Individualized model for predicting COVID-19 deterioration in patients with cancer: A multicenter retrospective study.

The 2019 novel coronavirus has spread rapidly around the world. Cancer patients seem to be more susceptible to infection and disease deterioration, but the factors affecting the deterioration remain unclear. We aimed to develop an individualized model for prediction of coronavirus disease (COVID-19) deterioration in cancer patients. The clinical data of 276 cancer patients diagnosed with COVID-19 in 33 designated hospitals of Hubei, China from December 21, 2019 to March 18, 2020, were collected and randomly divided into a training and a validation cohort by a ratio of 2:1. Cox stepwise regression analysis was carried out to select prognostic factors. The prediction model was developed in the training cohort. The predictive accuracy of the model was quantified by C-index and time-dependent area under the receiver operating characteristic curve (t-AUC). Internal validation was assessed by the validation cohort. Risk stratification based on the model was carried out. Decision curve analysis (DCA) were used to evaluate the clinical usefulness of the model. We found age, cancer type, computed tomography baseline image features (ground glass opacity and consolidation), laboratory findings (lymphocyte count, serum levels of C-reactive protein, aspartate aminotransferase, direct bilirubin, urea, and d-dimer) were significantly associated with symptomatic deterioration. The C-index of the model was 0.755 in the training cohort and 0.779 in the validation cohort. The t-AUC values were above 0.7 within 8 weeks both in the training and validation cohorts. Patients were divided into two risk groups based on the nomogram: low-risk (total points ≤ 9.98) and high-risk (total points > 9.98) group. The Kaplan-Meier deterioration-free survival of COVID-19 curves presented significant discrimination between the two risk groups in both training and validation cohorts. The model indicated good clinical applicability by DCA curves. This study presents an individualized nomogram model to individually predict the possibility of symptomatic deterioration of COVID-19 in patients with cancer.

Comparison of geometrical uncertainties in the radiotherapy for various treatment sites with two different immobilization marking methods.

OBJECTIVE: The skin marking method (SMM) and bow-form-ruler marking method (BFRM) are two commonly used patient marking methods in mainland China. This study aims to evaluate SMM and BFRM by comparing the inter-fraction setup errors from using these two methods together with vacuum cushion immobilization in patients underwent radiotherapy for different treatment sites. MATERIALS AND METHODS: Eighteen patients diagnosed with pelvic, abdominal and thoracic malignant tumors (with 6 patients per treatment site) were enrolled in this prospective study. All patients were immobilized with vacuum cushion. Each patient was marked by both SMM and BFRM before computed tomography (CT) simulation. Target location was verified by cone beam CT images with displacements assessed prior to each sampled treatment session. The localization errors in three translational and three rotational directions were recorded and analyzed. RESULTS: Images from 108 fractions in 18 patients produced 324 translational and 324 rotational comparisons for SMM and BFRM. The setup errors of all treatment sites showed no difference in two marking methods in any directions (p > 0.05). In subgroups of treatment site analysis, SMM significantly lessened the lateral and yaw setup errors compared to BFRM in the pelvic sites (0.39±1.85 mm vs -1.28±1.13 mm, p < 0.01 and -0.19±0.59° vs -0.61±0.59°, p < 0.05). However, in the abdominal subgroup, BFRM was superior to SMM for reduced vertical errors (0.17±2.73 mm vs 2.28±3.16 mm, p < 0.05). For the underweight or obese patients (with Body Mass Index, BMI < 18.5 or BMI≥24), SMM resulted in less yaw errors compared to BFRM (-0.05±0.38° vs -0.43±0.48°, p < 0.05). No significant difference between SMM and BFRM in setup errors of normal weighted patients (18.5≤BMI < 24) was observed for all three studied treatment sites. CONCLUSIONS: This study shows no significant difference in patient setup errors for various treatment sites between SMM and BFRM in general. SMM may be suitable for the pelvic tumor and patients with BMI < 18.5 or BMI≥24, while BFRM is recommended for the abdominal tumor sites.

