Pan-cancer efficacy and safety of anlotinib plus PD-1 inhibitor in refractory solid tumor: A single-arm, open-label, phase II trial.

The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD-1 inhibitor to treat refractory solid tumor. APICAL-RST is an investigator-initiated, open-label, single-arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD-1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression-free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty-one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention-to-treat cohort, and 24.3% and 81.1% in the efficacy-evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%-77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23-24.4), and the 12- and 36-month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty-one (75.6%) patients experienced at least one treatment-related adverse event. The most common adverse events were hypothyroidism, hand-foot syndrome and malaise. This phase II trial showed that anlotinib plus PD-1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor.

Acquired EML4-ALK fusion and EGFR C797S in cis mutation as resistance mechanisms to osimertinib in a non-small cell lung cancer patient with EGFR L858R/T790M.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) dramatically improve the clinical outcomes of non-small cell lung cancer (NSCLC) patients harboring EGFR -sensitive mutations. Despite the remarkable efficacy of first-and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is a primary contributor to the acquired resistance to first- and second-generation EGFR TKIs. Osimertinib, which is an irreversible third-generation EGFR TKI, was designed for EGFR -activating mutations as well as the EGFR T790M mutation in patients with advanced NSCLC and has demonstrated a convincing efficacy. However, acquired resistance to osimertinib after treatment inevitably occurs. The acquired resistance mechanisms to osimertinib are highly complicated and not fully understood, encompassing EGFR -dependent as well as EGFR -independent mechanisms. Treatment approaches for patients progressing from osimertinib have not been established. We present a case of a stage IV lung adenocarcinoma patient harboring EGFR L858R, acquired T790M after treatment with first-line gefitinib. She then acquired a new EML4-ALK gene fusion after treatment with osimertinib. A combination targeted therapy of osimertinib plus alectinib was initiated, with a progression-free survival of 5 months without any serious adverse reaction. After disease progression, EGFR C797S in cis was detected with a loss of the EML4-ALK fusion by targeted next-generation sequencing. Then therapy was changed to pemetrexed combined with bevacizumab plus camrelizumab, but no obvious effect was observed. The patient had achieved an overall survival of 31 months. As far as we know, this was the first reported case that an EGFR -mutant NSCLC patient-acquired ALK fusion mediating resistance to osimertinib, and sequential EGFR C797S mutation mediating resistance to combined targeted therapy with osimertinib and alectinib. Our case shows that EML4-ALK fusion is a rare but critical resistance mechanism to osimertinib, and C797S mutation in cis may be an underlying mechanism of acquired resistance mutation in double TKIs therapy. Furthermore, molecular detection and rebiopsy play important roles in the selection of therapeutic strategies when the disease progresses.

Prognostic value of tumor mutation burden in patients with advanced gastric cancer receiving first-line chemotherapy.

Background: Tumor mutation burden (TMB) is a promising biomarker positively associated with the benefit of immunotherapy and that might predict the outcome of chemotherapy. We described the prognostic value of TMB in advanced gastric cancer and explored the underlying mechanism. Methods: We enrolled 155 TMB-evaluated advanced gastric cancer patients and analyzed the relationship between clinicopathological characteristics and both overall survival (OS) and progression-free survival (PFS) among 40 patients treated with first-line chemotherapy. We further verified the distribution of TMB and analyzed the potential mechanism underlying the prognosis based on The Cancer Genome Atlas (TCGA) database. Results: Among the 155 patients, 29 (18.7%) were TMB-high (TMB ≥ 10), roughly the same as the proportion in the TCGA data. Of the 40 patients receiving first-line chemotherapy, the median OS (7.9 vs. 12.1 months; HR 3.18; p = 0.0056) and PFS (4.4 vs. 6.2 months; HR 2.94; p = 0.0099) of the tissue-tested TMB (tTMB)-high patients were inferior to those of the tTMB-low patients. Similarly, unfavorable median OS (9.9 vs. 12.1 months; HR 2.11; p = 0.028) and PFS (5.3 vs. 6.5 months; HR 2.49; p = 0.0054) were shown in the blood-tested TMB (bTMB)-high than in the bTMB-low patients. The Cox analysis demonstrated that both tTMB-high and bTMB-high were significant independent predictors of dreadful OS and PFS. The differentially expressed genes (DEGs) according to TMB status were most significantly enriched in the downregulated metabolic pathway among the TMB-high patients. Conclusions: TMB-high advanced gastric cancer patients accounted for around one-sixth and had a poorer prognosis than TMB-low patients when treated with first-line chemotherapy. The potential mechanism might be the downregulated metabolic activity in TMB-high patients.

Relative Telomere Length in Peripheral Blood Cells and Hypertension Risk among Mine Workers: A Case-Control Study in Chinese Coal Miners.

