Zhihua Guo

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.

Analysis of feasibility and safety of complete video-assisted thoracoscopic resection of anatomic pulmonary segments under non-intubated anesthesia

OBJECTIVE To explore the feasibility and safety of complete video-assisted thoracoscopic surgery (C-VATS) under non-intubated anesthesia for the resection of anatomic pulmonary segments in the treatment of early lung cancer (T1N0M0), benign lung diseases and lung metastases. METHODS The clinical data of patients undergoing resection of anatomic pulmonary segments using C-VATS under non-intubated anesthesia in the First Affiliated Hospital of Guangzhou Medical University from July 2011 to November 2013 were retrospectively analyzed to evaluate the feasibility and safety of this technique. RESULTS The procedures were successfully completed in 15 patients, including four men and eleven women. The average age was 47 [21-74] years. There were ten patients with adenocarcinoma, one with pulmonary metastases, and four with benign lung lesions. The resected sites included: right upper apical segment, two; right lower dorsal segment, one; right lower basal segment, two; left upper lingular segment, three; left upper apical segment, one; left upper anterior apical segment, two; left upper posterior segment, one; left lower basal segment, one; left upper posterior and apical segments, one; and left upper anterior and apical segments plus wedge resection of the posterior segment, one. One case had intraoperative bleeding, which was controlled with thoracoscopic operation and no blood transfusion was required. No thoracotomy or perioperative death was noted. Two patients had postoperative bleeding without the need for blood transfusions, and were cured and discharged. The pathologic stage for all patients with primary lung cancer was IA. After 4-19 months of follow-up, no tumor recurrence and metastasis was found. The overall mean operative length was 166 minutes (range 65-285 minutes), mean blood loss 75 mL (range 5-1,450 mL), mean postoperative chest drainage 294 mL (range 0-1,165 mL), mean chest drainage time 2 days (range 0-5 days), and mean postoperative hospital stay 5 days (range 3-8 days). CONCLUSIONS Complete video-assisted throacoscopic segmentectomy under anesthesia without endotracheal intubation is a safe and feasible technique that can be used to treat a selected group of IA patients with primary lung cancer, lung metastases and benign diseases.

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.

Nonintubated thoracoscopic lobectomy plus lymph node dissection following segmentectomy for central type pulmonary masses

Lung cancer is the most common cancer worldwide. In the United States, it causes more cancer-related deaths than the next four causes (breast cancer, prostate cancer, colon cancer, and pancreatic cancer) of cancer-related mortality combined (1). About 30% of people have already progressed to stage III lung cancer and 40% to stage IV at the time they are diagnosed (2). Although chest X-ray and sputum cytology, when applied in health check-ups, can identify some relatively small tumors, they are not able to lower the overall mortality (3). More recently, the low-dose spiral CT scanning reduces the mortality of lung cancer when applied for lung cancer screening (4,5).

Video-assisted thoracoscopic surgery segmentectomy by non-intubated or intubated anesthesia: a comparative analysis of short-term outcome

BACKGROUND The aim of this study was to reveal the short-term outcomes of video-assisted thoracoscopic surgery (VATS) segmentectomy without tracheal intubation compared with intubated general anesthesia with one-lung ventilation (OLV). METHODS We performed a retrospective review of our institutional database of consecutive 140 patients undergoing VATS anatomical segmentectomy from July 2011 to June 2015. Among them, 48 patients were treated without tracheal intubation using a combination of thoracic epidural anesthesia (TEA), intrathoracic vagal blockade, and sedation (non-intubated group). The other 92 patients were treated with intubated general anesthesia (intubated group). Safety and feasibility was evaluated by comparing the perioperative profiles and short-term outcomes of these two groups. RESULTS Two groups had comparable surgical durations, intraoperative blood loss, postoperative chest tube drainage volume, and numbers of dissected lymph nodes (P>0.05). Patients who underwent non-intubated segmentectomy had higher peak end-tidal carbon dioxide (EtCO2) during operation (44.81 vs. 33.15 mmHg, P<0.001), less white blood cell changes before and after surgery (△WBC) (6.08×10(9) vs. 7.75×10(9), P=0.004), earlier resumption of oral intake (6.76 vs. 17.58 hours, P<0.001), shorter duration of postoperative chest tube drainage (2.25 vs. 3.16 days, P=0.047), less cost of anesthesia (¥5,757.19 vs. ¥7,401.85, P<0.001), and a trend toward shorter postoperative hospital stay (6.04 vs. 7.83 days, P=0.057). One patient (2.1%) in the non-intubated group required conversion to intubated OLV since a significant mediastinal movement. In the intubated group, there was one patient (1.1%) required conversion to thoracotomy due to uncontrolled bleeding. The incidence difference of postoperative complications between groups was not significant (P=0.248). There was no in-hospital death in either group. CONCLUSIONS Compared with intubated general anesthesia, non-intubated thoracoscopic segmentectomy is a safe, technically feasible and economical alternative with comparable short-term outcomes. Patients underwent non-intubated thoracoscopic segmentectomy could gain a prompt recovery.