SUZ12 RNA interference inhibits the invasion of gastric carcinoma cells.

In order to observe the regulation effects of SUZ12 gene to the invasion of gastric carcinoma cells and the mechanisms, the expressions of SUZ12 protein in 86 patients with different infiltrating degree (Tis-T4), lymph node metastasis (N0-N3) and far metastasis (M0-M1) were detected by immunohistochemical staining. The siRNA to SUZ12 was designed and synthesized and transfected into MKN28 cells. The effects of SUZ12 siRNA to cell invasion were detected by soft agar colony forming test and Transwell cabin model. The related protein was detected by Western-Blot. We found the expression of SUZ12 in gastric carcinoma tissues (23.58±9.89%) was obviously higher than that in para-cancer tissue (1.12%±0.12%) (p<0.01). The expression of SUZ12 was related to the infiltrating degree, and demonstrated an increasing tendency from Tis-T4, or from N0-N3. The expression of SUZ12 in M0 was obviously lower than in M1, p<0.01. The level of SUZ12 was descent obviously after transfected SUZ12 siRNA (p<0.01). The number of cell clone was reduced in dose dependent of siRNA and the cells permeated through filter membrane were decreased after transfected siRNA. Inhibition of SUZ12 caused an obviously descent of VEGF, MMP-2 and MMP-9 (0.22±0.06, 0.12±0.03, 0.08±0.02) compared to non transfected group (0.87±0.08, 0.92±0.16, 1.05±0.18) respectively (p<0.01). We draw the conclusion that the expression of SUZ12 is increasing along with the degree of infiltrating and metastasis of gastric carcinoma. SUZ12 siRNA inhibits the invasion of gastric carcinoma cells and the expression of VEGF, MMP-2 and MMP-9.

SUZ12 RNA Interference Inhibits the Invasion of Gastric Carcinoma Cells.

In order to observe the regulation effects of SUZ12 gene to the invasion of gastric carcinoma cells and the mechanisms, the expressions of SUZ12 protein in 86 patients with different infiltrating degree (Tis-T4), lymph node metastasis (N0-N3) and far metastasis (M0-M1) were detected by immunohistochemical staining. The siRNA to SUZ12 was designed and synthesized and transfected into MKN28 cells. The effects of SUZ12 siRNA to cell invasion were detected by soft agar colony forming test and Transwell cabin model. The related protein was detected by Western-Blot. We found the expression of SUZ12 in gastric carcinoma tissues (23.58 ± 9.89%) was obviously higher than that in para-cancer tissue (1.12% ± 0.12%) (p < 0.01). The expression of SUZ12 was related to the infiltrating degree, and demonstrated an increasing tendency from Tis-T4, or from N0-N3. The expression of SUZ12 in M0 was obviously lower than in M1, p < 0.01. The level of SUZ12 was descent obviously after transfected SUZ12 siRNA (p < 0.01). The number of cell clone was reduced in dose dependent of siRNA and the cells permeated through filter membrane were decreased after transfected siRNA. Inhibition of SUZ12 caused an obviously descent of VEGF, MMP-2 and MMP-9 (0.22 ± 0.06, 0.12 ± 0.03, 0.08 ± 0.02) compared to non transfected group (0.87 ± 0.08, 0.92 ± 0.16, 1.05 ± 0.18) respectively (p < 0.01). We draw the conclusion that the expression of SUZ12 is increasing along with the degree of infiltrating and metastasis of gastric carcinoma. SUZ12 siRNA inhibits the invasion of gastric carcinoma cells and the expression of VEGF, MMP-2 and MMP-9.

BRAF V600E mutation as a predictive factor of anti-EGFR monoclonal antibodies therapeutic effects in metastatic colorectal cancer: a meta-analysis.

