Efficacy and safety of second-line camrelizumab combined with apatinib and chemotherapy in patients with advanced lung adenocarcinoma: A prospective, open-label, multicentric study.

OBJECTIVES: Camrelizumab (a programmed cell death protein 1 inhibitor) and apatinib (an angiogenesis inhibitor) are considered as potential treatments for advanced lung adenocarcinoma (LUAD). This study aimed to evaluate the efficacy and safety of second-line camrelizumab combined with apatinib and chemotherapy (albumin-bound paclitaxel, docetaxel, or pemetrexed) in patients with advanced LUAD. METHODS: Twenty-nine patients with advanced LUAD underwent second-line camrelizumab combined with apatinib and chemotherapy were enrolled in this prospective, open-label, multicentric study. Follow-up with a median duration of 18.0 months was conducted. RESULTS: There were 0 (0.0 %), 11 (37.9 %), 14 (48.4 %), and 3 (10.3 %) patients achieving complete response, partial response, stable disease, and progressive disease, respectively. Meanwhile, treatment response was not evaluated in 1 (3.4 %) patient. The objective response and disease control rates were 37.9 % and 86.3 %, respectively. In terms of survival, the median (95 % confidence interval) progression-free survival (PFS) was 11.1 (5.2-17.0) months, with 1-year and 2-year PFS rates of 40.4 % and 20.5 %, respectively. The median overall survival (OS) was not reached; the 1-year and 2-year OS rates were 72.0 % and 64.8 %, respectively. Current treatment cycles ≥ 8 were associated with better PFS and OS (both P < 0.001). In addition, 21 (72.4 %) patients experienced at least one treatment-emergent adverse event (TEAE), which was mostly of grade I and II. The most commonly occurring TEAE was leukopenia (17.2 %), liver dysfunction (17.2 %), hypothyroidism (13.8 %), hand-foot syndrome (13.8 %), and thrombocytopenia (13.8 %). CONCLUSION: Second-line camrelizumab combined apatinib and chemotherapy might serve as a potential treatment with acceptable safety in patients with advanced LUAD.

Stomatin-like protein-2 attenuates macrophage pyroptosis and H9c2 cells apoptosis by protecting mitochondrial function.

Myocytes undergoing hypoxia condition can recruit macrophages and cause pro-inflammation initiation around the injury area. Mitochondrial dysfunction is related to macrophage pyroptosis. Stomatin-like protein-2 (SLP-2) can regulate mitochondrial biogenesis and function. Whether SLP-2 could affect macrophage pyroptosis remains unclear. In this study, bone marrow derived macrophages (BMDMs) were extracted from WT and SLP-2 knocked out mice, then stimulated by LPS/Nigericin. Western blot showed that SLP-2-/- promoted the expression of NLRP3, GSDMD-N, caspase-11 in macrophages, which means the deficiency of SLP-2 augments macrophage pyroptosis. Higher fluorescence intensity of dihydroethidium and TUNEL represented the increased ROS releasing and macrophage programmed death in SLP-2 deficiency groups. The immunofluorescence intensity of MtioTracker Red decreased and that of mitochondrial ROS (mtROS) increased in SLP-2 deletion groups with LPS/Nigericin stimulation, representing the increased mitochondrial damage. The expression level of HIF-1α increased in SLP-2 deletion macrophages with LPS and Nigericin stimulation. The level of Parkin and the ratio of LC3II/I decreased in SLP-2 deficiency macrophages after stimulated by LPS/Nigericin, compared with untreated macrophages. H9c2 cells were cultured in hypoxia condition before being cocultured with macrophage supernatant. The cocultured H9c2 cells were injured due to the serious pyroptosis of SLP-2 deficiency macrophages. According to these results, we suggest that SLP-2 can reduce macrophage pyroptosis and relieve hypoxia H9c2 cells injury through protecting mitochondrial function.

Utility and specificity of plasma heat shock protein 90 alpha, CEA, and CA199 as the diagnostic test in colorectal cancer liver metastasis.