Hypertension is a common chronic disease in middle-aged and elderly people and is an important risk factor for many cardiovascular diseases. Its pathogenesis remains unclear. Epidemiological studies have found that the loss of telomere length in peripheral blood cells can increase the risk of coronary heart disease, myocardial infarction, and other diseases. However, a correlation between loss of telomere length and hypertension has not been established. In this study, we aimed to explore the association between telomere length and the risk of essential hypertension (EH) in Chinese coal miners. A case-control study was performed with 215 EH patients and 222 healthy controls in a large coal mining group located in North China. Face-to-face interviews were conducted by trained staff with the necessary medical knowledge. Relative telomere length (RTL) was measured by a quantitative real-time PCR assay using DNA extracted from peripheral blood. In the control group, the age-adjusted RTL was statistically significantly lower in miners performing hard physical labour compared with nonphysical labour (P = 0.043). A significantly shorter age-adjusted RTL was found in the control group of participants who consumed alcohol regularly compared with those who do not consume alcohol (P = 0.024). Age-adjusted RTL was negatively correlated with body mass index (BMI) and alcohol consumption. Hypertension was also found to be significantly correlated with factors such as age, BMI, alcohol consumption, smoking, and tea consumption. Our results suggest that RTL is associated with hypertension in coal miners.

Role of endoplasmic reticulum stress and oxidative stress in vinyl chloride-induced hepatic steatosis in mice.

Vinyl chloride (VC) is a common industrial organochlorine, shown to cause hepatic angiosarcoma and hepatic steatosis. However, the role of endoplasmic reticulum stress (ERS) and oxidative stress (OS) in hepatic steatosis after subchronic exposure to VC in mice, is unclear. Based on body weight, forty healthy SPF male C57BL/6 J mice were randomly divided into a control group and three VC exposure groups (57.3, 286.7, and 1433.6 ppm) (n = 10 each). VC was administered by static inhalation in a 50 L sealed plexiglass inhalation chamber for 2 h per day, five days per week for 16 weeks. Serum and liver tissues were analyzed for liver enzymes and lipids. Hepatic cytochrome P450 2E1 (CYP2E1) and OS related indicators malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were measured. The mRNA expressions of ERS downstream genes, including glycoregulatory protein-78 (GRP-78), sterol regulatory element binding protein-1 (SREBP-1), Acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) were detected by real-time PCR (RT-PCR) and their protein levels examined by western blotting. The CYP2E1 levels increased after VC administration in a dose-dependent manner. MDA levels increased (P < .05) and SOD and GSH levels decreased (P < .05) in the liver of each group with the increase in the dose of VC. ERS and expressions of downstream genes (GRP-78, SREBP-1, ACC, and FAS) were enhanced after VC administration. These results suggested that OS and ERS could be induced by VC, which may lead to an increase in fatty acid synthesis in the liver, further aggravating hepatic steatosis.

Association between methylation of DNA damage response-related genes and DNA damage in hepatocytes of rats following subchronic exposure to vinyl chloride.

In the present study, we investigated the association between methylation of DNA damage response-related genes such as cyclin-dependent kinase inhibitor (CDKN)2A, Ras association (RalGDS/AF-6) domain family member (RASSF)1A, O6-methylguanine DNA methyltransferase (MGMT), Kirsten rat sarcoma viral oncogene homolog (KRAS), and spleen-associated tyrosine kinase (SYK) and DNA damage in hepatocytes of rats following subchronic exposure to vinyl chloride (VC). Sixty-four healthy rats were randomly divided into three VC exposure groups (5, 25, and 125 mg/kg) and an untreated negative control group (n = 16 each). VC was administered by intraperitoneal injection every other day for a total of three times a week. Eight randomly selected rats from each group were sacrificed at the end of 6 and 12 weeks, and liver tissue was harvested for the comet assay and for assessment of DNA methylation level and mRNA expression of related genes by PCR. Overall methylation levels in the genome of hepatocytes in VC-exposed rats were higher than those in the control group at 6 and 12 weeks (P < 0.05), although no differences were observed with regarding to dose (P > 0.05). After 12 weeks of exposure, differences in the methylation of RASSF1A and MGMT promoter regions were observed between the high-dose group and other groups (P < 0.05), whereas no differences were observed for the KRAS, SYK, and CDKN2A promoters (P > 0.05). These results suggest that DNA damage and increased genome-wide methylation are biomarkers for VC exposure and that RASSF1A and MGMT promoter methylation is related to the carcinogenic mechanism of VC.

[Effects of Mushroom Residue Application Rates on Net Greenhouse Gas Emissions in the Purple Paddy Soil].

