Efficacy and safety of radiofrequency ablation in the treatment of inoperable patients with pulmonary malignant nodules.

BACKGROUND: Radiofrequency ablation (RFA) has been recently applied as an alternative treatment in the patients with pulmonary malignancies. The aim of our study was to assess the incidence of complications and survival rate of RFA for malignant lung nodules, and evaluate the efficacy and safety of RFA in the treatment of inoperable patients with pulmonary malignant nodules. METHODS: The clinical data of 50 patients with primary and metastatic lung malignant nodules treated with RFA from June 2015 and July 2017 in Hebei General Hospital were considered, and the characteristics and clinical data of these patients were analysed. Complications, progression-free survival and overall survival at 1, 2 and 5 years of these patients were evaluated. RESULTS: Following the procedure. There were no major complications and deaths during the operation. 26 (52%) patients presented mild-to-moderate chest pain that was easily controlled by analgesic drugs. 8 (16%) patients with pneumothorax, 4 (8%) haemoptysis, 6 (12%) pneumonia, 7 (14%) pleural effusion and 1 (2%) postoperative bronchopleural fistula. Needle-track implantation was observed in 2 (4%) patients. Median progression-free survival (PFS) was 24.6 months. The PFS at 1, 2, 5 years was 76%, 52% and 20%, respectively. Median overall survival (OS) was 35.5 months. The OS at 1, 2 and 5 years was 80%, 58% and 32%, respectively. CONCLUSION: RFA is a safe and effective alternative treatment for the inoperable patients with primary or metastatic pulmonary malignant nodules. The clinical impact and long-term results of RFA need to be further confirmed in a larger series of patients, and RFA should ideally be compared with surgery.

In vivo assessment of the pharmacokinetic interactions between donafenib and dapagliflozin, donafenib and canagliflozin in rats.

Donafenib (DONA), a deuterium derivative of sorafenib, is used for advanced hepatocellular carcinoma (HCC). Dapagliflozin (DAPA) and canagliflozin (CANA) are sodium-glucose co-transporter 2 (SGLT2) inhibitors used for T2DM, which is frequently comorbid with HCC. Three drugs are substrates of UGT1A9 isoenzyme. This study aimed to evaluate donafenib-dapagliflozin and donafenib-canagliflozin pharmacokinetic interactions and explore the potential mechanisms. Rats were divided into seven groups (n = 6) that received donafenib (1), dapagliflozin (2), canagliflozin (3), dapagliflozin and donafenib (4), canagliflozin and donafenib (5), donafenib and dapagliflozin (6), donafenib and canagliflozin (7). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple doses of dapagliflozin caused donafenib maximum plasma concentration (Cmax) to increase 37.01%. Canagliflozin increased donafenib Cmax 1.77-fold and the area under the plasma concentration-time curves (AUC0-t and AUCinf) 1.39- and 1.41-fold, respectively, while reducing the apparent clearance (CLz) 28.38%. Multiple doses of donafenib increased dapagliflozin AUC0-t 1.61-fold, AUCinf 1.77-fold, whereas its CLz reduced 40.50%. Furthermore, donafenib caused similar changes in canagliflozin pharmacokinetics. The PCR results demonstrated that dapagliflozin inhibited the mRNA expression of Ugt1a7 in liver and donafenib decreased the expression of Ugt1a7 mRNA in liver and intestine. Increased exposure to these drugs may be due to their metabolism inhibition mediated by Ugt1a7. These pharmacokinetic interactions observed in this study may be of clinical significance, which may help adjust dose properly and avoid toxicity effects in patients with HCC and T2DM.

Effects of voriconazole and fluconazole on the pharmacokinetics of almonertinib in rats by UPLC-MS/MS.