Background: Plasma heat shock protein 90 alpha (Hsp90α) has been suggested as a novel biomarker for the diagnosis and prognosis of cancer. Carcinoembryonic antigen (CEA) and carbohydrate antigen199 (CA199) are traditional tumor biomarkers for colorectal cancer (CRC). Previous studies have shown that Hsp90α and the combination of Hsp90α and CEA are optimal biomarkers for CRC at an early stage. However, research on the use of Hsp90α alone or in combination with CEA and/or CA199 in diagnosing CRC development, particularly liver metastasis, is limited. This study sought to investigate the value of Hsp90α alone or in combination with CEA/CA199 in diagnosing CRC liver metastasis. Methods: The clinical data of 472 CRC patients were retrospectively analyzed, which were confirmed by clinical manifestations and a histopathological examination associated with an imaging diagnosis. The levels of Hsp90α, and CEA, and CA199 were assessed by enzyme-linked immunoassays and electrochemiluminescence immunoassays. Liver metastasis was diagnosed by imaging or pathology of the liver. Logistic regression models were used to analyze associations between Hsp90α, CEA, and CA199, and liver metastasis in CRC. The areas under the curves (AUCs) were used to compare the utility of Hsp90α, CEA, and CA199 in the diagnosis of CRC liver metastasis (CRLM). Additionally, we compared the diagnostic utility of the models, including the Hsp90α plus 1 of the other serum markers, and a combination of the 3 serum makers. Results: The plasma levels of Hsp90α, CEA, and CA199 were positively associated with a higher risk of CRLM [odds ratios (OR) ranging from 1.36-2.72]. The AUCs of CEA, CA199, and Hsp90α for CRLM were 0.80, 0.69, and 0.55, respectively. The AUCs for the combination of Hsp90α and CEA, combination of Hsp90α and CA199, combinations of Hsp90α, CEA, and CA199 were 0.75, 0.66, 0.76, respectively. The combination of Hsp90α, CEA, and CA199 did not improve the diagnostic utility for liver metastasis in CRC. Conclusions: The level of Hsp90α was elevated in CRC and was associated with CRLM. Thus, the Hsp90α is a potential biomarker for CRLM. CEA has the largest diagnostic utility for CRLM. Adding Hsp90α to CEA/CA199 did not improve their diagnostic utility for CRLM.

Efficacy and safety of intermittent versus continuous dose apatinib plus docetaxel as second-line therapy in patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma: a randomized controlled study.

Background: Previous studies of the second-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJAC) had reported that apatinib combined with chemotherapy improved the treatment outcomes. However, the benefits were sometimes limited due to the tolerance of continuous dose regimen. This randomized controlled study aimed to investigate the efficacy and safety of intermittent or continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. Methods: Advanced GC/GEJAC patients who failed first-line chemotherapy were recruited (enrollment time: from September 15, 2017 to July 21, 2019), and randomly assigned to either the intermittent dose group (IG group) or the continuous dose group (CG group) (1:1 ratio) using the block randomization method. In the IG group, patients received apatinib 500 mg/d for 5 consecutive days then held for 2 days plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. In the CG group, patients received apatinib 500 mg daily plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. The progression free survival (PFS) was evaluated every two cycles and follow-ups were performed monthly. The primary endpoint was PFS, and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: In total, 76 eligible patients were enrolled and randomly assigned (1:1 ratio). The IG group exhibited similar PFS compared to the CG group [median PFS: 3.88 (95% CI: 1.72-6.03) months vs. 3.98 (95% CI: 1.06-6.90) months, P=0.546] and OS [median OS: 9.00 (95% CI: 5.31-12.70) months vs. 9.40 (95% CI: 5.20-13.59) months, P=0.310]. ORR (21.1% vs. 18.4%, P=0.773) and DCR (60.5% vs. 60.5%, P=1.000) were of not statistically different between the IG and CG groups. As for safety, the IG group exhibited less frequent hypoproteinemia (31.6% vs. 55.3%, P=0.037) and lactate dehydrogenase increased (18.4% vs. 44.7%, P=0.014), while no differences in other adverse events were observed between the two groups. Conclusions: Intermittent dose apatinib plus docetaxel was equally effective and more tolerable than continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. Trial Registration: ClinicalTrials.gov NCT03334591.

Long non-coding RNA Bhmt-AS attenuates hepatic gluconeogenesis via modulation of Bhmt expression.

Dysregulation of gluconeogenesis contributes to the pathogenesis of metabolic disease, such as type-2 diabetes. The role of long non-coding RNAs (lncRNAs) in the pathogenesis of diabetes has recently received increased attention. In the present study, we identified a novel lncRNA, betaine-homocysteine methyltransferase-antisense (Bhmt-AS), and examined its expression patterns under pathophysiological conditions. Our results revealed that the expression of Bhmt-AS was significantly increased in the livers of fasted and db/db mice and was induced by gluconeogenic hormonal stimuli. The Bhmt-AS was also shown to be a concordant regulator of Bhmt expression. Functionally, depletion of Bhmt-AS suppressed hepatic glucose production both in vivo and in vitro. Adenovirus-mediated hepatic knockdown of Bhmt-AS improved pyruvate tolerance, glucose tolerance, and insulin sensitivity. Furthermore, overexpression of Bhmt restored the decreased glucose production caused by knockdown of Bhmt-AS in primary hepatocytes. Taken together, we uncovered a novel antisense lncRNA (Bhmt-AS) that is co-expressed with Bhmt and concordantly and specifically regulates Bhmt expression both in vitro and in vivo to regulate hepatic gluconeogenesis.

