Versatile dopamine-functionalized hyaluronic acid-recombinant human collagen hydrogel promoting diabetic wound healing via inflammation control and vascularization tissue regeneration.

The management of chronic wounds in diabetes remains challenging due to the complexity of impaired wound healing, delayed healing, susceptibility to infection, and elevated risk of reopening, highlighting the need for effective chronic wound management with innovative approaches such as multifunctional hydrogels. Here, we have produced HA-DA@rhCol hydrogels consisting of dopamine-modified hyaluronic acid and recombinant human collagen type-III (rhCol) by oxidative coupling of the catechol group using the H2O2/HRP catalytic system. The post-reactive hydrogel has a good porous structure, swelling rate, reasonable degradation, rheological and mechanical properties, and the catechol group and dopamine impart to the hydrogel tissue adhesiveness, antioxidant capacity, and excellent photothermal effects leading to superior in vitro antimicrobial activity. In addition, the ability of rhCol to confer hydrogels to promote angiogenesis and wound repair has also been investigated. Cytotoxicity and hemolysis tests demonstrated the good biocompatibility of the hydrogel. Wound closure, collagen deposition and immunohistochemical examination confirmed the ability of the hydrogel to promote diabetic wound healing. In summary, the adhesive hemostatic antioxidative hydrogel with rhCol to promote wound healing in diabetic rat is an excellent chronic wound dressing.

The efficacy and safety of apatinib plus capecitabine in platinum-refractory metastatic and/or recurrent nasopharyngeal carcinoma: a prospective, phase II trial.

BACKGROUND: Previous studies have shown that monotherapy with apatinib, an oral tyrosine kinase inhibitor, has promising efficacy for treating recurrent or metastatic (RM) nasopharyngeal carcinoma (NPC) patients. In this study, we aimed to assess the efficacy and safety of apatinib combined with capecitabine as a second-line therapy or beyond for treating RM-NPC patients who failed the first-line platinum-based chemotherapy. METHODS: In this single-arm, phase II study, we enrolled RM-NPC patients who had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The sample size was determined using Simon's two-stage design. All patients were administered with apatinib 500 mg once daily and capecitabine 1000 mg/m2 twice per day on days 1-14 of each 21-day cycle. The primary endpoint was the objective response rate (ORR), and the secondary endpoints comprised disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: We enrolled 64 patients from September 2018 to August 2020. The ORR and DCR were 39.1% (95% CI, 27.1-52.1) and 85.9% (95% CI, 75.0-93.4), respectively. The median DoR was 14.4 months (95% CI, 7.8-21.0). As of April 20, 2021, the median follow-up duration was 12.0 months. The median PFS was 7.5 months (95% CI, 5.0-10.0) and the median OS was 15.7 months (95% CI, 11.3-20.1). The most common toxicities of any grade were anemia (75.0%), hand-foot syndrome (65.6%), and proteinuria (64.0%). Grade 3-4 toxicities were observed in 36 (56.3%) patients, with hypertension (14.1%), mucositis (12.4%), and fatigue (10.9%) most commonly observed. CONCLUSIONS: Apatinib plus capecitabine shows promising efficacy as a second-line treatment option in pretreated platinum-refractory RM-NPC patients. Dose selection of this combination needs further investigation considering the toxicity. TRIAL REGISTRATION: Chi-CTR1800017229.

Preclinical characterization and phase I clinical trial of CT053PTSA targets MET, AXL, and VEGFR2 in patients with advanced solid tumors.