Almonertinib was included in the first-line treatment of non-small cell lung cancer with EGFR T790M mutations by the Chinese Society of Clinical Oncology in 2021. Considering that immunocompromised lung cancer patients are prone to opportunistic fungal infections, and most triazole antifungal drugs are moderate or strong inhibitors of CYP3A4, this study was conducted to develop and validate an accurate and rapid ultra-performance liquid chromatography tandem mass spectrometry method for quantifying almonertinib in plasma and for investigating the pharmacokinetic changes of almonertinib caused by voriconazole and fluconazole in rats. After liquid-liquid extraction with tert-butyl methyl ether, an XSelect HSS T3 column (2.1 × 100 mm, 2.5 µm, Waters) was used for the chromatographic separation of almonertinib and sorafenib-D3 (internal standard). The analytes were detected using an AB Sciex Triple Quad 5,500 mass spectrometer in the positive ionization mode. The method exhibited great linearity (0.5-200 ng/ml, r > 0.997) and stability under the established experimental conditions. All validation experiments were in accordance with the guidelines, and the results were all within the acceptable limits. This method was successfully applied to the researches of pharmacokinetics and drug interactions for almonertinib in rats. Voriconazole and fluconazole significantly altered the pharmacokinetic profiles of almonertinib and increased the systemic exposure of almonertinib in rats to different degrees, but further human trials should be conducted to validate the results.

Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats.

Sorafenib (SOR), an inhibitor of multiple kinases, is a classic targeted drug for advanced hepatocellular carcinoma (HCC) which often coexists with type 2 diabetes mellitus (T2DM). Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in patients with T2DM. Notably, co-administration of SOR with DAPA is common in clinical settings. Uridine diphosphate-glucuronosyltransferase family 1 member A9 (UGT1A9) is involved in the metabolism of SOR and dapagliflozin (DAPA), and SOR is the inhibitor of UGT1A1 and UGT1A9 (in vitro). Therefore, changes in UGT1A9 activity caused by SOR may lead to pharmacokinetic interactions between the two drugs. The objective of the current study was to develop an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of SOR and DAPA in plasma and to evaluate the effect of the co-administration of SOR and DAPA on their individual pharmacokinetic properties and the mechanism involved. The rats were divided into four groups: SOR (100 mg/kg) alone and co-administered with DAPA (1 mg/kg) for seven days, and DAPA (1 mg/kg) alone and co-administered with SOR (100 mg/kg) for seven days. Liquid-liquid extraction (LLE) was performed for plasma sample preparation, and the chromatographic separation was conducted on Waters XSelect HSS T3 column with a gradient elution of 0.1% formic acid and 5 mM ammonium acetate (Phase A) and acetonitrile (Phase B). The levels of Ugt1a7 messenger RNA (mRNA) were determined in rat liver and intestine using quantitative real-time polymerase chain reaction (qRT-PCR). The method was successfully applied to the study of pharmacokinetic interactions. DAPA caused a significant decrease in the maximum plasma concentrations (Cmax) and the area under the plasma concentration-time curves (AUC0-t) of SOR by 41.6% and 50.5%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) significantly increased 2.85- and 1.98-fold, respectively. When co-administering DAPA with SOR, the AUC0-t and the elimination half-life (t1/2Z) of DAPA significantly increased 1.66- and 1.80-fold, respectively, whereas the CLz/F significantly decreased by 40%. Results from qRT-PCR showed that, compared with control, seven days of SOR pretreatment decreased Ugt1a7 expression in both liver and intestine tissue. In contrast, seven days of DAPA pretreatment decreased Ugt1a7 expression only in liver tissue. Therefore, pharmacokinetic interactions exist between long-term use of SOR with DAPA, and UGT1A9 may be the targets mediating the interaction. Active surveillance for the treatment outcomes and adverse reactions are required.

Proton Pump Inhibitors and the Risk of Community-Acquired Pneumonia: An Updated Meta-analysis.

