[Advances in the use of bevacizumab for the treatment of respiratory papilloma].

Respiratory papilloma is a relatively common benign tumor of the respiratory tract, and a few patients may develop malignant changes. The disease has an insidious onset and lacks specific clinical manifestations, and its manifestations are closely related to the growth mode, location and size of the tumor. It can involve multiple parts, such as the larynx, trachea, bronchus, and lung parenchyma, which cause coughing, hoarseness, dysphonia, and, in severe cases, may lead to obstruction of the respiratory tract. At present, the treatment of respiratory papilloma lacks standardization, and there is no effective method to cure the disease. Surgery remains the main treatment for alleviating patients' symptoms and preventing airway obstruction. However, due to the high recurrence rate of respiratory papilloma, multiple surgeries are often needed, which reduces the quality of life of patients and increases their disease burden and economic burden. Bevacizumab, a vascular endothelial growth factor-binding antibody inhibitor, is a promising adjuvant treatment modality that shows good potential for reducing symptoms and the frequency of surgery. This article aimed to review the efficacy and safety of bevacizumab for the treatment of respiratory papilloma and discuss the differences and efficacy of the systemic application and intralesional injection of bevacizumab for the treatment of respiratory papilloma.

Idiopathic pulmonary fibrosis therapy development: a clinical pharmacology perspective.

Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly heterogeneous patient populations, and a lack of robust pharmacodynamic biomarkers. Moreover, because lung biopsy is invasive and dangerous, making the extent of fibrosis as a direct longitudinal measurement of IPF disease progression unfeasible, most clinical trials studying IPF can only assess progression of fibrosis indirectly through surrogate measures. This review discusses current state-of-art practices, identifies knowledge gaps, and brainstorms development opportunities for preclinical to clinical translation, clinical populations, pharmacodynamic endpoints, and dose optimization strategies. This article highlights clinical pharmacology perspectives in leveraging real-world data as well as modeling and simulation, special population considerations, and patient-centric approaches for designing future studies.

Taking Microbiota into Consideration in Mesenchymal Stem Cell Research.

Mesenchymal stem cells (MSCs) are a promising therapy in regenerative medicine, but the clinical efficacy has yet to be identified, because the functions of MSCs are modulated by many factors, including the age and health condition of donors, origin of the tissue, and several other unknown factors. Recently, it has been revealed that, besides host factors, the microbiota that inhabits the human body is a modulator of MSCs as well. Here, we highlight the role of microbiota in the alteration of MSCs functions, with a specific focus on the self-renewal ability, multiple differentiation potential, and the immunomodulation capacity of MSCs. We also review the clinical trials and model research on the synergic and antagonistic effects of microbiota in stem cell therapy. In addition, we discuss the underlying mechanisms of the interplay between microbiota and MSCs, which are elucidated using omics approaches followed by verification experiments. As oral and maxillofacial tissues are important sources of MSCs, as well as a major access to diverse microbes, further studies are needed to elucidate these interactions in the oral field to make greater advancements in regenerative medicine.

[Clinical effects of anterograde sural neurovascular flap in repairing skin and soft tissue defect around the knee].

Objective: To explore the clinical effects of anterograde sural neurovascular flap in repairing skin and soft tissue defect around the knee. Methods: Nine patients with skin and soft tissue defect around the knee admitted to Beijing Fengtai YouAnMen Hospital from May 2011 to December 2018, were included in this retrospective descriptive study, including 8 males and 1 female, aged 16 to 65 years. The wound area after debridement ranged from 8 cm×5 cm to 18 cm×10 cm. Anterograde sural neurovascular flap was used to repair the wounds in 9 patients, with the area ranging from 9 cm×6 cm to 20 cm×12 cm. The donor sits of flaps in 2 patients were closed and sutured directly, and the donor sits of flaps in 7 patients were repaired with medial split-thickness skin graft of the ipsilateral thigh. The flap survival, complications, and follow-up after operation were recorded. Results: The flaps survived and the blood supply was good in 8 patients and the wounds were closed. One patient developed skin ischemic necrosis which was cured after three weeks of dressing change. All the skin grafts in the donor site of flap in 7 patients survived. In 6 months to 5 years of follow-up after surgery, the skin flap had good texture, color, and shape, and normal sensation. Except for one patient whose knee had poor recovery of function, the knee joint function of the other patients recovered well. Conclusions: The anterograde sural neurovascular flap has the advantages of high survival rate, satisfactory appearance and functional recovery post surgery, and is an ideal flap for repairing the skin and soft tissue defect around the knee.