Background: CT053PTSA is a novel tyrosine kinase inhibitor that targets MET, AXL, VEGFR2, FLT3 and MERTK. Here, we present preclinical data about CT053PTSA, and we conducted the first-in-human (FIH) study to evaluate the use of CT053PTSA in adult patients with pretreated advanced solid tumors. Methods: The selectivity and antitumor activity of CT053PTSA were assessed in cell lines in vitro through kinase and cellular screening panels and in cell line-derived tumor xenograft (CDX) and patient-derived xenograft (PDX) models in vivo. The FIH, phase I, single-center, single-arm, dose escalation (3 + 3 design) study was conducted, patients received at least one dose of CT053PTSA (15 mg QD, 30 mg QD, 60 mg QD, 100 mg QD, and 150 mg QD). The primary objectives were to assess safety and tolerability, to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended dose of CT053PTSA for further study. Secondary objectives included pharmacokinetics, antitumor activity. Results: CT053 (free-base form of CT053PTSA) inhibited MET, AXL, VEGFR2, FLT3 and MERTK phosphorylation and suppressed tumor cell angiogenesis by blocking VEGF and HGF, respectively, in vitro. Moreover, cell lines with high MET expression exhibited strong sensitivity to CT053, and CT053 blocked the MET and AXL signaling pathways. In an in vivo study, CT053 significantly inhibited tumor growth in CDX and PDX models. Twenty eligible patients were enrolled in the FIH phase I trial. The most common treatment-related adverse events were transaminase elevation (65%), leukopenia (45%) and neutropenia (35%). DLTs occurred in 3 patients, 1/6 in the 100 mg group and 2/4 in the 150 mg group, so the MTD was set to 100 mg. CT053PTSA was rapidly absorbed after the oral administration of a single dose, and the Cmax and AUC increased proportionally as the dose increased. A total of 17 patients in this trial underwent tumor imaging evaluation, and 29.4% had stable disease. Conclusions: CT053PTSA has potent antitumor and antiangiogenic activity in preclinical models. In this FIH phase I trial, CT053PTSA was well tolerated and had a satisfactory safety profile. Further trials evaluating the clinical activity of CT053PTSA are ongoing.

A Phase Ib Study of Lucitanib (AL3810) in a Cohort of Patients with Recurrent and Metastatic Nasopharyngeal Carcinoma.

BACKGROUND: Lucitanib is a novel multi-target inhibitor of FGFR1-3, VEGFR 1-3, and PDGFR α/ß. Here, we evaluated the safety, tolerability, and preliminary efficacy of lucitanib in recurrent and metastatic nasopharyngeal carcinoma (RM-NPC). METHODS: Patients with pretreated RM-NPC were randomly divided into two treatment arms: continuous or intermittent treatment. The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). RESULTS: One hundred percent of patients in the continuous arm and 90% of patients in the intermittent arm had at least one treatment-related AE (TRAE). Grade ≥3 related TRAEs occurred in 5 patients in the continuous arm (5/10, 50%). No TRAEs grade >3 occurred in the intermittent arm. The ORR and DCR of the continuous arm was 20% and 90%, and the intermittent arm was 10% and 60%, respectively. All responses were observed by the first evaluation. The duration of response was more than 1 year, with two patients still on treatment with sustained response at more than 3 years. CONCLUSION: Lucitanib has promising clinical activity and tolerable safety profile in heavily pretreated patients with NPC. Patients who responded to lucitanib treatment generally achieved a long DoR. Lucitanib is now being evaluated in phase II/III studies. CLINICALTRIALS.GOV IDENTIFIER: NCT03260179.

Alkaliphilus flagellatus sp. nov., Butyricicoccus intestinisimiae sp. nov., Clostridium mobile sp. nov., Clostridium simiarum sp. nov., Dysosmobacter acutus sp. nov., Paenibacillus brevis sp. nov., Peptoniphilus ovalis sp. nov. and Tissierella simiarum sp. nov., isolated from monkey faeces.

Non-human primates harbour diverse microbiomes in their guts. As a part of the China Microbiome Initiatives, we cultivated and characterized the gut microbiome of cynomolgus monkeys (Macaca fascicularis). In this report, we communicate the characterization and taxonomy of eight bacterial strains that were obtained from faecal samples of captive cynomolgus monkeys. The results revealed that they represented eight novel bacterial species. The proposed names of the eight novel species are Alkaliphilus flagellatus (type strain MSJ-5T=CGMCC 1.45007T=KCTC 15974T), Butyricicoccus intestinisimiae MSJd-7T (MSJd-7T=CGMCC 1.45013T=KCTC 25112T), Clostridium mobile (MSJ-11T=CGMCC 1.45009T=KCTC 25065T), Clostridium simiarum (MSJ-4T=CGMCC 1.45006T=KCTC 15975T), Dysosmobacter acutus (MSJ-2T=CGMCC 1.32896T=KCTC 15976T), Paenibacillus brevis MSJ-6T (MSJ-6T=CGMCC 1.45008T=KCTC 15973T), Peptoniphilus ovalis (MSJ-1T=CGMCC 1.31770T=KCTC 15977T) and Tissierella simiarum (MSJ-40T=CGMCC 1.45012T=KCTC 25071T).