OBJECTIVE: To investigate the correlation between BRAF V600E mutation and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) therapeutic effects in metastatic colorectal cancer. METHODS: Studies were included into meta-analysis to investigate the association between BRAF V600E mutation and clinical outcome in metastatic colorectal cancer patients treated with anti-EGFR MoAbs. RESULTS: A total of 7 studies were included in this meta-analysis. The 7 studies included 1352 patients in total, sample sizes ranged from 67 to 493. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were collected from included studies and were used to assess the strength of the relation. In patients with wild-type KRAS, the pooled odds ratio for ORR of mutant BRAF over wild-type BRAF was 0.27 (95% CI=0.10-0.70). BRAF mutation predicted a deterioration in PFS and OS in wild-type KRAS patients treated with anti-EGFR MoAbs (hazard ratio=2.78, 95% CI=1.62-4.76; hazard ratio=2.54, 95% CI=1.93-3.32). CONCLUSION: BRAF V600E mutation is related to lack of response and worse survival in wild-type KRAS metastatic colorectal cancer patients treated with anti-EGFR MoAbs.

A systemic review of glutathione S-transferase P1 Ile105Val polymorphism and colorectal cancer risk.

OBJECTIVES: To investigate the correlation between glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism and colorectal cancer (CRC) risk. METHODS: Studies were identified to investigate the association between GSTP1 Ile105Val polymorphism and CRC risk. Systematic computerized searches of the PubMed, Chinese National Knowledge Infrastructure, WANFANG and SinoMed were performed. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were used to measure GSTP1 Ile105Val polymorphisms and CRC risk. RESULTS: A total of 23 retrospective studies were included in the meta-analysis. During all studies including 6,981 cases and 8,977 controls, sample sizes ranged from 146 to 2,144. Overall, the pooled results revealed that Ile105Val polymorphism was not associated with CRC risk and confused results were found in subgroup analyses. Further meta-analyses were conducted after excluding low-quality studies. GSTP1 Ile105Val is associated with increased risk of CRC limited in studies with matched control. There was no significant heterogeneity in all genetic comparisons, but heterogeneity existed in subgroup analyses of heterozygous and dominant comparisons. The meta-regression analyses indicated that matched controls were the significant factor influencing between-study heterogeneity in all possible influential factors including published year, ethnicity, source of control, sample size, Hardy-Weinberg equilibrium (HWE) in control and matched controls. Sensitivity analysis revealed the pooled ORs were not changed before and after removal of each single study in all genetic comparisons, indicating the robustness of the results. CONCLUSIONS: GSTP1 Ile105Val might be associated with increased risk of CRC. However, more high-quality case-control studies should be performed to confirm the authenticity of our conclusion.

Advancement and Applications of Nanotherapy for Cancer Immune Microenvironment.

Cancer treatment has evolved rapidly due to major advances in tumor immunity research. However, due to the complexity, heterogeneity, and immunosuppressive microenvironment of tumors, the overall efficacy of immunotherapy is only 20%. In recent years, nanoparticles have attracted more attention in the field of cancer immunotherapy because of their remarkable advantages in biocompatibility, precise targeting, and controlled drug delivery. However, the clinical application of nanomedicine also faces many problems concerning biological safety, and the synergistic mechanism of nano-drugs with immunity remains to be elucidated. Our study summarizes the functional characteristics and regulatory mechanisms of nanoparticles in the cancer immune microenvironment and how nanoparticles activate and long-term stimulate innate immunity and adaptive immunity. Finally, the current problems and future development trends regarding the application of nanoparticles are fully discussed and prospected to promote the transformation and application of nanomedicine used in cancer treatment.

Prediction of Tumor Microenvironment Characteristics and Treatment Response in Lung Squamous Cell Carcinoma by Pseudogene OR7E47P-related Immune Genes.