BACKGROUND: Some studies suggested an increased risk of community-acquired pneumonia (CAP) among proton pump inhibitors (PPI) users. However, the published evidence is inadequate to define the association between PPI use and the risk of CAP. OBJECTIVE: The aims of our meta-analysis were to systematically assess the association between the risk of CAP and PPI use in adults to reduce the adverse effects of PPI and ensure the safety of medication for patients. METHODS: A comprehensive literature search was conducted, published between January 1, 2004, and February 1, 2021. The primary outcome was the incidence of CAP. This meta-analysis was performed using odds ratios (ORs) with 95% CIs as effective measures; 13 studies including 2 098 804 patients were enrolled in our meta-analysis. RESULTS: Our study revealed that the incidence of CAP was higher in PPI users than non -PPI users [OR = 1.37 (95% CI = 1.22-1.53)], especially for PPI duration < 30 days [OR = 1.49 (95% CI = 1.34-1.66)]. Compared with non-PPI use, PPI use increased the incidence of CAP in the stroke disease population [OR = 1.52 (95% CI = 1.33-1.75)], but not in the liver disease population [OR = 1.13 (95% CI = 0.98-1.30)]. CONCLUSIONS AND RELEVANCE: Using PPI could increase the risk of CAP when compared to not using PPI. PPI use increased the incidence of CAP in patients with stroke. Clinicians and clinical pharmacists should weigh the benefits before medication and strictly control the indication of the prescription, so as to reduce adverse reactions.

The effect of intraoperative dexmedetomidine on cognitive dysfunction after surgery: a updated meta-analysis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is one of the most common. Neuroprotective effects of dexmedetomidine (DEX) are reported in previous studies but evidence regarding the POCD is still unclear. In order to gain latest evidence, the present study analyzes the outcomes of randomized controlled trials (RCTs) which utilized DEX with general anaesthesia perioperatively. METHOD: Four online databases (PubMed, Embase, the Cochrane Library, and CNKI) were used to find relevant RCTs to conduct systematic analysis. All studies comparing the incidence of POCD or MMSE score between the DEX group and the placebo or comparator group in patients undergoing general anaesthetic surgery were eligible for inclusion. Based on the inclusion and exclusion criteria, the studies were selected. This meta-analysis was performed using odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous data and standardized mean difference (SMD) and 95% CIs for continuous data as effective measures. RESULTS: In total of 21 studies were included in this meta-analysis. The results showed that the incidence of POCD in DEX group was significantly lower than the control group on the first (OR = 0.36, 95% CI 0.24-0.54),third (OR = 0.45,95% CI 0.33-0.61) and seventh (OR = 0.40,95% CI 0.26-0.60) postoperative days; the MMSE scores in DEX group were higher than the control group on the first (SMD = 1.24, 95% CI 1.08-1.41), third(SMD = 1.09, 95%CI 0.94-1.24) and seventh (SMD = 3.28, 95% CI 1.51-5.04) postoperative days. CONCLUSIONS: Intraoperative DEX use can ameliorate the POCD of patients who received surgical operations under general anesthesia, and effectively reduce the incidence of POCD and improve MMSE score.

Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Adjuvant Setting for Patients with Resected Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer: A Meta-Analysis with 11 Trials.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have recently become the standard first-line therapy for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. This study aimed to define the role of EGFR-TKI treatment in the adjuvant setting of patients with resected EGFR-mutant NSCLC. METHODS: Three online databases (PubMed, Embase, and the Cochrane Library) were used to conduct systematic research to search for studies published before June 1, 2020. The disease-free survival (DFS) and overall survival (OS) of patients with resected EGFR-mutant NSCLC after radical surgery treated with EGFR-TKIs versus non-EGFR-TKIs in the adjuvant setting were compared. Based on rigorous self-defined inclusion and exclusion criteria, studies were selected, and a meta-analysis was performed using hazard rate (HR) and 95% CIs as effective measures. RESULTS: Eleven studies, published between 2011 and 2020, with a total of 1,900 patients, were included in this meta-analysis. EGFR-TKI treatment showed a significant beneficial effect on DFS (HR 0.42; 95% CI 0.31-0.57) and OS (HR 0.62; 95% CI 0.45-0.86) for patients with resected EGFR-mutant NSCLC after radical resection in the adjuvant setting. CONCLUSION: Our meta-analysis results suggested that EGFR-TKI treatment improved the DFS and OS of completely resected patients with EGFR-mutant NSCLC compared with non-EGFR-TKI treatment in the adjuvant setting. In the future, our conclusion should be confirmed by additional large-scale and well-designed clinical trials.

Treatment of intrathoracic anastomotic leak after esophagectomy with the sump drainage tube.