Rational application of gefitinib in NSCLC patients with sensitive EGFR mutations based on pharmacokinetics and metabolomics.

Gefitinib has been available in the market for 20 years, but its pharmacokinetic mechanism of response is little known. In this study, we examined the pharmacokinetic and metabolomic profiles in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. A total of 216 advanced NSCLC patients were enrolled, and administered gefitinib at the standard dosage of 250 mg/day, which was established in heterogeneous subjects with non-sensitive mutations. We identified and quantified three main metabolites (named as M1, M2 and M3) in the plasma of patients, the correlations between the concentration of gefitinib/metabolites and efficacy were analyzed. In exploratory and validation set, gefitinib concentration was not correlated with clinical effects. Considering the result that the therapeutic effects of 250 mg/2-day was better than that of 250 mg/day in a multiple center clinical trial, the standard dose might be higher than that for maximal efficacy according to the hypothetical dose-response curve. Among the three metabolites, the IC50 of M2 in HCC827 and PC9 cell lines was significantly lower, and Conc.brain/Conc.plasma of M2 in mice was significantly higher than those of gefitinib, suggesting its higher potential to penetrate blood-brain barrier and might be more effective in the treatment of brain metastatic tumor than gefitinib. Consistently and attractively, higher M2 plasma concentration was found to be correlated with better clinical outcome in patients with brain metastases (the median PFS of CM2 < 12 ng/mL and CM2 ≥ 12 ng/mL were 17.0 and 27.1 months, respectively, P = 0.038). The plasma concentration of M2 ≥ 12 ng/mL was a strong predictor of the PFS of NSCLC patients. In conclusion, for NSCLC patients with EGFR sensitive mutations, the standard dose is suspectable and could be decreased reasonably. M2 plays an important role in efficacy and may be more effective in the treatment of metastatic tumor than gefitinib.

Predictive value of a reduction in the level of high-density lipoprotein-cholesterol in patients with non-small-cell lung cancer undergoing radical resection and adjuvant chemotherapy: a retrospective observational study.

BACKGROUND: Cancer patients often exhibit chemotherapy-associated changes in serum lipid profiles, however, their prognostic value before and after adjuvant chemotherapy on survival among non-small-cell lung cancer (NSCLC) patients is unknown. METHODS: NSCLC patients undergoing radical resection and subsequent adjuvant chemotherapy from 2013 to 2017 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Fasted serum lipid levels were measured before and after chemotherapy. The optimal lipid cut-off values at baseline and fluctuation were determined using X-tile™. The fluctuations in serum lipid levels and disease-free survival (DFS) were assessed. RESULTS: Serum cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, apolipoprotein (Apo) A-I, and ApoB all significantly increased after adjuvant chemotherapy. X-tile determined 1.52 mmol/L of HDL-C and 0.74 g/L of ApoB as the optimal cut-off values before chemotherapy. Patients with HDL-C ≥ 1.52 mmol/L (median DFS: not reached vs. 26.30 months, P = 0.0005) and a decreased HDL-C level after adjuvant chemotherapy (median DFS: 80.43 vs. 26.12 months, P = 0.0204) had a longer DFS. An HDL-C level that increased by ≥ 0.32 mmol/L after chemotherapy indicated a worse DFS. A high baseline ApoB level were associated with a superior DFS. In the univariate analysis and the multivariate Cox analyses, a high baseline HDL-C level and a HDL-C reduction after adjuvant chemotherapy were independent indicators for superior DFS. High baseline HDL-C was related to N0-1 stage (χ2 = 6.413, P = 0.011), and HDL-C fluctuation was significantly correlated with specific chemotherapy regimens (χ2 = 5.002, P = 0.025). CONCLUSIONS: Adjuvant chemotherapy increased various lipid levels in resected NSCLC patients. A higher HDL-C level before chemotherapy and a reduced HDL-C level after adjuvant chemotherapy were independent predictors of longer DFS in patients with curable NSCLC.