Insights into the novel function of system Xc- in regulated cell death.

System Xc-, also named cystine/glutamate antiporter, is an important intracellular antioxidant element. It is composed of the light chain SLC7A11 (xCT) and the heavy chain SLC3A2 (4F2hc) and functions as raw materials for the synthesis of glutathione (GSH). Recent studies have demonstrated that system Xc- plays an important role in different types of regulated cell death, which is referred to cell death controlled by dedicated molecular machinery. It has been shown that system Xc- involves in ferroptosis, apoptosis, and autophagy-dependent cell death, contributing to different diseases and drug resistance, such as cancer, neurological disorders, and cisplatin resistance to cancers. To date, the intervention of system Xc- by its inhibitors or activators displays a beneficial effect on the treatment of certain diseases. In this review, we summarize recent findings on the role of system Xc- in regulated cell death, including molecular mechanisms and potential therapeutic applications.

Comparing nanoparticle polymeric micellar paclitaxel and solvent-based paclitaxel as first-line treatment of advanced non-small-cell lung cancer: an open-label, randomized, multicenter, phase III trial.

BACKGROUND: Polymeric micellar paclitaxel (pm-Pac) is a novel Cremophor EL-free, nanoparticle micellar formulation of paclitaxel. We aimed to compare the efficacy and safety between pm-Pac plus cisplatin and solvent-based paclitaxel (sb-Pac) plus cisplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 448 stage IIIB to IV NSCLC patients were randomly assigned (2:1) to receive six 3-week cycles of either pm-Pac (230 mg/m2) plus cisplatin (70 mg/m2; n = 300), followed by dose escalation of pm-Pac to 300 mg/m2 from the second 3-week cycle if prespecified toxic effects were not observed after the first cycle, or sb-Pac (175 mg/m2) plus cisplatin (70 mg/m2; n = 148). The primary end point was objective response rate (ORR) assessed by independent review committees (IRCs). The secondary end points included IRC-assessed progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Patients in the pm-Pac-plus-cisplatin group showed significant improvements in IRC-assessed ORR compared with those in the sb-Pac-plus-cisplatin group (50% versus 26%; rate ratio 1.91; P < 0.0001). Additionally, subgroup analysis showed that a higher ORR was consistently observed in both squamous and nonsquamous histological types. IRC-assessed median PFS was significantly higher in the pm-Pac-plus-cisplatin group than in the sb-Pac-plus-cisplatin group (6.4-month versus 5.3-month; hazard ratio 0.63; P = 0.0001). Median OS was not significantly different between the two groups. The incidence of treatment-related serious adverse events (9% versus 18%; P = 0.0090) was significantly lower in the pm-Pac-plus-cisplatin group than in the sb-Pac-plus-cisplatin group. CONCLUSION: Pm-Pac plus cisplatin yielded superior ORR and PFS along with a favorable safety profile and should become an option for patients with advanced NSCLC. CLINICAL TRIAL IDENTIFIER: ClinicalTrials.gov NCT02667743; https://clinicaltrials.gov/ct2/show/NCT02667743.

[Comprehensive treatment on ten patients with perianal necrotizing fasciitis].

Ten patients with perianal necrotizing fasciitis were admitted to our department from June to December 2016. There were 8 men and 2 women among the patients, aged 42 to 69 years. Early and complete debridement surgery and comprehensive supportive treatment during perioperative period were carried out to quickly stabilize the patient's overall condition, and wounds were sutured directly or repaired with autologous scalps and or adjacent local random flaps. After debridement, wound areas ranged from 10 cm×8 cm to 54 cm×21 cm, and area of the flap was about 8 cm×5 cm. The donor site of flap was sutured directly. After the operation, all skin grafts and the flap survived, and wounds of all patients healed. During follow-up of six months to one year, there was no recurrence of perianal necrotizing fasciitis, and functions of the involved lower extremities didn't be influenced.

