooled-Data Analysis on Diagnostic Operating Characteristics of Immunohistochemistry.

Lung cancer is often diagnosed by molecular markers for prediction and treatment. To date, the golden standard for detection of anaplastic lymphoma kinase (ALK) rearrangements is fluorescence in situ hybridization (FISH). We performed a pooled-data analysis on the diagnostic operating characteristics of immunohistochemistry (IHC) assay on non–small cell lung cancer (NSCLC). We searched Embase, Pubmed, and Springer databases. The results of IHC were evaluated using a modified H-score. We used a 2-level bivariate meta-analysis following a random effect model to summarize sensitivity and specificity and fit hierarchical summary receiver-operating characteristic curves. We also performed sensitivity analysis using different antibodies to investigate potential heterogeneity. Twelve studies consisting of a total of 3754 NSCLC specimens were analyzed. When we defined 1+/2+/3+, 2+/3+, and 3+ as ALK positive, we found the sensitivities to be 99% (95% confidence interval [CI], 97%-100%), 86% (95% CI, 73%-93%), and 56% (95% CI, 36%-74%) and the specificities to be 98% (95% CI, 95%-99%), 99% (95% CI, 99%-100%), and 100% (95% CI, 100%-100%), respectively. We demonstrated that when defining 3+ as positive and 0 as negative the sensitivity was 99% and specificity was 100%. In our sensitivity analysis, we found the sensitivity of D5F3 and 5A4 antibodies to be much higher than that of ALK1. We concluded that IHC scores 0 and 3+ were nearly 100% concordant with FISH-negative and FISH-positive status, respectively. However, IHC scores 1+ and 2+ might require further confirmatory testing by FISH assay. IHC assay using D5F3 and 5A4 antibodies reliably detected NSCLC with ALK rearrangement and may be useful as a screening method to identify these tumors.

Successful treatment of gefitinib-induced acute interstitial pneumonitis with corticosteroid and non-invasive BIPAP-ventilation

This is the case of a 63 year-old male who was diagnosed adenocarcinoma in the left upper lung with ipsilateral malignant pleural effusion. At diagnosis it had already spread to left pulmonary HLN (hilar lymph node) and left supraclavicular lymph node and mediastinal lymph nodes. The patient received combined chemotherapy with bevacizumab and GP (gemcitabine and carboplatin) for 6 courses. Disease progression on chest CT scan was recognized, daily treatment with oral gefitinib (250 mg/day) was commenced. One week later, he was admitted under the impression of gefitinib-related interstitial pneumonitis, gefitinib was discontinued immediately and methylprednisolone with BIPAP assisted ventilation were used. The patient was followed up for 2 months after the start of treatment with corticosteroids and BIPAP assisted ventilation and remained well.

Gemcitabine plus cisplatin chemotherapy with concurrent para-toluenesulfonamide local injection therapy for peripherally advanced nonsmall cell lung cancer larger than 3 cm in the greatest dimension.

Para-toluenesulfonamide (PTS), active ingredient being PTS, is a new anticancer drug applied through local intratumoral injection. The aim of this phase II clinical trial was to investigate the response and toxicity of standard gemcitabine (GEM) plus cisplatin (CIS) chemotherapy with concurrent intratumoral injection of PTS in peripherally advanced nonsmall cell lung cancer. Patients received 1250 mg/m2 of GEM on day 1, 8, and 75 mg/m2 of CIS on day 1, every 21 days for four cycles. PTS was injected intratumorally through percutaneous injection under computed tomography guidance on days 5, 12, 15, and 18 of cycle 1, and repeated on days 5 and 12 of cycle 2 if a less than 50% necrotic area was achieved after the first cycle according to the computed tomography scan. Twelve (46.2%) patients had metastatic disease, whereas 14 (53.8%) patients had stage IIIB disease. All 26 patients were assessable for response. Overall response rate by intention-to-treat was 53.8% (95% confidence interval: 34.6–73.0%). Median progression-free survival and overall survival were 6.5 months (95% confidence interval: 3.8–10.2 months) and 14.5 months (10.0–18.0 months), respectively. One-year and 2-year survivals were 57.7 and 22.4%, respectively. The grade 3–4 hematologic adverse events were neutropenia in six patients (23.1%), anemia in three (11.5%), and thrombocytopenia in four patients (15.4%). Nonhematologic toxicities were generally mild and usually not dose-limiting. Although grade 1–2 emesis occurred in nine patients (34.6%), only one had grade 3 vomiting. Grade 1–2 cough, local pain, and peripheral neurotoxocity developed in 12 (46.2%), three (11.5%), and five (19.2%) patients, respectively. There were no treatment-related deaths. GEM/CIS chemotherapy with concurrent PTS local injection therapy is a well-tolerated modality with potential activity in previously untreated peripheral advanced nonsmall cell lung cancer patients.

[Correlation between pre-treatment anemia and prognosis in non-small cell lung cancer patients].

BACKGROUND AND OBJECTIVE The patients with non-small cell lung cancer (NSCLC) might contract anemia, however, whether anemia is one of the independent prognostic factors to the patients with NSCLC is still controversial. So the aim of this study is to investigate the correlation between anemia and overall survival (OS) in patients with NSCLC. METHODS 1 018 patients with operable NSCLC were retrospectively analyzed in our hospital from January 2000 to December 2008. RESULTS The occurrence of anemia before operation was 252/1 018 (24.1%). The OS in NSCLC patients without anemia was (2 425.98 +/- 50.03) days, and the OS in patients with anemia was (2 107.15 +/-93.86) days. There was significant difference in the OS between them (P = 0.001). The patients with anemia in stage I had shorter survival time than those without anemia (P < 0.001). But there was no difference in other stage patients. TNM stage, gender, tumor size and lymph nodes metastasis were correlated with OS using Cox regression analysis. CONCLUSIONS Anemia is correlated with survival in operable NSCLC patients. Moreover, it is an independent prognostic factor in NSCLC patients with stage I.

Development and clinical validation of a circulating tumor DNA test for the identification of clinically actionable mutations in nonsmall cell lung cancer

Molecular analysis of potentially actionable mutations has become routine practice in oncological pathology. However, testing a wide range of oncogenes and mutations can be technically challenging because of limitations associated with tumor biopsy. Circulating tumor DNA (ctDNA) is a potential tool for the noninvasive profiling of tumors. In this study, we developed a next‐generation sequencing (NGS)‐based test for the detection of clinically relevant mutations in ctDNA and evaluated the feasibility of using this ctDNA NGS‐based assay as an alternative to tissue genotyping. Tissue and matched blood samples were obtained from 72 patients with advanced nonsmall cell lung cancer (NSCLC). NGS‐based testing was performed using plasma cell‐free DNA (cfDNA) samples of all 72 patients as well as tumor DNA samples of 46 patients. Of the remaining 26 patients, tDNA was tested by amplification refractory mutation system PCR (ARMS‐PCR) because of insufficient tissue sample or quality for NGS. Of the 46 patients who had tDNA and cfDNA NGS performed, we found 20 patients were concordant between tDNA and ctDNA alterations and 21 sample pairs were discordant because of additional alterations found in tDNA. Considering all clinically relevant alterations, the concordance rate between tDNA and ctDNA alterations was 54.9% with a sensitivity of 53.2% and a specificity of 75.0%. Our findings demonstrate that targeted NGS using cfDNA is a feasible approach for rapid and accurate identification of actionable mutations in patients with advanced NSCLC, and may provide a safe and robust alternative approach to tissue biopsy.