OBJECTIVE: Pseudogenes are initially regarded as nonfunctional genomic sequences, but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activities. Olfactory receptor family 7 subfamily E member 47 pseudogene (OR7E47P) is expressed broadly in lung tissues and has been identified as a positive regulator in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD). This study aimed to elucidate the correlation between OR7E47P and tumor immunity in lung squamous cell carcinoma (LUSC). METHODS: Clinical and molecular information from The Cancer Genome Atlas (TCGA) LUSC cohort was used to identify OR7E47P-related immune genes (ORIGs) by weighted gene correlation network analysis (WGCNA). Based on the ORIGs, 2 OR7E47P clusters were identified using non-negative matrix factorization (NMF) clustering, and the stability of the clustering was tested by an extreme gradient boosting classifier (XGBoost). LASSO-Cox and stepwise regressions were applied to further select prognostic ORIGs and to construct a predictive model (ORPScore) for immunotherapy. The Botling cohorts and 8 immunotherapy cohorts (the Samstein, Braun, Jung, Gide, IMvigor210, Lauss, Van Allen, and Cho cohorts) were included as independent validation cohorts. RESULTS: OR7E47P expression was positively correlated with immune cell infiltration and enrichment of immune-related pathways in LUSC. A total of 57 ORIGs were identified to classify the patients into 2 OR7E47P clusters (Cluster 1 and Cluster 2) with distinct immune, mutation, and stromal programs. Compared to Cluster 1, Cluster 2 had more infiltration by immune and stromal cells, lower mutation rates of driver genes, and higher expression of immune-related proteins. The clustering performed well in the internal and 5 external validation cohorts. Based on the 7 ORIGs (HOPX, STX2, WFS, DUSP22, SLFN13, GGCT, and CCSER2), the ORPScore was constructed to predict the prognosis and the treatment response. In addition, the ORPScore was a better prognostic factor and correlated positively with the immunotherapeutic response in cancer patients. The area under the curve values ranged from 0.584 to 0.805 in the 6 independent immunotherapy cohorts. CONCLUSION: Our study suggests a significant correlation between OR7E47P and TME modulation in LUSC. ORIGs can be applied to molecularly stratify patients, and the ORPScore may serve as a biomarker for clinical decision-making regarding individualized prognostication and immunotherapy.

Inhibition of RhoA/ROCK signaling pathway promotes the apoptosis of gastric cancer cells.

BACKGROUND/AIMS: Ras homologue A (RhoA) plays a crucial role in the proliferation, apoptosis,adhesion and migration of gastric cancer cells. Rho associated kinase (ROCK) is an effector protein of RhoA. METHODOLOGY: In the present study, RhoA activity was inhibited by siRNA targeting RhoA andY-27632, an inhibitor of ROCK, and the role of RhoA/ROCK signaling pathway in the apoptosis of gastric cancer cells was investigated. RESULTS: RNAi of RhoA inhibited the survival and promoted the apoptotic of AGS cells. RhoA RNAi caused an obvious decrease of ROCK1 expression but an increase of caspase-3/cleaved-caspase-8. Inhibition of ROCK by Y-27632 inhibited the activity of RhoA and promoted the apoptosis. CONCLUSIONS: We speculate that RhoA/ROCK signaling pathway plays an important role in the regulation of apoptosis of gastric cancer, and to inhibit this pathway may promote the apoptosis of cancer cells. Thus, inhibition of RhoA/ROCK signaling pathway may become a novel target in the treatment of gastric cancer.

Bioinformatic and Experimental Analyses Reveal That KIF4A Is a Biomarker of Therapeutic Sensitivity and Predicts Prognosis in Cervical Cancer Patients.