[Initiation, development, and achievements of burn rehabilitation therapy in China].

Burn rehabilitation in China started from compression therapy in the mid-1970s, which showed the dual effects of prevention and treatment of hypertrophic scars. It not only promoted functional rehabilitation but also strengthened the confidence of patients in rehabilitation treatment. Thereafter, more therapies were brought into practice, such as intra-scar injection of triamcinolone acetonide, application of plastic splints, hydrotherapy, exercises with equipment, skin care, local therapeutic massage, active and passive exercises, as well as external use of drugs for inhibiting scars and pigments. Since the beginning of the 21st century, rehabilitation therapies have been gradually increasing. Psychological rehabilitation, occupational therapy, external use of silicone gel, wax therapy and sound, light, electricity, and radiation therapy have been carried out. Many hospitals have established foundations and held summer camps for children. As far as the whole country is concerned, compared with the huge demand, we still face a number of problems such as shortage of working staff, limited working space, capital chain rupture, lack of multi-disciplinary cooperation, untimely treatment, and incomplete rehabilitation. Nowadays, with increasing knowledge of burn rehabilitation and number of practitioners, improvement of equipment and economic situation, the pace of rehabilitation has accelerated, and the overall implementation of burn rehabilitation therapy has shown great vitality. Patients with burn injury involving over 80% total burn surface area (TBSA) of total burn area or full-thickness burn over 60% TBSA were cured and recovered in different levels of hospitals nationwide, which not only reflects the superb level of burn treatment in China but also reflects the overall improvement of rehabilitation level of the country.

The era of immunogenomics/immunopharmacogenomics.

Although germline alterations and somatic mutations in disease cells have been extensively analyzed, molecular changes in immune cells associated with disease conditions have not been characterized in depth. It is clear that our immune system has a critical role in various biological and pathological conditions, such as infectious diseases, autoimmune diseases, drug-induced skin and liver toxicity, food allergy, and rejection of transplanted organs. The recent development of cancer immunotherapies, particularly drugs modulating the immune checkpoint molecules, has clearly demonstrated the importance of host immune cells in cancer treatments. However, the molecular mechanisms by which these new therapies kill tumor cells are still not fully understood. In this regard, we have begun to explore the role of newly developed tools such as next-generation sequencing in the genetic characterization of both cancer cells and host immune cells, a field that is called immunogenomics/ immunopharmacogenomics. This new field has enormous potential to help us better understand changes in our immune system during the course of various disease conditions. Here we report the potential of deep sequencing of T-cell and B-cell receptors in capturing the molecular contribution of the immune system, which we believe plays critical roles in the pathogenesis of various human diseases.

Hepatitis B virus and risk of non-Hodgkin lymphoma: An updated meta-analysis of 58 studies.

Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta-analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53 714 NHL cases and 1 778 591 controls were finally included. Pooled estimates indicated a significantly increased NHL risk in HBV-infected individuals (summary odds ratio [sOR]: 2.50; 95% confidence interval [CI]: 2.20-2.83) regardless of the study design (case-control studies: sOR: 2.47; 95% CI: 2.16-2.82; cohort studies: sOR: 2.64; 95% CI: 1.78-3.91). Considerable heterogeneity was observed across studies that was primarily attributed to the NHL subtypes (meta-regression: P < .05). Overall, B-cell NHL (sOR: 2.46; 95% CI: 1.97-3.07) presented a stronger association with HBV infection than T-cell NHL (sOR: 1.67; 95% CI: 1.34-2.10). Within the B-cell NHL subtypes, HBV infection was significantly associated with diffuse large B-cell lymphoma (DLBCL, sOR: 2.06; 95% CI: 1.48-2.88) and follicular lymphoma (FL, sOR: 1.54; 95% CI: 1.11-2.12), but not with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and Burkitt lymphoma. The results of this meta-analysis support a positive link between HBV infection and NHL development. Further investigations for the mechanisms underlying HBV-induced NHL are warranted.

Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy.

Background: Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM. Patients and methods: Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled. Results: A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P < 0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P = 0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression. Conclusion: CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.