BACKGROUND: Intrathoracic esophagogastric anastomotic leak is one of the deadliest complications after esophagectomy. In recent years, we have implemented new method for the treatment of intrathoracic esophagogastric anastomotic leak with the nasogastric placement of sump drainage tube through fistula into abscess cavity. The aim of this study is to compare the efficacy of the new method and conventional therapies for intrathoracic anastomotic leak after esophagectomy. METHOD: Esophagectomy and esophagogastric anastomotic procedures were performed in 875 patients at our institution from January 2008 to December 2019. Of these patients, 43(4.9%) patients developed intrathoracic anastomotic leaks postoperatively were enrolled into our study and their clinical data were retrospectively assessed. 20 (47%) patients from January 2008 to December 2012 received conventional treatments (group 1) known as the traditional "three-tube method", and 23 (53%) patients from January 2013 to December 2019 received new treatments (group 2), consisted of conventional therapies and the nasogastric placement of sump drainage tube through fistula into abscess cavity. RESULTS: The presence of intrathoracic anastomotic leak was proven by contrast esophagography in 43 patients (4.9%). Among them, The average duration of chest tube was 47 days in group 1 and 28 days in group 2. The average length of leak treatment was 52 days in group 1 and 35 days in group 2. The average length of postoperative hospital stay was 56 days in group 1 and 39 days in group 2, respectively. 7(35%) patients among 20 patients died from intrathoracic anastomotic leak in group 1; and 3(13%) patients among 23 patients died from intrathoracic anastomotic leak in group 2. Compared with the conventional treatments (group 1), The average duration of chest tube was significantly decreased in the new treatments (group 2) (P < 0.01), as well as the length of leak treatment (P < 0.05) and the length of postoperative hospital stay (P < 0.01). However, there was no significant difference in the mortality rate (P = 0.148 > 0.05). CONCLUSION: In conclusion, Our results showed this method of the nasogastric placement of sump drainage tube through fistula appears to be an safe, effective, technically feasible treatment option for intrathoracic esophagogastric anastomotic leak. The efficacy and feasibility could be further investigated with a well-designed and large-scale RCT research.

Long non-coding RNA SPRY4-IT1 as a promising indicator for three field lymph-node dissection of thoracic esophageal carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma(ESCC) is one of the most common tumors worldwide. Esophagectomy with three-field lymph node dissection(3FLND) is the radical surgical procedure for esophageal cancer. However, 3FLND is not widely used due to it's higher mortality rate and higher incidence of postoperative complications. There is an urgent need to identify novel biomarkers that can guide the most proper lymph-node dissection in esophageal cancer patients. METHOD: Ninety-two patients with thoracic ESCC undergoing 3FLND were enrolled into our study from the Department of Thoracic Surgery of the Fourth Hospital affiliated to the Hebei Medical University and Hebei General Hospital between Jun 2011 and Dec 2015. Retrospectively collected data from these 92 patients was used to explore the relationship between the lymph-node metastasis、recurrence and the SPRY4-IT1 expression level and to determine whether 3FLND should be performed in patients with thoracic ESCC. RESULTS: The findings revealed that the SPRY4-IT1 expression was significantly higher in esophageal cancer tissues than in adjacent noncancerous tissues. (P < 0.01). Furthermore, the high expression of SPRY4-IT1 was significantly correlated with tumor differentiation (P = 0.029), T classification (P = 0.013), lymph node metastasis(P = 0.022) and pathological stage (P = 0.001). The increased expression of SPRY4-IT1 was associated with a higher risk of cervical and superior mediastinal lymph-node metastasis(P = 0.039).However, no significant association was observed between the risk of cervical and superior mediastinal lymph-node recurrence and the SPRY4-IT1 expression level in the thoracic ESCC patients performed 3FLND(P = 0.509). CONCLUSIONS: Our data support the assumption that the high expression of SPRY4-IT1 is associated with a high risk of lymph node metastasis and it has potential application as a indicator for guiding on three-field lymph node dissection in patients with thoracic ESCC. Randomized controlled trials with a large cohort of patients will be needed to confirm this conclusion in the future.