Clinical research of individualized therapy in advanced esophageal cancer based on the ERCC1 C8092A genotype.

The present study aimed to explore the role and clinical value of the detection of Excision repair cross-complementing 1(ERCC1) C8092A polymorphisms in individualized therapy of patients with advanced esophageal cancer. A total of 127 patients with advanced esophageal cancer were enrolled between January 2010 and January 2014 in Anhui Provincial Hospital. Patients were randomly assigned in a 1:2 ratio to a standard treatment group or an individualized treatment group, respectively, prior to ERCC1 C8092A assessment. Patients in the standard treatment group were treated with paclitaxel and cisplatin. The DNA was obtained from the peripheral blood of individualized treatment patients, amplified by PCR and sequenced to determine the ERCC1 C8092A polymorphism prior to the administration of chemotherapies. Patients with the ERCC1 C8092A genotype of A/A or A/C received paclitaxel and cisplatin, and those with the genotype of C/C received paclitaxel and fluorouracil. The primary endpoint was response rate (RR). The secondary endpoints included toxicity of chemotherapy, progression-free survival (PFS) and overall survival (OS) times. Differences between the groups were evaluated by χ2 test. Differences in survival were analyzed by Kaplan-Meier survival curves. The survival rate was analyzed by log-rank test. Follow-up data was obtained until December 2015. The RR was obtained for 15 patients (34.8%) in the standard treatment group and 45 patients (53.6%) in the individualized treatment group (χ2=3.095; P=0.046). For adverse events, nausea and vomiting and anemia were significantly decreased in the individualized treatment group compared with the standard treatment group (P=0.001 and P=0.004, respectively). The median progression free survival time was 4.4 months [95% confidence interval (CI)3.8-5.0 months] in the standard treatment group and 6.6 months (95% CI, 5.8-7.4 months) in the individualized treatment group (P=0.018). The median overall survival time was 11.4 months (95% CI, 10.1-12.7 months) in the standard treatment group and 14.2 months (95% CI, 13.2-15.2 months) in the individualized treatment group (P=0.008). The RR, toxicity of chemotherapy, PFS and OS were significantly improved in the individualized treatment group compared with the standard treatment group. Detection of ERCC1 gene polymorphisms maybe performed for patients with advanced esophageal cancer to improve individualized therapy, which requires additional study.

Relationship between Helicobacter pylori infection and vomiting induced by gastrointestinal cancer chemotherapy.

BACKGROUND: Nausea and vomiting are the most common adverse reactions to chemotherapy. AIM: To discuss the relationship between Helicobacter pylori and chemotherapy-induced nausea and vomiting (CINV). METHODS: A total of 112 patients with malignant tumours of the gastrointestinal tract was selected. Based on the 14C-urea breath test results, the patients were divided into H. pylori-positive (n = 59) and H. pylori-negative (n = 53) groups. Both groups received prophylactic antiemetic treatment during chemotherapy. The incidence of nausea and vomiting and their effects on the patients' life functions was recorded using the Multinational Association of Supportive Care in Cancer (MASCC) Antiemetic Tool (MAT) and the Functional Living Index Emesis (FLIE) from 0-120 h after chemotherapy. Records of the H. pylori-positive and H. pylori-negative groups were compared. RESULTS: The rates of nausea and vomiting remission were higher in the H. pylori -negative group than in the H. pylori -positive group. The proportions of no effect in daily life (NIDL) patients in the nausea and vomiting section were 73.4 and 75.5% in the H. pylori -negative group respectively. There was a higher proportion of NIDL patients in the H. pylori -negative group than in the H. pylori -positive group (P < 0.001, P = 0.046). A multivariate unconditional logistic regression analysis was performed, and the results showed that H. pylori infection was a factor affecting the nausea scores on the FLIE (odds ratio = 0.757, 95% confidence interval 0.597-0.960, P = 0.021). CONCLUSION: H. pylori infection in patients with cancer may be a factor that increases CINV.