OBJECTIVE: This study aims to investigate the expression, prognostic value, and function of kinesin superfamily 4A (KIF4A) in cervical cancer. METHODS: Cervical cancer cell lines (Hela and SiHa) and TCGA data were used for experimental and bioinformatic analyses. Overall survival (OS) and progression free survival (PFS) were compared between patients with high or low KIF4A expression. Copy number variation (CNV) and somatic mutations of patients were visualized and GISTIC 2.0 was used to identify significantly altered sites. The function of KIF4A was also explored based on transcriptome analysis and validated by experimental methods. Chemotherapeutic and immunotherapeutic benefits were inferred using multiple reference databases and algorithms. RESULTS: Patients with high KIF4A expression had better OS and PFS. KIF4A could inhibit proliferation and migration and induce G1 arrest of cervical cancer cells. Higher CNV load was observed in patients with low KIF4A expression, while the group with low KIF4A expression displayed more significantly altered sites. A total of 13 genes were found to mutate more in the low KIF4A expression group, including NOTCH1 and PUM1. The analysis revealed that low KIF4A expression may indicate an immune escape phenotype, and patients in this group may benefit more from immunotherapy. With respect to chemotherapy, cisplatin and gemcitabine may respond better in patients with high KIF4A expression, while 5-fluorouracil etc. may be responded better in patients with low KIF4A expression CONCLUSION: KIF4A is a tumor suppressor gene in cervical cancer, and it can be used as a prognostic and therapeutic biomarker in cervical cancer.

Identification of serum biomarkers for lung cancer using magnetic bead-based SELDI-TOF-MS.

AIM: To identify novel serum biomarkers for lung cancer diagnosis using magnetic bead-based surface-enhanced laser desorption/ionization time-of-flight mass spectrum (SELDI-TOF-MS). METHODS: The protein fractions of 121 serum specimens from 30 lung cancer patients, 30 pulmonary tuberculosis patients and 33 healthy controls were enriched using WCX magnetic beads and subjected to SELDI-TOF-MS. The spectra were analyzed using Bio-marker Wizard version 3.1.0 and Biomarker Patterns Software version 5.0. A diagnostic model was constructed with the marker proteins using a linear discrimination analysis method. The validity of this model was tested in a blind test set consisted of 8 randomly selected lung cancer patients, 10 pulmonary tuberculosis patients and 10 healthy volunteers. RESULTS: Seventeen m/z peaks were identified, which were significantly different between the lung cancer group and the control (tuberculosis and healthy control) groups. Among these peaks, the 6445, 9725, 11705, and 15126 m/z peaks were selected by the Biomarker Pattern Software to construct a diagnostic model for lung cancer. This four-peak model established in the training set could discriminate lung cancer patients from non-cancer patients with a sensitivity of 93.3% (28/30) and a specificity of 90.5% (57/63). The diagnostic model showed a high sensitivity (75.0%) and a high specificity (95%) in the blind test validation. Database searching and literature mining indicated that the featured 4 peaks represented chaperonin (M9725), hemoglobin subunit beta (M15335), serum amyloid A (M11548), and an unknown protein. CONCLUSION: A lung cancer diagnostic model based on bead-based SELDI-TOF-MS has been established for the early diagnosis or differential diagnosis of lung cancers.

A case report of aggressive course of CD30+ primary cutaneous anaplastic large cell lymphoma.

INTRODUCTION: CD30+ primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a rare T-cell neoplasm, and has been reported to present with an indolent behavior. The PC-ALCL with aggressive behavior has not been reported in the literature. PATIENT CONCERNS: We treated a patient with PC-ALCL that exhibited indolent behavior in the past 2 years and aggressive behavior within the last 3 months before presentation. DIAGNOSIS: Aggressive CD30+ primary cutaneous anaplastic large cell lymphoma. INTERVENTIONS: The radiotherapy regimen was individualized in terms of the target volume delineation and dose prescription, and the dose-response relationship was evaluated. OUTCOMES: The mean distance of microscopic infiltration was 14.1 mm in depth and 14.3 mm circumferentially. The lesion completely regressed after the delivery of 40 Gy in 20 fractions over 4 weeks. The tumor did not recur over the next year. CONCLUSION: An aggressive disease course is rare for indolent CD30+ PC-ALCL, which has similar histopathological characteristics as indolent PC-ALCL. The radiotherapy strategy should be individualized with curative intent.

Adenosquamous carcinoma may have an inferior prognosis to signet ring cell carcinoma in patients with stages I and II gastric cancer.