Bevacizumab plus chemotherapy for patients with advanced pulmonary adenocarcinoma harboring EGFR mutations.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and bevacizumab plus chemotherapy were effective for EGFR-mutant patients. However, the appropriated treatment orders remained controvertible. We investigated the efficacy of treatment orders between bevacizumab plus chemotherapy and EGFR-TKIs for EGFR-mutant patients with advanced pulmonary adenocarcinoma. PATIENTS AND METHODS: This study involved 40 EGFR-mutant patients with advanced pulmonary adenocarcinoma who were treated with bevacizumab plus carboplatin and paclitaxel (Bev + CP) and EGFR-TKIs in different treatment orders or gemcitabine plus cisplatin (GP) in first-line setting. Seventeen patients were treated with Bev + CP and 10 cases with GP in first-line treatment. Thirteen patients received EGFR-TKIs after first-line Bev + CP regimen, while 13 patients were treated with first-line EGFR-TKIs. Progression-free survival (PFS), the response rate (ORR) and overall survival (OS) were evaluated. RESULTS: Median PFS of Bev + CP treatment was significantly longer in first-line than non-first-line settings (11.7 vs. 5.6 months, P = 0.003). Median OS was 37.8 months for EGFR-mutant patients with first-line Bev + CP followed by second-line EGFR-TKIs and 31.0 months for those with first-line EGFR-TKIs and non-first-line Bev + CP, respectively (P = 0.509). Median PFS was 11.7 (95% CI 10.6-12.8) months for Bev + CP group and 4.7 (95% CI 4.4-5.0) months for GP group with the hazard ratio of 0.17 (P = 0.001). ORR was 70.6 and 50.0% in the two groups, respectively (P = 0.415). However, there was no significant difference in median OS (33.7 vs 27.8 months, P = 0.293). CONCLUSIONS: First-line Bev + CP followed by EGFR-TKIs might possibly provide favorable prognosis for EGFR-mutant patients. Bev + CP regimen significantly prolonged PFS in first-line than non-first-line settings. These findings warrant further investigations.

[Qidong Chronic Hepatitis B Cohort: participants enrollment and comparison of baseline characteristics by gender stratification].

Objective: To establish a study cohort of chronic hepatitis B (CHB) in Qidong and evaluate its baseline characteristics. Methods: CHB outpatients of the Third People's Hospital of Qidong were invited to participate in baseline survey from January 1, 2016, including questionnaire survey, liver function detection, serum detection of HBV infection and upper abdomen ultrasound detection. Anticipated sample size was at least one thousand. Baseline data were inputted by EpiData 3.1 software and then cleaned and analyzed by SAS 9.3 software. Results: As of 18 July, 2016, a total of 1 006 participants had been enrolled into the current study, including 615 males with an average age of (44.26±9.97) years and 391 females with an average age of (46.66±11.17) years. The difference in family history of liver disease was not significant between males and females (P>0.05), while the differences in other key information, such as age, education level, tobacco consumption, alcohol drinking, tea consumption, and antiviral intervention, were significant between males and females (P<0.05). Among the key clinical parameters, such as ALT, HBeAg, HBsAg, HBV DNA, albumin, and width of splenic vein and portal vein, only the abnormal rates of ALT and total bilirubin levels were higher in males than in females, the difference was significant (P<0.05). Conclusion: Outpatient department-based CHB cohort was established successfully in Qidong, and sub-cohort could be divided according to the differences on baseline characteristics.

[Effects of combined application of culture supernatant of human umbilical cord mesenchymal stem cells and ciprofloxacin on Staphylococcus aureus in vitro].