Meta-analysis of association between CT-based features and tumor spread through air spaces in lung adenocarcinoma.

OBJECTIVE: Spread through air space (STAS) is a novel invasive pattern of lung adenocarcinoma and is also a risk factor for recurrence and worse prognosis of lung adenocarcinoma after sublobar resection. The aims of this study are to evaluate the association between computed tomography (CT)-based features and STAS for preoperative prediction of STAS in lung adenocarcinoma, eventually, which could help us choose appropriate surgical type. METHODS: Systematic research was conducted to search for studies published before September 1, 2019. The association between CT-based features of radiological tumor size>2 cm、pure solid nodule、 part-solid nodule or Percentage of solid component (PSC)>50% and STAS was evaluated. According to rigorous inclusion and exclusion criteria. Eight studies including 2385 patients published between 2015 and 2018 were finally enrolled in our meta-analysis. RESULTS: Our results clearly depicted that there is no significant relationship between radiological tumor size>2 cm and STAS with the combined OR of 1.47(95% CI:0.86-2.51). Meta-analysis of 3 studies showed that pure solid nodule in CT image were more likely to spread through air spaces with pooled OR of 3.10(95%CI2.17-4.43). Meta-analysis of 5 studies revealed the part-solid nodule in CT image may be more likely to appear STAS in adenocarcinoma (ADC) (combined OR:3.10,95%CI:2.17-4.43). PSC>50% in CT image was a significant independent predictor in the diagnosis of STAS in ADC from our meta-analysis with combined OR of 2.95(95%CI:1.88-4.63). CONCLUSION: In conclusion, The CT-based features of pure solid nodule、part-solid nodule、PSC>50% are promising imaging biomarkers for predicting STAS in ADC and may substantially influence the choice of surgical type. In future, more studies with well-designed and large-scale are needed to confirm the conclusion.

Clinical application and observation of single-port inflatable mediastinoscopy combined with laparoscopy for radical esophagectomy in esophageal squamous cell carcinoma.

BACKGROUND: Transthoracic esophagectomy is a crucial independent risk factor for the incidence of postoperative cardiopulmonary complications in elderly or comorbid patients. To reduce postoperative cardiopulmonary complications and promote postoperative recovery. We made an attempt to adopt the single-port inflatable mediastinoscopy combined with laparoscopy for radical esophagectomy in esophageal cancer to observe the clinical application and effect. METHOD: Data of patients with esophageal carcinoma were collected in the Hebei General Hospital from May 2018 to November 2019. The operation time, surgical blood loss, the number of dissected lymph nodes, duration of drainage tube, duration of time on the ventilator, the length of stay in ICU, postoperative complications, the length of postoperative hospital stay were collected to assess the safety and feasibility of the single-port inflatable mediastinoscopy combined with laparoscopy for radical esophagectomy in esophageal cancer. RESULTS: A total of 22 patients with esophageal cancer were analyzed in our research. There were no cases of conversion to thoracotomy、perioperative death or postoperative cardiopulmonary complications. The average operation time of all enrolled patients was 4.26 ± 0.52 h、The surgical blood loss was 142 ± 36.50 ml、The amount of dissected lymph nodes were 21.6 ± 4.2、The duration of drainage tube was 5.8 ± 2.5 days、The duration of time on the ventilator was 6.5 ± 3.4 h、The length of stay in ICU was 1.2 ± 0.4 days、The postoperative hospital stay was 12.6 ± 2.5 days. Among all the enrolled patients, one patient (4.5%) developed anastomotic fistula on the third day after surgery. Anastomotic stricture was found in 5 patients (22.7%). Pleural effusion was found in 4 cases (18.2%). Recurrent laryngeal nerve injury caused hoarseness or cough after drinking water in 3 cases (13.6%).There was one patient (4.5%) of conversion to laparotomy as the patient had serious peritoneal adhesion. All of the patients were discharged successfully. CONCLUSION: Our results showed that this surgery of single-port inflatable mediastinoscopy combined with laparoscopy for radical esophagectomy in esophageal squamous cell carcinoma is safe and feasible. The feasibility and safety could be further and better investigated with a RCT to achieve more conclusive results.