The efficacy of first-line chemotherapy in recurrent or metastatic nasopharyngeal carcinoma: a systematic review and meta-analysis.

BACKGROUND: The standard first-line chemotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) has not been well established. We conducted a pooled meta-analysis to evaluate the efficacy of commonly used first-line chemotherapy in this disease. METHODS: Electronic databases including PubMed, Embase, and Corchrane library were searched for eligible literatures. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS) were pooled with the 95% confidence interval (CI) using R software. RESULTS: Totally 973 patients were available for analysis from 14 phase II single arm clinical trials and 2 phase III randomized clinical trials. Four regimens were identified including 5-fluorouracil plus platinum (FP), gemcitabine plus platinum (GP), taxanes plus platinum (TP), and triplet combination regimen. Of these four regimens, triplet combination regimen demonstrated best short-term efficacy with a highest ORR (0.74; 95% CI, 0.62-0.87), DCR (0.91; 95% CI, 0.87-0.95), and 6-month PFS rate (0.83; 95% CI, 0.75-0.91), while 1-year OS rate (0.74; 95% CI, 0.61-0.87) was a little lower than TP regimen. Meanwhile, TP regimen showed best prognosis with a highest 1-year OS rate of 0.79 (95% CI, 0.65-0.92) and pretty good short-term efficacy with an ORR of 0.60 (95% CI, 0.48-0.72) and a DCR of 0.92 (95% CI, 0.86-0.98) comparable with triplet combination therapy. FP regimen had the lowest ORR (0.52; 95% CI, 0.38-0.65) and 1-year OS rate (0.63; 95% CI, 0.57-0.69). Efficacy of GP regimen fell between FP and TP regimens with an ORR of 0.54 (95% CI, 0.38-0.65), a DCR of 0.85 (95% CI, 0.71-0.93), a 6-month PFS rate of 0.69 (95% CI, 0.60-0.78) and a 1-year OS rate of 0.71 (95% CI, 0.61-0.80). CONCLUSIONS: Among four commonly used first-line chemotherapy regimens for R/M NPC, triplet combination regimen showed best short-term efficacy but failed to improve prognosis. TP regimen demonstrated fairly good short-term efficacy and best long-term efficacy, followed by GP regimen, while FP regimen was the lowest.

The Efficacy and Toxicity of Lobaplatin-contained Chemotherapy in Extensive-stage Small-cell Lung Cancer.

To assess the efficacy and toxicity of Lobaplatin (LBP) -contained chemotherapy on extensive stage small-cell lung cancer (ES-SCLC), we conducted a prospective, single-arm, and multicenter Phase IV clinical trial on Lobaplatin (ChiCTR-ONC-13003471), and used the patient clinical data obtained from our cancer center to perform the analysis. Previously untreated patients with ES-SCLC were given LBP intravenously (IV) at 30 mg/m2 on day 1 and etoposide IV at 100 mg/m2 on day 1, 2, and 3. The treatment was cycled every 21 days, lasting for four to six cycles. The patients with second-line treatment or above were also included in the study, and they were treated with LBP-contained regimen: a single dose of LBP at 50 mg/m2 on day 1 through IV; combined application, LBP30 mg/m2 IV on day 1. From May 2015 to August 2016, 36 patients were enrolled in the study at our cancer center. For the 30 first-line patients, the median overall survival (OS) and the median progression-free survival (PFS) was 13.0 months (ranging from 11.2 to 14.7 months) and 4.7 months (ranging from 1.6 to 7.7 months) respectively, with overall response rate of 57 % and disease control rate of 85.7%. For the 6 patients with second-line treatment or above, one patient got a partial response (PR) and four patients got a stable disease (SD). The most frequent drug-related adverse effects were leukopenia and neutropenia, and no grade 3/4 hepatotoxicity or nephrotoxicity was observed. These results indicated that LBP-contained chemotherapy was effective and tolerable for extensive stage SCLC in terms of response and survival. However, due to the small sample size of this study, we need to wait for the OS data of phase Ⅲ clinical trial and the final data of this multicenter Phase IV study to draw the conclusion.