BACKGROUND: Primary gastric adenosquamous carcinoma (ASC) is an exceedingly rare histological subtype. Gastric signet ring cell carcinoma (SRC) is a unique subtype with distinct tumor biology and clinical features. The prognosis of gastric ASC vs SRC has not been well established to date. We hypothesized that further knowledge about these distinct cancers would improve the clinical management of such patients. AIM: To investigate the clinicopathological characteristics and prognosis of gastric ASC vs SRC. METHODS: A cohort of gastric cancer patients was retrospectively collected from the Surveillance, epidemiology, and end results program database. The 1:4 propensity score matching was performed among this cohort. The clinicopathological features and prognosis of gastric ASC were compared with gastric SRC by descriptive statistics. Kaplan-Meier method was utilized to calculate the median survival of the two groups of patients. Cox proportional hazard regression models were used to identify prognostic factors. RESULTS: Totally 6063 patients with gastric ASC or SRC were identified. A cohort of 465 patients was recruited to the matched population, including 370 patients with SRC and 95 patients with ASC. Gastric ASC showed an inferior prognosis to SRC after propensity score matching. In the post-matching cohort, the median cancer specific survival was 13.0 (9.7-16.3) mo in the ASC group vs 20.0 (15.7-24.3) mo in the SRC group, and the median overall survival had a similar trend (P < 0.05). ASC and higher tumor-node-metastasis stage were independently associated with a poor survival, while radiotherapy and surgery were independent protective factors for improved prognosis. Subgroup survival analysis revealed that the prognosis of ASC was inferior to SRC only in stages I and II patients. CONCLUSION: ASC may have an inferior prognosis to SRC in patients with stages I and II gastric cancer. Our study supports radiotherapy and surgery for the future management of this clinically rare entity.

[The effect of PTC1 transfection on the growth and apoptosis of human pulmonary adenocarcinoma cell A549].

OBJECTIVE: To investigate the effects of the tumor suppressor gene PTC on the growth inhibition and down-regulation of epidermal growth factor receptors (EGFR) in pulmonary adenocarcinoma cell A549. METHODS: Pulmonary adenocarcinoma cell A549 were divided into wild type group, mutant type group, blank group and control group. They were transfected with wild-type PTC1 plasmids, mutant-PTC1 plasmids and blank plasmids, respectively. After transfection, the cell growth curve was drown every day for a week. The expression of PTC1 and EGFR were detected by western blot. Flow cytometry was used to analyze apoptosis and cell cycle of the transfected cells. RESULTS: After transfected with wild-type PTC1, the growth rates of A549 cells were slow down, but the other groups of cells had no change. Compared with the control group, the expression of EGFR were down-regulated. The apoptosis rates in wild type group was 24.5%, and the mutant type group was 8.3% (P < 0.01). But the apoptosis rate of blank group has no change. CONCLUSION: Wild-type PTC1 could induce apoptosis and inhibitory effect on A549 cells.

Radiotherapy for oligometastatic tumor improved the prognosis of patients with non-small cell lung cancer (NSCLC).

BACKGROUND: This study was conducted to investigate if radiotherapy improved the overall survival (OS) of patients with oligometastatic non-small cell lung cancer (NSCLC). METHODS: From January 2012 to August 2015, 323 NSCLC patients with distant metastasis were administered radiotherapy. Ninety-five patients with oligometastatic NSCLC who were sensitive to the initial chemotherapy were treated with radiotherapy for the residual lesions. Initial treatment consisted of four to six cycles of induction chemotherapy. If the patients responded to the initial treatment without developing new metastases, the residual sites were radiated at a total dose of 56-66 Gy, including the primary and metastatic sites. OS, progression-free survival, and sites of progression were assessed. The Kaplan-Meier method was used to estimate the OS and progression-free survival probabilities. RESULTS: The median survival of the whole cohort was 15 months (95% confidence interval 6-40) and the median time to progression was 11 months (95% confidence interval 4-24). Sixty-seven patients had died by the end of follow-up. The one-year and two-year OS rates were 58% and 23%, respectively. Patients progressed either with brain (n = 14), bone (n = 11), lung (n = 10), liver (n = 7), adrenal gland (n = 5), or seven other sites of metastases (n = 3). Acute grade III esophageal toxicity was observed in 17 patients (18%) and grade III pulmonary toxicity in seven patients (7%). CONCLUSION: Oligometastatic non-progressive NSCLC patients may benefit from aggressive radiotherapy to the residual lesions with acceptable toxicity after systemic chemotherapy.

