Tiehong Zhang

The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapy

Insulin‐like growth factor‐1 receptor (IGF‐1R) targeted therapies have become one of the intriguing areas in anticancer drug development during the last decade. As one of these therapies, anti‐IGF‐1R monoclonal antibodies (mAbs) are also advancing further in development. Our purpose was to conduct a systematic review of the adverse events (AEs) caused by anti‐IGF‐1R monoclonal antibodies in cancer therapy.

Evaluation of Preoperative Hematologic Markers as Prognostic Factors and Establishment of Novel Risk Stratification in Resected pN0 Non-Small-Cell Lung Cancer

Background The aims of this study were to investigate whether the preoperative hematologic markers, the neutrophil-lymphocyte ratio (NLR) or the platelet-lymphocyte ratio (PLR) were prognostic indicators and to develop a novel risk stratification model in pN0 non-small-cell lung cancer (NSCLC). Methods We performed a retrospective analysis of 400 consecutive pN0 NSCLC patients. Prognostic values were evaluated by Cox proportional hazard model analyses and patients were stratified according to relative risks for patients’ survival. Results During the follow-up, 117 patients had cancer recurrence, and 86 patients died. In univariate analysis, age, gender, smoke status and tumor size as well as WBC, NEU, LYM, PLR and NLR were significantly associated with patients’ prognosis. In multivariate analysis, age, tumor size and NLR were independent predictors for patients’ overall survival (P = 0.024, 0.001, and 0.002 respectively). PLR didn’t associated with patients’ survival in multivariate analysis. Patients were stratified into 3 risk groups and the differences among the groups were significant according to disease free survival and overall survival (P = 0.000 and 0.000 respectively). Conclusions We confirmed that NLR other than PLR was an independent prognostic factor. Combination of NLR, age and tumor size could stratify pN0 NSCLC patients into 3 risk groups and enabled us to develop a novel risk stratification model.

Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy

Background Prognostic studies of insulin-like growth factor-1 receptor(IGF-1R) inhibitors in cancer therapy had promising results in infratests, which exhibited that IGF-1R signalling was crucial in cancer cells growth. However, the conclusion of later clinical trials revealed a dim future for IGF-1R inhibitors to treat cancer. We conducted this analysis to figure out how IGF-1R inhibitors acted in clinical cancer therapy. Material and Methods We searched up-to-date studies about the single agent of IGF-1R inhibitors or combination with other therapies in solid tumor. Five IGF-1R anti-agents were involved. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS). Result 17studies were enrolled. The results was not significant in overall survival (I2=37.1%, P=0.080, HR=1.08, 95% CI=0.97-1.21) and in progression-free survival (I2=0.0%, P=0.637, HR=1.05, 95% CI=0.98-1.12). OS for dalotuzumab, breast cancer, colorectal cancer, and PFS for prostate cancer even indicated harmful effects. Conclusion So far, anti-IGF-1R mono-antibodies did not make significant differences in solid tumor prognosis. On the contrary, pessimistic effects were shown in the dalotuzumab, breast cancer, colorectal cancer and prostate cancer subgroups. Further studies of IGF-1R anti-agents were needed, but unwarranted in unselected patients by predictive biomarkers.

The Effect of Diabetes Mellitus on Lung Cancer Prognosis: A PRISMA-compliant Meta-analysis of Cohort Studies.

AbstractPrevious studies suggested that diabetes mellitus (DM) was associated with risk and mortality of cancer, but studies investigating the correlation between DM and lung cancer prognosis remain controversial. Herein, a meta-analysis was performed to derive a more precise estimate of the prognostic role of DM in lung cancer.Medline and Embase were searched for eligible articles from inception to October 25, 2015. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) was calculated to evaluate the correlation between DM and lung cancer prognosis. Subgroup meta-analysis was performed based on the histology and the treatment methods.A total of 20 cohort studies from 12 articles were included in the meta-analysis. Also, 16 studies investigated the overall survival (OS) and 4 studies investigated the progression-free survival (PFS). DM was significantly associated with the inferior OS of lung cancer with the pooled HR 1.28 (95% CI: 1.10–1.49, P = 0.001). The association was prominent in the nonsmall cell lung cancer (NSCLC) subgroup (HR 1.35, 95%CI: 1.14–1.60, P = 0.002), whereas the association was not significant in the small cell lung cancer (SCLC) subgroup (HR 1.33, 95% CI: 0.87–2.03, P = 0.18). When NSCLC patients were further stratified by treatment methods, DM had more influence on the surgically treated subgroup than the nonsurgically treated subgroup. There was no obvious evidence for publication bias by Beggs and Eggers test.The results of this meta-analysis exhibit an association of DM with inferior prognosis amongst lung cancer patients, especially the surgically treated NSCLC patients. Given the small number of studies included in this meta-analysis, the present conclusion should be consolidated with more high-quality prospective cohort studies or randomized controlled trials.