Chemotherapy Near the End of Life for Chinese Patients with Solid Malignancies.

INTRODUCTION: There are increasing concerns about the negative impacts of chemotherapy near the end of life (EOL). There is discrepancy among different countries about its use, and little is known about the real-world situation in China. PATIENTS AND METHODS: This retrospective study was conducted at six representative hospitals across China. Adult decedents with a record of advanced solid cancer and palliative chemotherapy were consecutively screened from 2010 through 2014. The prevalence of EOL chemotherapy within the last 1 month of life was set as the primary outcome. The correlations among EOL chemotherapy, clinicopathological features, and overall survival (OS) were investigated. RESULTS: A total of 3,350 decedents who had had cancer were consecutively included; 2,098 (62.6%) were male and the median age was 56 years (range, 20-88). There were 177 (5.3%), 387 (11.6%), and 837 (25.0%) patients who received EOL chemotherapy within the last 2 weeks, 1 month, and 2 months of life, respectively. We identified inferior OS (median OS, 7.1 vs. 14.2 months; hazard ratio, 1.37; 95% confidence interval [CI], 1.23-1.53; p < .001), more intensive treatments (e.g., admitted to intensive care unit [ICU] in the last month of life, received cardiopulmonary resuscitation and invasive ventilation support), and hospital death (odds ratio, 1.53; 95% CI, 1.14-2.06; p = .005) among patients who received continued chemotherapy within the last month compared with those who did not. However, subgroup analyses indicated that receiving oral agents correlated with fewer ICU admissions and lower rates of in-hospital death. CONCLUSION: This study showed that EOL chemotherapy is commonly used in China. Intravenous chemotherapy at the EOL significantly correlated with poor outcomes and the role of oral anticancer agents warrants further investigation. The Oncologist 2017;22:53-60Implications for Practice: The role of chemotherapy toward the end of life (EOL) in patients with solid cancers is debatable. This article is believed to be the first to report the current prevalence of EOL chemotherapy in China. This study found that, compared with oral anticancer agents, intravenous chemotherapy at the EOL was significantly associated with poor outcomes. Therefore, the role of oral anticancer agents at the EOL stage deserves further investigation.

A retrospective analysis of the clinicopathological and molecular characteristics of pulmonary blastoma.

PURPOSE: The aim of this study was to analyze and summarize the clinicopathological and molecular characteristics of classic biphasic pulmonary blastoma (PB) to improve its diagnosis and treatment. PATIENTS AND METHODS: A retrospective analysis was performed in patients who were diagnosed with PB at Sun Yat-Sen University Cancer Center from March 1995 to March 2015. Genomic DNA was profiled using a capture-based targeted sequencing panel. RESULTS: Sixteen patients with an average age of 40 years were included in this study. Accurate preoperative diagnosis was very challenging as surgically resected tissues with immunohistochemical staining were required for the diagnosis. Surgery was the optimal treatment for localized disease and there was no standard management for metastatic disease. Mutations were detected among 9 out of the 56 genes profiled, including BRCA2, ERBB4, ALK, MET, BRAF, RAF1, PTEN, EGFR, and PIK3CA. CONCLUSION: Due to the low incidence rate and the reclassification of PB, no standard treatment is available. Although the numbers of cases are few with varying individual experiences, it is important to improve our understanding regarding this rare lung cancer. Targeted DNA sequencing may be of clinical use for molecular testing and the effects of targeted therapy need to be confirmed.

Low Prognostic Nutritional Index Correlates with Worse Survival in Patients with Advanced NSCLC following EGFR-TKIs.