UGT1A1 polymorphisms with irinotecan-induced toxicities and treatment outcome in Asians with Lung Cancer: a meta-analysis

Previous studies of irinotecan pharmacogenetics have shown that the UGT1A1*28 polymorphism has an effect on irinotecan (IRI)-induced toxicities in Caucasians. Yet compared with the UGT1A1*6 mutation, the UGT1A1*28 occurs at a much lower frequency in the Asians. Whether UGT1A1*6 and UGT1A1*28 are associated with IRI-induced neutropenia, diarrhea and IRI-based chemotherapy tumor response (TR) in Asians with lung cancer remains controversial. In this meta-analysis, we found a higher risk of neutropenia and diarrhea with IRI-based chemotherapy in Asians with lung cancer carrying the UGT1A1*6 polymorphism. However, UGT1A1*28 showed a weak correlation with diarrhea, but no significant correlation with neutropenia. Neither UGT1A1*6 nor UGT1A1*28 is associated with IRI-based chemotherapy TR. These data suggest that the UGT1A1*28 polymorphism may not be a suitable biomarker to predict IRI-induced toxicities and chemotherapy TR in Asians, while UGT1A*6 polymorphism is associated with a higher risk of IRI-induced neutropenia and diarrhea, but not IRI-based chemotherapy TR.

MAP kinase-interacting serine/threonine kinase 2 promotes proliferation, metastasis, and predicts poor prognosis in non-small cell lung cancer

We hypothesized that MAP kinase-interacting serine/threonine kinase 2 (MNK2) may contribute to non-small cell lung cancer (NSCLC) development, and serve as a new therapeutic target. Immunohistochemical staining evaluated the correlation between MNK2 expression and clinicopathological features in 367 NSCLC cancer tissues. We determined the effects of MNK2 silencing in NSCLC cell lines in vitro and in vivo. RT-PCR and western blotting was used to examine the impact of MNK2 on ERK and AKT pathways. MNK2 was overexpressed in NSCLC cell lines and tumor tissues. Patients with MNK2 overexpression had lower OS rates (P < 0.001). High expression of MNK2 was correlated with lymph node metastasis (P = 0.008). MNK2 functioned as an independent prognostic factor for poor survival in patients with NSCLC (P = 0.003). MNK2 down-regulation inhibited proliferation, migration and invasion in vitro (P < 0.001), and reduced tumor growth and invasion in nude mice (P < 0.05). MNK2 enhanced phosphorylation of eIF4E, a downstream target of ERK and AKT pathways, which promoted NSCLC proliferation and invasion. We conclude that MNK2 overexpression in NSCLC is associated with proliferation, migration, invasion, and lower survival rates in patients via the phosphorylated eIF4E-mediated signaling pathway.

Nomogram prediction for the survival of the patients with small cell lung cancer

BACKGROUND Small cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis. In this study, we aimed to build a nomogram to predict the survival of individual with SCLC by incorporating significant clinical parameters. METHODS The patients with SCLC were enrolled from the First Affiliated Hospital of Guangzhou Medical University (GMUFAH) between 2009 and 2013. We identified and incorporated the independent prognostic factors to build a nomogram to predict the survival of SCLC patients. The predictive accuracy and discriminative ability of the nomogram were evaluated by concordance index (C-index) and calibration curve. We also compared the accuracy of the built model with the 7th AJCC TNM and VALSG staging system. The nomogram was further validated in an independent cohort of 80 patients with SCLC from Cancer Center of Guangzhou Medical University (GMUCC) between 2009 and 2013. RESULTS A total of 275 patients with SCLC were included in the primary cohort, and seven independent prognostic factors were identified including age, N stage, metastasis status, histology, platelets to lymphocyte ratio (PLR), neuron specific enolase (NSE) and CYFRA21-1 as independent prognostic factors after using Cox regression model. A nomogram incorporating these prognostic factors was subsequently built. The calibration curves for possibilities of 1-, 2-year overall survival (OS) revealed optimal agreement between nomogram prediction and actual observation. The C-index of this nomogram was higher than that of TNM and VALSG staging system in both primary and validation cohort (nomogram vs. TNM, primary cohort 0.68 vs. 0.65, P<0.01, validation cohort 0.66 vs. 0.62, P<0.05; nomogram vs. VALSG, primary cohort 0.68 vs. 0.66, P<0.01, validation cohort 0.66 vs. 0.64, P<0.05). CONCLUSIONS In this study, we established and validated a novel nomogram for the prediction of OS for the patients with SCLC. This model could provide more accurate individual prediction of survival probability of SCLC than the existing staging systems.