Clinical features and prognosis-associated factors of non-small cell lung cancer exhibiting symptoms of bone metastasis at the time of diagnosis.

The present study aimed to analyze the clinical characteristics and prognosis-related factors of non-small cell lung cancer (NSCLC) patients with bone metastases at the time of diagnosis. A total of 46 NSCLC patients with skeletal metastases at the time of diagnosis from Anhui Provincial Hospital and Anhui Provincial Cancer Hospital Affiliated to Anhui Medical University (Hefei, China) between February 2010 and February 2012 were investigated retrospectively. The median age was 58 years, with a range of 40-80 years, the ratio of males and females was 2:1, and adenocarcinoma and squamous cell carcinoma accounted for 71.7 and 28.3% of cases, respectively. Furthermore, 84.8% of patients exhibited multiple skeletal metastases at more than two sites and 54.3% of patients experienced skeletal-related events at the time of diagnosis. The median overall survival (OS) time of the patients was 237 days, and Kaplan-Meier analysis demonstrated that patients with adenocarcinoma (P=0.002), single bone metastases (P=0.023), an Eastern Cooperative Oncology Group performance status of 0-1 (P<0.001) or positive expression of estrogen receptor (ER)-ß (P=0.039) exhibited significantly longer survival times. Furthermore, multivariate analysis identified the following independent predictors of OS: Tumor subtype (P=0.022), the number of bone metastases (P=0.016) and an ER-ß-positive tumor (P=0.035). In the cohort of NSCLC patients with bone metastases at the time of diagnosis, adenocarcinoma and multiple skeletal metastases were most common.

Hypoxia-inducible factor 1α in breast cancer prognosis.

BACKGROUND: Recent studies have assessed the relationship between hypoxia-inducible factor 1α (HIF-1α) expression and prognosis in breast cancer patients with inconsistent conclusions. To comprehensively and quantitatively summarize the evidence on the survival of patients with breast cancer, a meta-analysis was performed. METHODS: Systematic literature searching was applied to the databases of PubMed, Embase and Web of science until April 1, 2013. Pooled HR with 95% CI was used to evaluate the association between HIF-1α expression and survival in breast cancer patients. RESULTS: Fourteen papers including 2933 patients were subjected to the final analysis. Of these, 7 provided data on overall survival (OS), 8 on disease-free survival (DFS), 3 on distant metastasis-free survival (DMFS) and 3 on relapse-free survival (RFS). We observed that high expression of HIF-1α in breast cancer patients was an indicator of poor prognosis on OS (HR = 1.46, 95% CI: 1.12-1.92, P = 0.006), DFS (HR = 1.91, 95% CI: 1.43-2.57, P<0.001), DMFS (HR=2.17 95% CI: 1.16-4.05, P=0.015) and RFS (HR=1.33 95% CI: 1.09-1.61, P=0.005). Significant heterogeneity was observed in the analyses of OS and DFS. Subgroup analyses by the cut-off value and antibody for IHC were conducted. CONCLUSION: High expression of HIF-1α indicated a poor prognosis for patients with breast cancer.

A phase II study of paclitaxel and nedaplatin as front-line chemotherapy in Chinese patients with metastatic esophageal squamous cell carcinoma.

AIM: To evaluate the efficacy and safety of paclitaxel-nedaplatin combination as a front-line regimen in Chinese patients with metastatic esophageal squamous cell carcinoma (ESCC). METHODS: A two-center, open-label, single-arm phase II study was designed. Thirty-nine patients were enrolled and included in the intention-to-treat analysis of efficacy and adverse events. Patients received 175 mg/m² of paclitaxel over a 3 h infusion on 1 d, followed by nedaplatin 80 mg/m² in a 1 h infusion on 2 d every 3 wk until the documented disease progression, unacceptable toxicity or patient's refusal. RESULTS: Of the 36 patients assessable for efficacy, there were 2 patients (5.1%) with complete response and 16 patients (41.0%) with partial response, giving an overall response rate of 46.1%. The median progression-free survival and median overall survival for all patients were 7.1 mo (95%CI: 4.6-9.7) and 12.4 mo (95%CI: 9.5-15.3), respectively. Toxicities were moderate and manageable. Grade 3/4 toxicities included neutropenia (15.4%), nausea (10.3%), anemia (7.7%), thrombocytopenia (5.1%), vomiting (5.1%) and neutropenia fever (2.6%). CONCLUSION: The combination of paclitaxel and nedaplatin is active and well tolerated as a first-line therapy for patients with metastatic ESCC.