OBJECTIVE: This study was designed to demonstrate the prognostic value of prognostic nutritional index (PNI), a reflection systemic immunonutritional status, on the long-term survival of patients taking epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). METHODS: In this retrospective study, eligible advanced NSCLC patients with sensitive EGFR mutations (exon 19 deletion or L858R in exon 21) were included to investigate the correlation between the PNI and overall survival (OS). The PNI was calculated as 10 x serum albumin value (g/dl) + 0.005 x peripheral lymphocyte count (per mm3). The prognostic significance of PNI and other clinicopathologic factors was identified by univariate and multivariate analysis. RESULTS: Finally, 144 patients met the inclusion criteria. The optimal cut-off value of PNI for survival stratification was 48.78. Compared with high PNI group (n = 81), low PNI (n = 63) was significantly associated with elevated C-reactive protein (CRP) level and non-response to TKIs. Overall survival was superior in the high PNI group (HR, 0.44, p = 0.004), especially for patient with L858R (HR, 0.37, p = 0.009) rather than 19 deletion (HR, 0.69, p = 0.401). The independent prognostic value of PNI was validated by multivariate analysis. CONCLUSION: This pilot investigation demonstrated that low prognostic nutritional index correlates with worse survival for patients with advanced NSCLC and taking EGFR-TKIs. The assessment of a convenient index, known as PNI, worth attention in routine clinical practice for patients following EGFR-TKIs treatment.

The Efficacy of Combining EGFR Monoclonal Antibody With Chemotherapy for Patients With Advanced Nonsmall Cell Lung Cancer: A Meta-Analysis From 9 Randomized Controlled Trials.

Although epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have been proved synergistic effect when combined with cytotoxic agents for advanced nonsmall cell lung cancer (NSCLC), the results of relevant clinical trials remain controversial. The purpose of this meta-analysis was to assess the advantage and toxicity profile of chemotherapy plus EGFR-mAbs versus chemotherapy alone for patients with NSCLC.We rigorously searched electronic databases for eligible studies reporting EGFR-mAbs combined with chemotherapy versus chemotherapy alone for patients with advanced NSCLC. The primary outcome was overall survival (OS). Pooled results were calculated using proper statistical methods.Nine phase II/III randomized controlled trials involved a total of 4949 participants were included. In general, compared with chemotherapy alone, the addition of EGFR-mAbs significantly improved OS (hazard ratio [HR] = 0.91, 95% confidence interval [CI]: 0.86-0.97, P = 0.006), progression-free survival (HR = 0.83, 95% CI: 0.87-0.98, P = 0.01), response rate (odd ratio [OR] = 1.28, 95% CI: 1.12-1.47, P = 0.0003), and disease control rate (OR = 1.17, 95% CI: 1.01-1.36, P = 0.04). Subgroup analysis showed that apparent OS benefit present in patients with squamous NSCLC (HR = 0.83, 95% CI: 0.74-0.93, P = 0.001), and those treatment-naive population (HR = 0.88, 95% CI: 0.82-0.95, P = 0.0006). Several manageable adverse events were markedly increased by EGFR-mAbs, such as acne-like rash, infusion reactions, and diarrhea. The risk for some ≥Grade 3 toxicities, such as leukopenia, febrile neutropenia, and thromboembolic events were slightly increased by the addition of EGFR-mAbs. In general, the toxicities of the combination strategy were tolerable and manageable.The addition of EGFR-mAbs to chemotherapy provided superior clinical benefit along with acceptable toxicities to patients with advanced NSCLC, especially those harboring squamous cancer and treatment-naive. Further validation in front-line investigation, proper selection of the potential benefit population by tumor histology, and development of prognostic biomarkers are warranted for future research and clinical application of EGFR-mAbs.

Efficacy of Addition of Antiangiogenic Agents to Taxanes-Containing Chemotherapy in Advanced Nonsmall-Cell Lung Cancer: A Meta-Analysis and Systemic Review.

