Jiaxi He

Prognostic Significance of Programmed Cell Death 1 (PD-1) or PD-1 Ligand 1 (PD-L1) Expression in Epithelial-Originated Cancer: A Meta-Analysis

AbstractThe expression of programmed cell death 1 (PD-1) and its ligand (PD-L1) has been observed in various epithelial-originated malignancies. However, whether the expression of PD-L1 on tumor cells or the expression of PD-1 on tumor-infiltrating lymphocytes (TILs) is associated with patients’ survival remains controversial.Electronic databases were searched for eligible literatures. Data of hazard ratio (HR) for overall survival (OS) with 95% confidence interval (CI) according to the expression status of PD-L1 or PD-1 evaluated by immunohistochemistry were extracted. The outcomes were synthesized based on random-effects model. Subgroup analyses were proposed.Twenty-nine studies covering 12 types of epithelial-originated malignancies involving 7319 patients (2030/3641 cases for PD-L1 positive/negative, 505/1143 cases for PD-1 positive/negative) with available data of the outcome stratified by PD-L1/PD-1 status were enrolled. Epithelial-originated cancer patients with positive expression of PD-L1 on tumor tissues were associated with significantly poorer OS when compared to those with negative expression of PD-L1 (HR 1.81, 95% CI 1.33–2.46, P < 0.001). Similarly, patients with PD-1 positive expression on TILs had significantly shorter OS than the PD-1 negative group (HR 2.53, 95% CI 1.22–5.21, P = 0.012). In analyses of PD-L1, all subgroups showed consistent trends toward unfavorable prognoses of patients with positive PD-L1 expression, regardless of antibodies and evaluation cutoffs. Subgroup analyses on PD-1 were not available due to limited data.PD-L1 or PD-1 expression status is a significant prognostic factor in epithelial-originated malignancies.

Choice of Surgical Procedure for Patients With Non-Small-Cell Lung Cancer ≤ 1 cm or > 1 to 2 cm Among Lobectomy, Segmentectomy, and Wedge Resection: A Population-Based Study.

PURPOSE According to the lung cancer staging project, T1a (≤ 2 cm) non-small-cell lung cancer (NSCLC) should be additionally classified into ≤ 1 cm and > 1 to 2 cm groups. This study aimed to investigate the surgical procedure for NSCLC ≤ 1 cm and > 1 to 2 cm. METHODS We identified 15,760 patients with T1aN0M0 NSCLC after surgery from the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and lung cancer-specific survival (LCSS) were compared among patients after lobectomy, segmentectomy, or wedge resection. The proportional hazards model was applied to evaluate multiple prognostic factors. RESULTS OS and LCSS favored lobectomy compared with segmentectomy or wedge resection in patients with NSCLC ≤ 1 cm and > 1 to 2 cm. Multivariable analysis showed that segmentectomy and wedge resection were independently associated with poorer OS and LCSS than lobectomy for NSCLC ≤ 1 cm and > 1 to 2 cm. With sublobar resection, lower OS and LCSS emerged for NSCLC > 1 to 2 cm after wedge resection, whereas similar survivals were observed for NSCLC ≤ 1 cm. Multivariable analyses showed that wedge resection is an independent risk factor of survival for NSCLC > 1 to 2 cm but not for NSCLC ≤ 1 cm. CONCLUSION Lobectomy showed better survival than sublobar resection for patients with NSCLC ≤ 1 cm and > 1 to 2 cm. For patients in whom lobectomy is unsuitable, segmentectomy should be recommended for NSCLC > 1 to 2 cm, whereas surgeons could rely on surgical skills and the patient profile to decide between segmentectomy and wedge resection for NSCLC ≤ 1 cm.

The impact of visceral pleural invasion in node-negative non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND Visceral pleural invasion (VPI) is considered an aggressive and invasive factor in non-small cell lung cancer (NSCLC). Recent studies found that depending on tumor size, VPI influences T stage, but there is no consensus on whether VPI is important in node-negative NSCLC. In addition, its role in stage IB NSCLC is still uncertain. In this meta-analysis, we assessed the role of VPI in node-negative NSCLC according to various tumor sizes and especially in stage IB disease. METHODS A systematic literature search of four databases (EBSCO, PubMed, Ovid, and Springer) was performed to find relevant articles. The primary end point was 5-year overall survival. Pooled ORs were calculated using control as a reference group, and significance was determined by the Z-test. RESULTS Thirteen relevant studies in 27,171 patients were included in this study. The number of patients with VPI was 5,821 (21%). VPI was a significant adverse prognostic factor in patients with tumor size ≤ 3 cm (OR, 0.71; 95% CI, 0.64-0.79; P < .001), > 3 but ≤ 5 cm (OR, 0.69; 95% CI, 0.56-0.86; P < .001), and > 5 but ≤ 7 cm (OR, 0.70; 95% CI, 0.54-0.91; P = .007). A further comparison was made with stage IB NSCLC. Tumor size ≤ 3 cm with VPI was associated with a better survival than tumor size > 3 but ≤ 5 cm regardless of VPI (OR, 1.31; 95% CI, 1.19-1.45; P < .001). Exploratory analysis found no survival benefit between tumor size ≤ 3 cm with VPI and tumor size > 3 but ≤ 5 cm without VPI (OR, 1.16; 95% CI, 0.95-1.43; P = .15); however, the prognosis for tumor size > 3 but ≤ 5 cm with VPI was not as good as that for tumor size ≤ 3 cm with VPI. CONCLUSIONS VPI together with tumor size has a synergistic effect on survival in node-negative NSCLC. Patients with stage IB NSCLC and larger tumor size with VPI might be considered for adjuvant chemotherapy after surgical resection and need careful preoperative evaluation and postoperative follow-up. Further randomized clinical trials to determine the impact of adjuvant chemotherapy in patients with stage IB NSCLC with VPI are warranted.