Objective: To explore the effects of combined application of culture supernatant of human umbilical cord mesenchymal stem cells (hUCMSCs) and ciprofloxacin on Staphylococcus aureus (SA) in vitro. Methods: hUCMSCs were isolated from umbilical cord tissue of full-term healthy fetus after cesarean section and cultured. Cells in the third passage were used in the experiments after identification. SA strains isolated from wounds of burn patients in our burn wards were used in the experiments. Cells were divided into 0, 10, 100, and 1 000 ng/mL lipopolysaccharide (LPS) groups according to the random number table (the same dividing method below). Cells were cultured with culture medium of mesenchymal stem cells (MSCs) after being treated with medium containing the corresponding mass concentrations of LPS for 12 h. At post culture hour (PCH) 6, 12, and 24, 6 wells of culture supernatant of cells in each group were obtained to measure the content of LL-37 with enzyme-linked immunosorbent assay. Ninety blood agar plates were divided into ciprofloxacin control group (CC), ciprofloxacin+ supernatant group (CS), and ciprofloxacin+ supernatant+ LL-37 antibody group (CSL), with 30 blood agar plates in each group. Blood agar plates in group CC were coated with 1.5×10(8) colony forming unit (CFU)/mL bacteria solution prepared with normal saline. Blood agar plates in group CS were coated with 1.5×10(8) CFU/mL bacteria solution prepared with normal saline and culture supernatant of hUCMSCs (cultured by culture medium of MSCs, the same below) in double volume of normal saline. Blood agar plates in group CSL were coated with 1.5×10(8) CFU/mL bacteria solution prepared with normal saline, culture supernatant of hUCMSCs in double volume of normal saline, and 2.6 µL LL-37 antibody in the concentration of 2 µg/mL. At PCH 12, 24, and 48, 10 blood agar plates of each group were harvested to observe the distribution of SA colony on blood agar plate and to measure the diameter of bacterial inhibition ring of ciprofloxacin. The minimum inhibitory concentration (MIC) of ciprofloxacin against SA of each group was recorded. Fractional inhibitory concentration (FIC) indexes of ciprofloxacin in groups CS and CSL at PCH 12, 24, and 48 were calculated, and the effect of synergy was evaluated. Data were processed with analysis of variance of factorial design, one-way analysis of variance, LSD-t test, Kruskal-Wallis test, and Mann-Whitney U test. Results: (1) At each PCH, the content of LL-37 in culture supernatant of cells in 10, 100, and 1 000 ng/mL LPS groups was higher than that in 0 ng/mL LPS group (with t values from 11.22 to 33.36, P values below 0.01); the content of LL-37 in culture supernatant of cells in 100 and 1 000 ng/mL LPS groups was higher than that in 10 ng/mL LPS group (with t values from 2.24 to 18.73, P<0.05 or P<0.01); the content of LL-37 in culture supernatant of cells in 1 000 ng/mL LPS group was higher than that in 100 ng/mL LPS group (with t values from 12.46 to 14.70, P values below 0.01). (2) At PCH 12, 24, and 48, the bacterial colonies in groups CC, CS, and CSL began to integrate over time. At PCH 12, 24, and 48, the diameters of bacterial inhibition ring of ciprofloxacin in group CC were 26, 24, and 23 mm, respectively, with no obvious change. At PCH 12, 24, and 48, the diameters of bacterial inhibition ring of ciprofloxacin in groups CS and CSL were 82, 71, 68 mm, and 74, 59, 56 mm, respectively, significantly longer than those of group CC. (3) At each PCH, the MIC of ciprofloxacin against SA was significantly higher in group CC than in groups CS and CSL (with Z values from 6.22 to 6.71, P values below 0.01); the MIC of ciprofloxacin against SA was significantly higher in group CSL than in group CS (with Z values all equal to 6.72, P values below 0.01). (4) FIC indexes of ciprofloxacin in groups CS and CSL at PCH 12, 24, and 48 were 0.011, 0.032, 0.032, and 0.122, 0.350, 0.350, respectively. The results indicated that culture supernatant of hUCMSCs had synergistically antibacterial effect on ciprofloxacin. Conclusions: hUCMSCs can secrete LL-37, and the secretion level is increased with increase of LPS concentration. Combination of culture supernatant of hUCMSCs and ciprofloxacin can decrease the dosage of ciprofloxacin in resisting SA. Once LL-37 is neutralized, the synergistically antibacterial effect of culture supernatant of hUCMSCs is decreased.

Clinical significance and prognostic value of femoral lymph node metastasis in FIGO stage III vulvar carcinoma.