Prognostic Impact of Elevation of Vascular Endothelial Growth Factor Family Expression in Patients with Non-small Cell lung Cancer: an Updated Meta-analysis

BACKGROUND The vascular endothelial growth factor family has been implicated in tumorigenesis and metastasis. The prognostic value of each vascular endothelial growth factor family member, particular VEGF/ VEGFR co-expression, in patients with non-small lung cancer remains controversial. MATERIALS AND METHODS Relevant literature was identified by searching PubMed, EMBASE and Web of Science. Studies evaluating expression of VEGFs and/or VEGFRs by immunohistochemistry or ELISA in lung cancer tissue were eligible for inclusion. Hazard ratios (HRs) and 95% confidence intervals (CIs) from individual study were pooled by using a fixed- or random-effect model, heterogeneity and publication bias analyses were also performed. RESULTS 74 studies covering 7,631 patients were included in the meta-analysis. Regarding pro-angiogenesis factors, the expression of VEGFA (HR=1.633, 95%CI: 1.490-1.791) and VEGFR1 (HR=1.924, 95%CI: 1.220-3.034) was associated separately with poor survival. Especially, VEGFA over-expression was an independent prognostic factor in adenocarcinoma (ADC) (HR=1.775, 95%CI: 1.384-2.275) and SCC (HR=2.919, 95%CI: 2.060-4.137). Co-expression of VEGFA/VEGFR2 (HR=2.011, 95%CI: 1.405-2.876) was also significantly associated with worse survival. For lymphangiogenesis factors, the expression of VEGFC (HR=1.611, 95%CI: 1.407-1.844) predicted a poor prognosis. Co-expression of VEGFC/VEGFR3 (HR=2.436, 95%CI: 1.468-4.043) emerged as a preferable prognostic marker. CONCLUSIONS The expression of VEGFA (particularly in SCC and early stage NSCLC), VEGFC, VEGFR1 indicates separately an unfavorable prognosis in patients with NSCLC. Co-expression VEGFA/ VEGFR2 is comparable with VEGFC/VEGFR3, both featuring sufficient discrimination value as preferable as prognostic biologic markers.

Antitumor effects and molecular mechanisms of figitumumab, a humanized monoclonal antibody to IGF-1 receptor, in esophageal carcinoma

The insulin-like growth factor type 1 receptor (IGF-1R) plays an essential role in the development of numerous cancers. Figitumumab (CP) is not only a monocloncal antibody, it also has agonist activity on IGF-1R. The antitumor activity of CP in esophageal squamous cell carcinoma (ESCC) is still unclear. In our study, we identified IGF-1R as an independent prognostic factor in ESCC patients, and investigated the antitumor effects of CP in ESCC cell lines. CP suppressed tumor growth and sensitized cells to chemotherapeutic drugs. In addition, CP inhibited cell proliferation, migration, colony forming activity and anti-apoptosis induced by IGF-1. Our results showed that CP not only inhibited IGF-1 induced receptor autophosphorylation and downstream signaling, but also triggered β-arrestin1 and G protein-coupled receptor kinases (GRKs) mediated ERK1/2 activation, indicating CP as a biased agonist for IGF-1R. Inhibition of ERK1/2 enhanced the antitumor activity of CP. Furthermore, CP was a more powerful agonist for IGF-1R down-regulation than IGF-1, and dysregulation of β-arrestin1 and GRKs affected this down-regulation. Thus, we demonstrated antitumor activities of CP on ESCC, and as a biased agonist, CP induced ERK1/2 activation and receptor down-regulation required β-arrestin1 and GRKs, suggesting a promising role for targeting IGF-1R in ESCC.

The Number of Resected Lymph Nodes (nLNs) Combined with Tumor Size as a Prognostic Factor in Patients with Pathologic N0 and Nx Non-Small Cell Lung Cancer

Background The prognostic role of the number of resected lymph nodes (nLNs) in pathologic N0 (lymph node negative) and Nx (no lymph node examined) non-small cell lung cancer (NSCLC) patients remains uncertain. Guidelines for optimal nLNs have not been established. In the current study, we evaluated whether a higher number of resected lymph nodes (LNs) results in better survival in different tumor size categories among NSCLC patients without metastatic LNs. Method A retrospective study was conducted. Based on nLNs (LN = 0, 1–7, >7) and tumor size (Ta: ≤3.5cm, Tb: >3.5cm) during surgery, patients were categorized into 6 groups (LN0Ta, LN0Tb, LN1–7Ta, LN1–7Tb, LN7-Ta and LN7-Tb). Survival and multivariate analyses were carried out to determine whether nLNs combined with tumor size was significant for overall survival (OS) or disease free survival (DFS) after adjusting for potential confounders. Results A total of 428 patients were enrolled in the study. Multivariate analysis demonstrated that nLNs, tumor size and pathological stage were the independent prognosticators for OS and DFS. Data from our study suggested that lung cancer lymphadenectomy with more than 7 LNs removed should be considered a benchmark for surgery or pathology at an early stage. Survival was significantly better in the LN7-Ta group, compared with other 5 groups (p<0.001). Conclusions The combined predictor (nLNs combined with tumor size) is an independent prognostic factor and a reasonable stratification criterion in patients with pathologic N0 and Nx NSCLC. The validation of our finding is warranted in further investigation.