Effects of HER2 status on the prognosis of male breast cancer: a population-based study.

OBJECTIVE: This study was designed to analyze the effects of human epidermal growth factor receptor-2 (HER2) status on the prognosis of male breast cancer (MBC). METHODS: The SEER database was used to identify MBC patients diagnosed between 2010 and 2015. Patients were divided into HER2-negative and HER2-positive groups and chi-square test was used to compare the demographics. Propensity score matching (PSM) was used to remove confounding factors. The log-rank test was used to compare the overall survival (OS) and disease-specific survival (DSS) between the two groups. Univariate and multivariate Cox regression analyses were used to evaluate the effects of different variables on the prognosis of MBC patients. Subgroup analysis was conducted by using R software to explore the benefit of OS and DSS in the subgroup of MBC patients. RESULTS: In the matched cohort, the log-rank test showed that there was a longer OS (P=0.044) in the HER2-negative group, and the 4-year OS rate in HER2-negative patients was significantly improved (P=0.008), but there was no difference in the DSS (P=0.408) and the 4-year DSS rates (P=0.198) between the two groups. Univariate and multivariate Cox regression also showed that the HER2 status did not independently associate with DSS (P=0.444). Subgroup analysis showed that HER2-negative patients experienced a longer OS in the subgroup of tumors 2-4 cm in size, no distant metastasis and who had received radiotherapy, but none of subgroup was found a significant difference in DSS between different HER2 status. CONCLUSION: This study identified that HER2 status had a clear influence on OS in patients with MBC, and there was a longer OS and a higher 4-year OS rate in the HER2-negative group. In addition, we observed that HER2 status had no significant effect on DSS in patients with MBC.

Clinical and molecular characteristics associated with the efficacy of PD-1/PD-L1 inhibitors for solid tumors: a meta-analysis.

We conducted a meta-analysis to estimate the impact of different clinical and molecular characteristics on the efficacy of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. PubMed and Web of Science were searched for related trials. Eleven eligible studies, comprising 5,663 patients, were included in this meta-analysis. We found that the PD-1/PD-L1 inhibitor was associated with a 31% reduction in the risk of death (hazard ratio [HR]=0.69; 95% CI 0.64-0.74; P<0.00001) for patients with melanoma, non-small-cell lung cancer (NSCLC), urothelial carcinoma, head and neck carcinoma, and renal cell carcinoma. In subgroup analyses, all the patients with PD-L1-positive tumors had overall survival (OS) benefits from PD-1/PD-L1 inhibitors regardless of PD-L1 expression level, and a dose-effect relationship between the expression of PD-L1 and OS benefit from PD-1/PD-L1 inhibitors was observed. There was an OS improvement for patients with a smoking history (P<0.00001), but no OS benefit was observed for nonsmokers (P=0.28). In addition, first-line therapy had better OS than second-line or later treatment (P=0.02). No significant improvement of OS was observed (P=0.70) in patients aged ≥75 years. The relative treatment efficacy was similar according to sex (male vs female, P=0.60), performance status (0 vs ≥1, P=0.68), tumor histology (squamous NSCLC vs non-squamous NSCLC vs melanoma vs urothelial carcinoma vs head and neck carcinoma vs renal cell carcinoma, P=0.64), and treatment type (PD-1 inhibitor vs PD-L1 inhibitor, P=0.36). In conclusion, PD-L1-positive tumors, smoking history, and first-line treatment were potential factors for the efficacy of PD-1/PD-L1 inhibitors. Patients with higher PD-L1 expression might achieve greater OS benefits. In addition, sex, performance status, tumor histology, and treatment type could not predict the efficacy of this therapy. In contrast, patients aged >75 years and nonsmokers might not get OS benefits from this treatment. These results may improve treatment strategies and patient selection for PD-1/PD-L1 inhibitors.