Impact of examined lymph node count on precise staging and long-term survival of resected non-small-cell lung cancer: A population study of the US SEER database and a Chinese multi-institutional registry

Purpose We investigated the correlation between the number of examined lymph nodes (ELNs) and correct staging and long-term survival in non–small-cell lung cancer (NSCLC) by using large databases and determined the minimal threshold for the ELN count. Methods Data from a Chinese multi-institutional registry and the US SEER database on stage I to IIIA resected NSCLC (2001 to 2008) were analyzed for the relationship between the ELN count and stage migration and overall survival (OS) by using multivariable models. The series of the mean positive LNs, odds ratios (ORs), and hazard ratios (HRs) were fitted with a LOWESS smoother, and the structural break points were determined by Chow test. The selected cut point was validated with the SEER 2009 cohort. Results Although the distribution of ELN count differed between the Chinese registry (n = 5,706) and the SEER database (n = 38,806; median, 15 versus seven, respectively), both cohorts exhibited significantly proportional increases from N0 to N1 and N2 disease (SEER OR, 1.038; China OR, 1.012; both P < .001) and serial improvements in OS (N0 disease: SEER HR, 0.986; China HR, 0.981; both P < .001; N1 and N2 disease: SEER HR, 0.989; China HR, 0.984; both P < .001) as the ELN count increased after controlling for confounders. Cut point analysis showed a threshold ELN count of 16 in patients with declared node-negative disease, which were examined in the derivation cohorts (SEER 2001 to 2008 HR, 0.830; China HR, 0.738) and validated in the SEER 2009 cohort (HR, 0.837). Conclusion A greater number of ELNs is associated with more-accurate node staging and better long-term survival of resected NSCLC. We recommend 16 ELNs as the cut point for evaluating the quality of LN examination or prognostic stratification postoperatively for patients with declared node-negative disease.

Original ResearchLung CancerThe Impact of Visceral Pleural Invasion in Node-Negative Non-small Cell Lung Cancer: A Systematic Review and Meta-analysis

BACKGROUND Visceral pleural invasion (VPI) is considered an aggressive and invasive factor in non-small cell lung cancer (NSCLC). Recent studies found that depending on tumor size, VPI influences T stage, but there is no consensus on whether VPI is important in node-negative NSCLC. In addition, its role in stage IB NSCLC is still uncertain. In this meta-analysis, we assessed the role of VPI in node-negative NSCLC according to various tumor sizes and especially in stage IB disease. METHODS A systematic literature search of four databases (EBSCO, PubMed, Ovid, and Springer) was performed to find relevant articles. The primary end point was 5-year overall survival. Pooled ORs were calculated using control as a reference group, and significance was determined by the Z-test. RESULTS Thirteen relevant studies in 27,171 patients were included in this study. The number of patients with VPI was 5,821 (21%). VPI was a significant adverse prognostic factor in patients with tumor size ≤ 3 cm (OR, 0.71; 95% CI, 0.64-0.79; P < .001), > 3 but ≤ 5 cm (OR, 0.69; 95% CI, 0.56-0.86; P < .001), and > 5 but ≤ 7 cm (OR, 0.70; 95% CI, 0.54-0.91; P = .007). A further comparison was made with stage IB NSCLC. Tumor size ≤ 3 cm with VPI was associated with a better survival than tumor size > 3 but ≤ 5 cm regardless of VPI (OR, 1.31; 95% CI, 1.19-1.45; P < .001). Exploratory analysis found no survival benefit between tumor size ≤ 3 cm with VPI and tumor size > 3 but ≤ 5 cm without VPI (OR, 1.16; 95% CI, 0.95-1.43; P = .15); however, the prognosis for tumor size > 3 but ≤ 5 cm with VPI was not as good as that for tumor size ≤ 3 cm with VPI. CONCLUSIONS VPI together with tumor size has a synergistic effect on survival in node-negative NSCLC. Patients with stage IB NSCLC and larger tumor size with VPI might be considered for adjuvant chemotherapy after surgical resection and need careful preoperative evaluation and postoperative follow-up. Further randomized clinical trials to determine the impact of adjuvant chemotherapy in patients with stage IB NSCLC with VPI are warranted.