OBJECTIVES: To determine the clinical significance and prognostic value of femoral lymph node metastasis (FLNM) in patients with International Federation of Gynecology and Obstetrics (FIGO) stage III vulvar carcinoma. METHODS: The medical records of patients with vulvar carcinoma who underwent inguinofemoral lymphadenectomy between 1990 and 2013 were retrospectively reviewed. RESULTS: Of 66 patients with stage III vulvar carcinoma, 42 had superficial lymph node metastasis (SLNM) only and 24 had FLNM. Significantly higher rates of extracapsular invasion (P = 0.008), multiple nodal metastasis (P = 0.042), and advanced FIGO substage (P = 0.026) as well as a larger tumor diameter (≥4 cm, P = 0.023) and greater depth of invasion (≥5 mm, P = 0.020) were observed among patients with FLNM compared to those with SLNM only. After a median follow-up of 46 months (range, 6-172 months), 35 patients experienced relapse and 30 died from disease. The 5-year cancer-specific survival (CSS) rates were 70.1% and 30.8% for patients with SLNM only and FLNM, respectively (P = 0.001). In multivariate analysis, only FLNM was found to be an independent risk factor for reduced recurrence-free survival (RFS) and CSS among patients with stage III vulvar cancer (hazard ratio [HR] = 2.277, P = 0.037 for RFS; HR = 2.360, P = 0.042 for CSS). When the FLNM cases were considered together as stage IIIC, significant differences emerged in the RFS (P = 0.002) and CSS (P = 0.004) among the re-divided FIGO substages. CONCLUSIONS: FLNM represented an unfavorable status of node metastasis with a worse prognosis compared to that of SLNM alone, and this should be considered in a future FIGO staging system for vulvar cancer.

MicroRNA-related genetic variants in iron regulatory genes, dietary iron intake, microRNAs and lung cancer risk.

Background: Genetic variations in MicroRNA (miRNA) binding sites may alter structural accessibility of miRNA binding sites to modulate risk of cancer. This large-scale integrative multistage study was aimed to evaluate the interplay of genetic variations in miRNA binding sites of iron regulatory pathway, dietary iron intake and lung cancer (LC) risk. Patients and methods: The interplay of genetic variant, dietary iron intake and LC risk was assessed in large-scale case-control study. Functional characterization of the validated SNP and analysis of target miRNAs were performed. Results: We found that the miRNA binding site SNP rs1062980 in 3' UTR of Iron-Responsive Element Binding protein 2 gene (IREB2) was associated with a 14% reduced LC risk (P value = 4.9×10 - 9). Comparing to AA genotype, GG genotype was associated with a 27% reduced LC risk. This association was evident in males and ever-smokers but not in females and never-smokers. Higher level of dietary iron intake was significantly associated with 39% reduced LC risk (P value = 2.0×10 - 8). This association was only present in individuals with AG + AA genotypes with a 46% reduced risk (P value = 1.0×10 - 10), but not in GG genotype. The eQTL-analysis showed that rs1062980 significantly alters IREB2 expression level. Rs1062980 is predicted to alter a miR-29 binding site on IREB2 and indeed the expression of miR-29 is inversely correlated with IREB2 expression. Further, we found that higher circulating miR-29a level was significantly associated with 78% increased LC risk. Conclusion: The miRNA binding site SNP rs1062980 in iron regulatory pathway, which may alter the expression of IREB2 potentially through modulating the binding of miR-29a, together with dietary iron intake may modify risk of LC both individually and jointly. These discoveries reveal novel pathway for understanding lung cancer tumorigenesis and risk stratification.

A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations.

BACKGROUND: A phase III trial was conducted to compare the safety and efficacy of erlotinib with that of gefitinib in advanced non-small cell lung cancer harbouring epidermal growth factor receptor mutations in exon 19 or 21. METHODS: Eligible patients were randomised to receive erlotinib (150 mg per day) or gefitinib (250 mg per day) orally until disease progression or unacceptable toxicity. We aimed to determine whether erlotinib is superior to gefitinib in efficacy. The primary end point was progression-free survival. RESULTS: A total of 256 patients were randomised to receive erlotinib (N=128) or gefitinib (N=128). Median progression-free survival was not better with erlotinib than with gefitinib (13.0 vs 10.4 months, 95% confidence interval (CI) 0.62-1.05, P=0.108). The corresponding response rates and median overall survival were 56.3% vs 52.3% (P=0.530) and 22.9 vs 20.1 months (95% CI 0.63-1.13, P=0.250), respectively. There were no significant differences in grade 3/4 toxicities between the two arms (P=0.172). CONCLUSIONS: The primary end point was not met. Erlotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21, and the two treatments had similar toxicities.