Spontaneous ventilation anesthesia combined with uniportal and tubeless thoracoscopic lung biopsy in selected patients with interstitial lung diseases

Background The current guidelines emphasize the significant role of video-assisted thoracic surgical lung biopsy (VATS-LB) for a definite diagnosis of interstitial lung diseases (ILD), but they also encourage physicians to maintain the balance between the surgical benefits as well as risks. Both spontaneous ventilation video-assisted thoracic surgery (VATS) and uniportal VATS have emerged as remarkable progresses in VATS. We combined these two types of VATS and refined them to uniportal spontaneous ventilation VATS without urinary catheterization and chest tube drainage [uniportal and tubeless VATS (UT-VATS)] to perform LB in selected patients with ILD. Methods From January 2014 to May 2015, 43 patients were included in the study. The surgical data was retrospectively analyzed. Results The mean diffusion capacity for carbon monoxide (DLCO) of patients was 57.6%±13.0%, forced vital capacity (FVC) was 73.1%±17.0%. There was no 30-day mortality. No patient required a switch to intubated anesthesia. The mean age was 49.6±10.7 years. The general median operative duration was 22±5 minutes, with 25±3 minutes for multiple specimens and 15±2 minutes for single specimen, respectively. Intra-operative conversion to 2-portal VATS followed by chest tube drainage and urinary catheterization occurred in 3 (7.0%) patients due to extensive pleural adhesion, and postoperative chest tube insertion was documented in 1 (2.3%) patient due to subcutaneous emphysema. No postoperative mechanical ventilation was noted. Precise histopathological diagnosis was achieved in 38 (88.4%) patients. Conclusions Uniportal and tubeless thoracoscopic LB using spontaneous ventilation anesthesia can be considered a feasible and safe operation method for selected patients with ILD.

Primary spontaneous pneumothorax: simultaneous treatment by bilateral non-intubated videothoracoscopy

OBJECTIVES Through a retrospective study, we assessed the feasibility and safety of simultaneous bilateral thoracoscopic wedge resection of blebs or bullae for the treatment of primary spontaneous pneumothorax (PSP) under thoracic epidural anaesthesia with spontaneous ventilation. METHODS This retrospective analysis involved a cohort of 37 consecutive patients undergoing simultaneous bilateral thoracoscopic bullectomy under spontaneous ventilation thoracic epidural anaesthesia (n = 15) or intubated general anaesthesia (n = 22) between July 2011 and September 2015. The perioperative data, short-term outcomes and recurrence rates of the two groups were compared. RESULTS The two groups had comparable preoperative demographic profiles. There were no conversions to thoracotomy or intubated single-lung ventilation. The peak end-tidal carbon dioxide in the non-intubated group was significantly higher than that in the intubated group (mean: 48 vs 34 mmHg, P < 0.001). Both groups had comparable surgical duration, blood loss and lowest intraoperative pulse oxygen saturation level. Postoperatively, the two groups had comparable chest tube duration, volume of fluid administration, length of hospital stay and complication rates. No mortality occurred. The total anaesthesia cost in non-intubated group was significantly lower (mean: CNY 4584 vs 5649, P = 0.016). The mean follow-up was 23.6 ± 12.9 months in the non-intubated group and 21.1 ± 13.4 months in the intubated group. Two recurrent pneumothoraxes in 2 patients were observed after surgical procedures for PSP. One recurrence developed in the non-intubated group (7%) and one in the intubated group (5%). CONCLUSIONS Simultaneous bilateral non-intubated thoracoscopic bullectomy is not only well tolerated and technically feasible but also a safe alternative for selected patients with simultaneous bilateral PSP or with high risk of contralateral recurrence.