Invasion Types Are Associated With Poor Prognosis in Lung Squamous Carcinoma Patients

AbstractAlthough the prognostic significance of the histologic patterns in lung adenocarcinoma is being identified, no significant prognostic indicators in lung squamous carcinoma are accepted as a standard universally. The aim of this study was to evaluate the histologic characteristics incorporating the defined invasion types and distinguish the features that can reflect prognosis.We reviewed all slices of 132 patients with lung squamous carcinoma. The cases were classified according to the World Health Organization (WHO) classification and were evaluated for tumor budding, single cell invasion, large cell invasion, cytologic atypia degree, mitotic count, number of buds, tumor nest size, fibrosis, and necrosis.In univariate analysis, overall survival was associated significantly with age (P = 0.023), lymph nodes metastasis (P < 0.001), distant organ metastasis (P < 0.001), pleural invasion (P < 0.001), tumor budding (P = 0.003), single cell invasion (P = 0.001), mitotic count (P < 0.001), and the cytologic atypia degree (P = 0.009). However, the subtypes of 2004 WHO classification showed no association with outcome (P = 0.209). In multivariate analysis, the independent significant prognostic indicators of lung squamous carcinoma were tumor budding (hazard ratio [HR] = 0.466, P = 0.005), single cell invasion (HR = 0.447, P = 0.003), mitotic count (HR = 0.502, P = 0.048) and cytologic atypia degree (HR = 0.479, P = 0.024).Lung squamous carcinomas with the invasion types were associated with a poor prognosis.

Lower mean corpuscular hemoglobin concentration is associated with unfavorable prognosis of resected lung cancer

BACKGROUND The association of preoperative red blood cell indexes in non-anemic patients undergoing lung resections for non-small-cell lung cancer with recurrence-free survival (RFS) and overall survival (OS) has never been investigated. METHODS We retrospectively examined the impact of preoperative red blood cell indexes on RFS and OS and the relationships between the indexes and clinicopathological factors in lung cancer. RESULTS A total of 649 patients were evaluated. The mean corpuscular hemoglobin concentration was showed as an independent prognostic factor in all patients for OS (hazard ratio [HR]: 0.697; 95% CI: 0.502-0.969; p = 0.032) and RFS (HR: 0.688; 95% CI: 0.519-0.914; p = 0.010). The mean corpuscular volume was an independent prognostic factor in all patients for OS (HR: 0.589; 95% CI: 0.380-0.912; p = 0.018), but not for RFS (HR: 0.684; 95% CI: 0.461-1.015; p = 0.059). CONCLUSION In conclusion, the results of this study suggest that mean corpuscular hemoglobin concentration is an independent prognostic factor for OS and RFS in non-small-cell lung cancer.

Albumin and Neutrophil Combined Prognostic Grade as a New Prognostic Factor in Non-Small Cell Lung Cancer: Results from a Large Consecutive Cohort

Objectives It has been reported nutritional status and systemic inflammation were associated with the outcome of patients with malignancies. However, the prognostic value of combination of them was really scarce, especially in non-small cell lung cancer (NSCLC). In order to find a more simple and efficient predictor, we hypothesized that pretreatment albumin and neutrophil combined prognostic grade (ANPG) could offer an improved prognostic ability in NSCLC patients. Methods We collected pretreatment albumin and neutrophil, clinicopathological, treatment and follow-up data of 1033 consecutive NSCLC patients treated between 2006 and 2011 in this retrospective study. The ANPG was calculated according to pretreatment albumin and neutrophil levels dichotomized by the optimal cut-off values, the quartile values and the clinical reference values. Kaplan-Meier (K-M) curves and Cox proportional regression were used for survival analyses. All the data was analyzed by SPSS 20.0. Results According to optimal cut-off values and quartile values, significant differences were found in different pretreatment albumin, neutrophil levels and ANPG from the K-M curve (all p<0.05). Univariate analyses and multivariate analyses disclosed ANPG was a more sensitive independent predictor for both overall survival (OS) and progression free survival (PFS) than either albumin level or neutrophil level (HRs were higher for ANPG). As for clinical reference values, no significant difference of pretreatment albumin levels was found in K-M curve and univariate analyses. All three indexes lost their significance in multivariate analyses. Conclusion Higher ANPG predicts worse OS and PFS in NSCLC patients independently, and it is more sensitive than hypoalbuminaemia and neutrophilia. It might be used as a reliable, convenient and more sensitive predictor to assist the identification of patients with poor prognosis and be a hierarchical factor in the future NSCLC clinical trials.