China is the leading country for production of edible mushrooms and also outputs numerous mushroom residues. The recycling of mushroom residue can solve environmental pollution problems, provide nutrients for the farmland, and play an important role in reducing greenhouse gas emissions and increasing soil carbon sequestration capacity. In order to investigate the effects of mushroom residue amounts on net greenhouse gas emissions in purple paddy soil, potted experiments using static opaque chamber and gas chromatography methods were used to study the changes of greenhouse gases, soil carbon sequestration, and net greenhouse gas emissions (NGHGE) in the paddy soil with five treatments: no fertilizer (CK), conventional fertilization (NPK), 9 t·hm-2 mushroom residue+NPK (LM), 18 t·hm-2 mushroom residue+NPK (MM), and 36 t·hm2 mushroom residue+NPK (HM) from March 2017 to September 2017.The results showed that: ① The greenhouse gas emissions (including CH4, CO2, and N2O) increased with increasing additions of mushroom residue. The emissions of CH4 from highest to lowest followed: HM > MM > LM≈NPK > CK. The HM treatment significantly increased the CH4 emission flux (P<0.01) more than the other treatments and showed an obvious single peak curve, while the CH4 emission flux with the LM treatment showed a bimodal curve, and the MM treatment showed a multiple peak curve. The CO2 emission flux followed: MM > NPK≈LM > HM > CK; and the curves for the LM, MM, and HM treatments were a single peak curve, bimodal curve, and multiple peak curve, respectively. The N2O cumulative emission from the NPK treatment was significantly higher than with the other treatments. The N2O emission flux of the NPK treatment was a bimodal curve and that of the HM treatment was a single peak curve, while the N2O emission flux of treatments LM and MM showed multiple peak curves. ② The carbon sequestration capacity with the LM treatment was lower than that of the other treatments and that from the MM treatment was the highest. The carbon sequestration capacity of the MM treatment increased by 59.2% compared to that of the NPK treatment and increased by 87.79% and 65.65% compared to that of the LM and HM treatments. The LM treatment has the highest carbon sequestration capacity, which was higher than that of the NPK and MM treatments and about 2.1 times greater than the CK treatment and HM treatment. ③ The minimum NGHGE value was -490.29 kg·hm-2 for the whole rice production period, and 18 t·hm-2 mushroom residue applied to the soil was the best way to reduce net greenhouse gas emissions in purple paddy soil.

[Systematic review of Chuankezhi injection for treating acute exacerbation of chronic obstructive pulmonary disease].

To evaluate the inflammatory factors, the pulmonary function, the efficiency and the safety of Chuankezhi injection for treating acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The randomized controlled trials (RCTs) on Chuankezhi injection for treating AECOPD were collected from 7 databases (PubMed, CNKI, et al) between inception to November 2016. Two reviewers independently screened literature and extracted the data according to the inclusion and exclusion criteria, and assessed methodological quality of included studies according to the criteria from Cochrane Reviewer's Handbook 5.3. Then, Meta-analysis was conducted by using RevMan 5.3 software. A total of 13 RCTs involving 1 016 patients were included. Meta-analysis results indicated that Chuankezhi group was superior to the control group in the clinical effectiveness [RR=1.15, 95% CI(1.06, 1.23), P=0.000 3], improved pulmonary functions including forced expiratory volume in one second (FEV1) [MD=0.21, 95% CI (0.15, 0.27), P<0.000 01], forced vital capacity (FVC) [MD=0.36, 95% CI（0.15, 0.56）, P=0.000 6], the first seconds breathing volume percentage of forced vital capacity (FEV1/FVC) [MD=6.85, 95% CI（4.68, 9.02）, P<0.000 01] and decreased the level of inflammatory factors including interleukin-6 (IL-6) [MD=-6.35, 95% CI (-8.23, -4.47), P<0.000 01], IL-8 [MD = -2.00, 95% CI ( -3.13, 0.87), P=0.000 5], tumor necrosis factor-α (TNF-α) [ MD=-2.79, 95% CI (-4.61,-0.97), P=0.003]. Besides, there were no frequently happened or serious adverse reactions observed in Chuankezhi group. The results showed that Chuankezhi injection could improve the efficiency and the pulmonary function, reduce inflammation for AECOPD with a high safety on the basis of routine symptomatic treatment. However, due to limited quantity and quality of the included studies, the conclusion above should be further verified by conducting more high quality RCTs.

A Preoperative Nutritional Index for Predicting Cancer-Specific and Overall Survival in Chinese Patients With Laryngeal Cancer: A Retrospective Study.

Pinato prognostic nutritional index (PNI) adequately predicts long-term outcomes of various malignancies. However, its value in predicting outcomes in laryngeal squamous cell carcinoma (LSCC) is unknown. All patients newly diagnosed with LSCC presenting to the Department of Head and Neck Oncology at Sun Yat-sen University Cancer Center between January 1, 1990 and July 31, 2010 were eligible. The PNI was calculated as serum albumin (g/L) + 5 × total lymphocyte count/L. The Cutoff Finder software program was used to classify the patients into 3 groups for which the PNI score was at least 70% sensitive, at least 70% specific, or equivocal. Cancer-specific survival was estimated using the Kaplan-Meier method, and predictors were assessed with Cox regression analysis. Median time between surgery and PNI administration for the 975 eligible patients was 83 months. Index score groups were significantly associated with age, T stage, TNM stage, and type of surgery. Five-year CSS and OS were 57.3% and 56.6% in patients with PNI scores below 48.65 (low-probability of survival), 72.8% and 71.3% with scores between 48.65 and 56.93 (moderate-probability of survival), and 77.6% and 75.3% with scores above 56.93 (high-probability of survival); 10-year CSS and OS were 44.2% and 42.7%, 61.6% and 55.6%, 68.3% and 63.5%, respectively. The PNI score groups significantly predicted CSS and OS (P < 0.001). The PNI is an inexpensive and readily available score that predicted survival in patients with LSCC after curative laryngectomy.