Prognosis of synchronous and metachronous multiple primary lung cancers: Systematic review and meta-analysis

BACKGROUND With the development of imaging technology, an increasing number of multiple primary lung cancers (MPLC) are diagnosed in recent years. However, there is still ambiguity in the stage classification rules for patients with MPLC. Our purpose was to access the prognosis of synchronous and metachronous MPLC. METHODS A systematic literature search was performed on four databases (EBSCO, Pubmed, OVID and Springer) to obtain relevant articles. We used published hazard ratios (HRs) of overall survival (OS) if available or estimates from the published survival data. RESULTS There were 1796 patients with MPLC in 22 relevant studies, who were eligible for analysis. We found that the OS of patients with synchronous MPLC was inferior to the one of metachronous MPLC patients when starting from the diagnosis of the first metachronous tumor (HR 3.36, 95% CI 2.39-4.74; p<0.001). However, there was no difference when starting from the diagnosis of the second metachronous tumor (HR 1.19, 95% CI 0.86-1.66; p=0.29). From further analysis we found the OS of patients with MPLC was superior to that of patients with intrapulmonary metastasis (HR 2.66, 95% CI 1.30-5.44; p=0.007). Besides, we found no difference in OS between synchronous (HR 1.39, 95% CI 0.98-1.96; p=0.06) and metachronous (HR 1.05, 95% CI 0.75-1.47; p=0.77) patients, in spite of the histology. In terms of unilateral and bilateral MPLC patients, the OS had no difference either (HR 1.30, 95% CI 1.00-1.69; p=0.05). CONCLUSION We found that MPLC had better OS than the lung cancer patients with intrapulmonary metastasis. And despite the tumor-free interval, the OS for metachronous MPLC was as good as that for synchronous MPLC. Furthermore, there was no difference of OS in different subgroups, including histology and position.

SCD1 is associated with tumor promotion, late stage and poor survival in lung adenocarcinoma

The discovery of Warburg effect opens a new era in anti-cancer therapy. Aerobic glycolysis is regarded as a hallmark of cancer cells and increasing literatures indicates that metabolic changes are critical for the maintenance and progression of cancer cells. Besides aerobic glycolysis, increased fatty acid synthesis is also required for the rapid growth of cancer cells, and is considered as one of the most typical metabolic symbols of cancer either. Thus, targeting fatty acid metabolism may provide a potential avenue for the diagnosis and therapeutic treatment of cancer. In this study, we have identified Sterol-CoA desaturase-1 (SCD1) which is the rate-limiting enzyme of unsaturated fatty acid synthesis, universally and highly expressed in lung adenocarcinoma and was required for the cell proliferation, migration and invasion. Both in vitro and in vivo studies demonstrated that high expression of SCD1 remarkably enhanced the ability of tumor formation and invasion, while knockdown of SCD1 significantly repressed tumorigenesis and induced cell apoptosis. Clinical association study suggested that high expression of SCD1 is more frequently observed in late stage patients and presents poor prognosis. Taken together, our results suggested that SCD1 is a potentially novel biomarker of lung adenocarcinoma, and targeting SCD1 may represent a new anti-cancer strategy.

Evaluation of the efficacy and safety of anti-PD-1 and anti-PD-L1 antibody in the treatment of non-small cell lung cancer (NSCLC): a meta-analysis

BACKGROUND Currently, blockade of the programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling pathway has been proved one of the most promising immunotherapeutic strategies against cancer. Several antibodies have been developed to either block the PD-1 or its ligand PD-L1 are under development. So far, a series of phase I trials on PD-1/PD-L1 antibodies for non-small cell lung cancer (NSCLC) have been completed, without reports of results from phase II studies. Thus, we sought to perform a meta-analysis incorporating all available evidences to evaluate the efficacy and safety of PD-1 or PD-L1 inhibition therapy. METHODS Electronic databases were searched for eligible literatures. Data of objective respond rate (ORR) and rate of adverse effects (AEs) with 95% confidence interval (CI) evaluated by immunohistochemistry (IHC) was extracted. The outcomes were synthesized based on random-effect model. Subgroup analyses were proposed. RESULTS In overall, ORR in the whole population with PD-1 blockage treatment is 22.5% (95% CI: 17.6% to 28.2%). Additionally, the rate of Grade 3-4 AEs is 16.7% (95% CI: 6.5% to 36.8%) and drug-related death rate is 2.5% (95% CI: 1.3% to 4.6%). As for patients with PD-L1 inhibition therapy, an overall ORR is 19.5% (95% CI: 13.2% to 27.7%). A higher rate of Grade 3-4 AEs (31.7%, 95% CI: 14.2% to 56.5%) is observed with a lower drug-related death rate (1.8%, 95% CI: 0.4% to 8.3%). In exploratory analyses of anti-PD-1 agents, we observed that greater ORR was presented in the median-dose cohort (3 mg/kg) than that of both low-dose (1 mg/kg) and high-dose (10 mg/kg) cohort (low-dose vs. median-dose: OR =0.12, P=0.0002; median-dose vs. high-dose: OR =1.47, P=0.18). CONCLUSIONS Anti-PD-1 and anti PD-L1 antibodies showed objective responses in approximately one fourth NSCLC patients with a tolerable adverse-effect profile. In addition, median-dose (3 mg/kg) might be a preferential dosage of anti-PD-1 agents.