The efficacy and safety of immune checkpoint inhibitor combination therapy in lung cancer: a systematic review and meta-analysis.

The value of immune checkpoint inhibitor (ICI) combination therapy for patients with lung cancer remains unclear. We conducted a meta-analysis using PubMed, Embase, and ClinicalTrials.gov databases to identify eligible randomized controlled trials (RCTs) that might provide a reference for clinical practice. The selection criteria were defined according to the population, intervention, comparison, outcome and study design (PICOS) framework. In all, 12 RCTs with 5,989 patients were included in this meta-analysis. Our results showed that ICI combination therapy was significantly associated with the improvement of overall response rate (ORR) (RR =1.44 [95% CI 1.19, 1.74], P=0.0002), progression-free survival (PFS) (HR =0.67 [95% CI 0.59, 0.77], P<0.00001), and OS (HR =0.81 [95% CI 0.70, 0.95], P=0.008) in lung cancer. In subgroup analyses, combination ICI therapy significantly prolonged OS in non-small-cell lung cancer (NSCLC) patients (HR =0.80 [95% CI 0.73, 0.88], P<0.00001) but not in SCLC (HR =0.94 [95% CI 0.82, 1.08], P=0.40) patients. Data suggested that PD-1 inhibitors had higher efficacy and safety profiles than PD-L1 and CTLA-4 inhibitors in combination ICI therapy for lung cancer patients. Furthermore, tolerability analysis revealed higher incidences of grade ≥3 AEs, fatigue, and increased transaminases from combination ICI therapy. In conclusion, our meta-analysis indicated that combination ICI therapy should be considered in clinical practice and future study designs for NSCLC patients. However, the current data do not support the large-scale clinical application of combination ICI therapy in SCLC patients.

Clinical Characteristics and Survival Outcomes for Non-Small-Cell Lung Cancer Patients with Epidermal Growth Factor Receptor Double Mutations.

Multiple randomized clinical trials have demonstrated that epidermal growth factor receptor (EGFR) exon 19 deletion (19Del) and exon 21 L858R mutation (L858R) are highly correlated with sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in non-small-cell lung cancer (NSCLC). A mutation in exon 20 (T790M) is reportedly associated with resistance to EGFR-TKIs. However, few studies have focused on patients harboring double mutations in these 3 mutation sites. In this retrospective study, forty-five patients (45/2546, 1.7%) harbored double mutations of 19Del, L858R, and T790M. Twenty-four patients with EGFR double mutations received EGFR-TKI therapy. Clinical characteristics of these patients, including the response to EGFR-TKIs and progression-free survival outcome for EGFR-TKI treatment (PFS-TKI), were analyzed. Patients with EGFR double mutations were more likely to be nonsmokers, have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1, have adenocarcinoma, and be at stage III-IV. The ORR, DCR, and median PFS-TKI in patients harboring EGFR double mutations were lower than in patients with a single EGFR-activating mutation. The differences in ORR and DCR were statistically insignificant between the 3 groups. Patients with double mutations of 19Del and T790M had longer PFS-TKIs than patients in the other 2 groups.

A consensus on immunotherapy from the 2017 Chinese Lung Cancer Summit expert panel.

The notable clinical success of cancer immunotherapy using checkpoint blockade suggests that it is likely to form the foundation of curative therapy for many malignancies. However, checkpoint blockades do not achieve sustained clinical response in most patients and thus amounts of problems needed to be figured out. Regarding these challenges, the 2017 Chinese Lung Cancer Summit expert panel organized a forum on the 14th Chinese Lung Cancer Summit to formally discuss these controversies. Five consensuses finally were reached to guide the application of checkpoint blockades.