Preclinical researches indicated a potential synergistic effect of taxanes-containing chemotherapy (TCC) and antiangiogenic agents (AAs) on the treatment of advanced nonsmall-cell lung cancer (NSCLC). The advantage of adding AA to TCC in the real world remains confusing. We summarized the current evidences from relevant phase II/III randomized controlled trials (RCTs) by performing this meta-analyses.Electronic databases were searched for eligible literatures. The primary endpoint was overall survival (OS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were calculated using RevMan 5.2.A total of 14 phase II/III RCTs involving 9703 participants were included. Compared to standard TCC, the addition of AA was associated with the significant better OS (HR 0.92, 95% CI 0.87-0.97, P = 0.002), prolonged progression-free survival (HR 0.79, 95% CI 0.71-0.87, P < 0.00001), superior response rate (risk ratio [RR] 1.69, 95% CI 1.47-1.95, P < 0.0001), and disease control rate (RR 1.19, 95% CI 1.08-1.32, P < 0.00001). Subgroup analyses indicated that patient treated with monoclonal antibodies (HR 0.89, 95% CI 0.82-0.96, P = 0.02) as well as application in second-line (HR 0.91, 95% CI 0.85-0.96, P = 0.02) acquired significant OS improvement. Other clinical factors directing significant OS improvement by the combination strategy included nonsquamous cancer (P = 0.002), nonsmokers (P = 0.0005), and female (P = 0.02). Toxicities were greater but generally mild or moderate in the combination group, and were mostly manageable.In summary, the addition of AAs to TCC could improve prognosis of advanced NSCLC. Furthermore, proper selection of patient population and AAs is crucial for clinical trials design and clinical practice in the future.

QoL analyses from INFORM study, a phase III study of gefitinib versus placebo as maintenance therapy in advanced NSCLC.

This report aimed to provide the full results of QoL assessment in INFORM study. QoL was assessed by FACT-L questionnaire. QoL improvement ratio in gefitinib arm was higher than placebo arm (FACT-L: 46% vs. 22%, p < 0.001; TOI: 41% vs. 18%, p < 0.001; LCS: 46% vs. 22%, p < 0.001). Gefitinib prolonged time-to-worsening of QoL (FACT-L: 2.8 m vs 1.4 m, p = 0.019; TOI: 3.5 m vs 1.4 m, p = 0.006; LCS: 2.8 vs 1.4 m, p = 0.028). Patients with an improvement in QoL had longer PFS (FACT-L: 9.4 m vs. 2.8 m vs. 2.7 m, P < 0.001; TOI: 9.9 m vs. 2.8 m vs. 2.1 m, P < 0.001; LCS: 9.4 m vs. 2.9 m vs. 2.1 m, P < 0.001) and OS (FACT-L: 25.4 m vs. 19.9 m vs. 14.4 m, P = 0.003; TOI: 25.7 m vs. 19.0 m vs. 12.7 m, P = 0.002; LCS: 25.4 m vs. 19.3 m vs. 14.7 m, P = 0.004) compared with patients with stable or worsened QoL. Furthermore, in patients with good QoL at baseline, the treatment of gefitinib couldn't improve OS compared to placebo, whereas patients with low QoL experienced marginal significant improvement in OS (20.6 m vs 14.4, p = 0.051). Our study indicated that gefitinib could improve patients' QoL, confirmed the prognostic value of QoL changes during treatment, and implied patients with low QoL at baseline may be the potential population which will gain OS benefit from maintenance EGFR-TKI therapy.

Clinical analysis of 50 Eastern Asian patients with primary pulmonary large-cell neuroendocrine carcinoma.