Adjuvant Chemotherapy for the Completely Resected Stage IB Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis.

AbstractAdjuvant chemotherapy is recommended for postoperative stage II-IIIB nonsmall cell lung cancer patients. However, its effect remains controversial in stage IB patients. We, therefore, performed a meta-analysis to compare the efficacy of adjuvant chemotherapy versus surgery alone in stage IB patients.Six electronic databases were searched for relevant articles. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS). The time-to-event outcomes were compared by hazard ratio using log-rank test.Sixteen eligible trials were identified. A total of 4656 patients were included and divided into 2 groups: 2338 in the chemotherapy group and 2318 in the control group (surgery only). Patients received platinum-based therapy, uracil-tegafur, or a combination of them. Our results demonstrated that patients can benefit from the adjuvant chemotherapy in terms of OS (HR 0.74 95% CI 0.63–0.88) and DFS (HR 0.64 95% CI 0.46–0.89). Patients who received 6-cycle platinum-based therapy (HR 0.45 95% CI 0.29–0.69), uracil-tegafur (HR 0.71 95% CI 0.56–0.90), or a combination of them (HR 0.51 95% CI 0.36–0.74) had better OS, but patients who received 4 or fewer cycles platinum-based therapy (HR 0.97 95% CI 0.85–1.11) did not. Moreover, 6-cycle platinum-based therapy (HR 0.29 95% CI 0.13–0.63) alone or in combination with uracil-tegafur (HR 0.44 95% CI 0.30–0.66) had advantages in DFS. However, 4 or fewer cycles of platinum-based therapy (HR 0.89 95% CI 0.76–1.04) or uracil-tegafur alone (HR 1.19 95% CI 0.79–1.80) were not beneficial.Six-cycle platinum-based chemotherapy can improve OS and DFS in stage IB NSCLC patients. Uracil-tegafur alone or in combination with platinum-based therapy is beneficial to the patients in terms of OS, but uracil-tegafur seems to have no advantage in prolonging DFS, unless it is administered with platinum-based therapy.

Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations.

EGFR and KRAS mutations are the two most common driver mutations in non-small cell lung cancer (NSCLC). Molecular target-based therapy using small molecules such as gefitinib has been used for inhibiting EGFR with good initial responses; however, drug resistance is common when using a mono-targeting strategy. At present, KRAS remains an undruggable target. As such, the development of new drugs targeting the downstream of KRAS and EGFR and their crosstalk pathways is critically needed to effectively treat NSCLC. The present study aimed to elucidate the anticancer effects of PI3K (BKM120) and MEK (PD1056309) inhibitors on NSCLC cell lines with KRAS or EGFR mutations. Inhibition of the EGFR and KRAS downstream P13K pathway using BKM120 significantly inhibited the growth of NSCLC cell lines with either EGFR or KRAS mutations. In addition, significant cell cycle arrest and induction of apoptosis were observed following BKM120 treatment. Notably, although the A549 and H358 NSCLC cell lines harbor the same KRAS mutation, A549 cells were less sensitive than H358 cells in the response to BKM120 treatment. Similarly, PC-9 and H1650 cells harbor the same EGFR mutation, however, H1650 was less sensitive to BKM120. Different sensitivity between NSCLC cell lines with the same oncogenic mutation suggests that multiple crosstalk pathways exit. Combined usage of BKM120 and PD1056309 synergistically enhanced apoptosis in the A549 cells and mildly enhanced apoptosis in the H1650 and H358 cells, suggesting the crosstalk of the MEK pathway with the P13K/Akt pathways in these cell lines. Overall, our findings suggest that inhibition of EGFR and KRAS downstream with a P13K/Akt inhibitor could be useful for treating NSCLC. However, for NSCLC exhibiting crosstalk with other survival pathways, such as the MEK pathway, combination treatment is required.