BACKGROUND: To understand the clinicopathological features of patients with primary pulmonary large-cell neuroendocrine carcinoma (LCNEC), including the frequency of epidermal growth factor receptor (EGFR) mutation, and to explore prognostic factors. METHODS: We investigated a cohort of 50 individuals from our center database who were diagnosed with operable pulmonary LCNEC and treated in Sun Yat-sen University Cancer Center. Serum albumin (ALB) and neuron-specific enolase (NSE) were also collected. Survival curves were obtained with the Kaplan-Meier method, and the differences between groups in survival were tested by the log-rank test. RESULTS: The median age was 59 years (range, 40-80 years). Fourteen patients underwent mutational analysis of EGFR; of these, 12 had wild-type EGFR and the remaining two had EGFR mutations in exons. The median disease-free survival (DFS) of pulmonary LCNEC was 49.3 months and that of overall survival (OS) was not reached. DFS and OS were shorter for patients with decreased serum ALB than for patients with normal serum ALB (P=0.003 and P=0.004, respectively). Meanwhile, a high level of NSE was also significantly associated with short DFS and OS (P=0.005 and P=0.000, respectively). Multivariate analysis showed that decrease in serum ALB was an independent prognostic factor for OS (P=0.046). CONCLUSION: The frequency of EGFR mutation in LCNEC patients is low. Serum ALB and NSE levels are valuable prognostic factors for LCNEC patients.

Multiple oncogenic mutations related to targeted therapy in nasopharyngeal carcinoma.

INTRODUCTION: An increasing number of targeted drugs have been tested for the treatment of nasopharyngeal carcinoma (NPC). However, targeted therapy-related oncogenic mutations have not been fully evaluated. This study aimed to detect targeted therapy-related oncogenic mutations in NPC and to determine which targeted therapy might be potentially effective in treating NPC. METHODS: By using the SNaPshot assay, a rapid detection method, 19 mutation hotspots in 6 targeted therapy-related oncogenes were examined in 70 NPC patients. The associations between oncogenic mutations and clinicopathologic factors were analyzed. RESULTS: Among 70 patients, 12 (17.1%) had mutations in 5 oncogenes: 7 (10.0%) had v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) mutation, 2 (2.8%) had epidermal growth factor receptor (EGFR) mutation, 1 (1.4%) had phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, 1 (1.4%) had Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, and 1 (1.4%) had simultaneous EGFR and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations. No significant differences were observed between oncogenic mutations and clinicopathologic characteristics. Additionally, these oncogenic mutations were not associated with tumor recurrence and metastasis. CONCLUSIONS: Oncogenic mutations are present in NPC patients. The efficacy of targeted drugs on patients with the related oncogenic mutations requires further validation.

Effects of an oral allosteric AKT inhibitor (MK-2206) on human nasopharyngeal cancer in vitro and in vivo.

AIM: Protein kinase B (AKT) signaling frequently is deregulated in human cancers and plays an important role in nasopharyngeal carcinoma (NPC). This preclinical study investigated the effect of MK-2206, a potent allosteric AKT inhibitor, on human NPC cells in vitro and in vivo. METHODS: The effect of MK-2206 on the growth and proliferation of CNE-1, CNE-2, HONE-1, and SUNE-1 cells was assessed by Cell Counting Kit 8 and colony formation assay. Flow cytometry was performed to analyze cell cycle and apoptosis. The effects of MK-2206 on the AKT pathway were analyzed by Western blotting. Autophagy induction was evaluated via electron microscopy and Western blot. To test the effects of MK-2206 in vivo, CNE-2 cells were subcutaneously implanted into nude mice. Tumor-bearing mice were treated orally with MK-2206 or placebo. Tumors were harvested for immunohistochemical analysis. RESULTS: In vitro, MK-2206 inhibited the four NPC cell line growths and reduced the sizes of the colonies in a dose-dependent manner. At 72 and 96 hours, the half maximal inhibitory concentration (IC50) values of MK-2206 in CNE-1, CNE-2, and HONE-1 cell lines were 3-5 µM, whereas in SUNE-1, IC50 was less than 1 µM, and MK-2206 induced cell cycle arrest at the G1 phase. However, our study found no evidence of apoptosis. MK-2206 induced autophagy in NPC cells, as evidenced by electron microscopy and Western blot, and inhibited the growth of tumors that were subcutaneously implanted in mice. Inhibition of downstream phosphorylation through the PRAS40 and S6 pathways seems to be the main mechanism for the MK-2206-induced growth inhibition. CONCLUSION: Our preclinical study suggests that MK-2206's antiproliferative effect may be useful for NPC treatment; however, strategies for reinforcing this effect are needed to maximize clinical benefit.