Causes of recurrence of paediatric inguinal hernia after single-port laparoscopic closure.

PURPOSE: This paper explores the causes of paediatric inguinal hernia (PIH) recurrence after single-port laparoscopic percutaneous extraperitoneal closure (SPLPEC). METHOD: From January 2015 to December 2020, the clinical data of 3480 children with PIHs who underwent SPLPEC were retrospectively reviewed, including 644 children who underwent SPLPEC with a homemade single-hook hernia needle from January 2015 to December 2016 and 2836 children who underwent the SPLPEC with a double-hook hernia needle and hydrodissection from January 2017 to December 2020. There were 39 recurrences (including communicating hydrocele) during the 2-5 years of follow-up. The findings of redo-laparoscopy were recorded and correlated with the revised video of the first operation to analyse the causes of recurrence. RESULT: Thirty-three males and 6 females experienced recurrence, and 8 patients had a unilateral communicating hydrocele. The median time to recurrence was 7.1 months (0-38). There were 20 cases (3.11%) in the single-hook group and 19 cases (0.67%) in the double-hook group. Based on laparoscopic findings, recurrence most probably resulted from multiple factors, including uneven tension of the ligation (10 cases), missing part of the peritoneum (14 cases), loose ligation (8 cases), broken knot (5 cases), and knot reaction (2 cases). All children who underwent repeat SPLPEC were cured by double ligations or reinforcement with medial umbilical ligament. CONCLUSION: The main cause of recurrence is improper ligation. Tension-free and complete PIH ligation are critical to the success of surgery, which requires avoiding the peritoneum skip area and the subcutaneous and muscular tissues. Redo-laparoscopic surgery was suitable for the treatment of recurrent inguinal hernia (RIH). For giant hernias, direct ligation of the internal ring incorporating the medial umbilical ligament (DIRIM) may be needed.

[Association of heart valve calcification with cardiovascular outcomes in patients on maintenance hemodialysis].

OBJECTIVE: To investigate the impact of heart valve calcification (HVC) on cardiovascular outcomes in patients on maintenance hemodialysis (MHD). METHODS: We enrolled 302 Chinese patients on MHD between 2009 and 2011 including 99 with HVC identified by echocardiography screening. All the patients were followed up for 2 years and survival analysis was performed with all-cause mortality, cardiovascular mortality and new onset cardiovascular events as the endpoints. Cox regression analysis was used for analyzing the impact of heart valve calcification on the cardiovascular outcomes of the patients. RESULTS: The mean age of the total patients was 58.2∓15.0 years when receiving the initial MHD, and 53.6% were male patients. The overall mortality, cardiovascular mortality and new on-set cardiovascular events in HVC and non-HVC groups were 30.3% vs 16.3%, 22.2% vs 6.9%, and 48.5% vs 25.6%, respectively (P<0.05). Kaplan-Meier survival analysis showed a significant difference in all-cause mortality (P=0.006), cardiovascular mortality (P<0.001) and new-onset cardiovascular events (P<0.001) between HVC and non-HVC groups. After adjustment, Cox regression analysis identified HVC as a risk factor for increased all-cause mortality (HR=1.88; 95%CI: 1.11-3.19), cardiovascular mortality (HR=3.47, 95%CI: 1.76-6.84) and cardiovascular events (HR=1.64, 95% CI: 1.09-2.47). CONCLUSIONS: HVC is an independent risk factor for increased cardiovascular mortality and new cardiovascular events in patients on MHD.

IL-13 receptor α2 is a negative prognostic factor in human lung cancer and stimulates lung cancer growth in mice.

IL-13 receptor subunit alpha-2 (IL13Rα2) is associated with poor prognosis in some cancers. However, the role of IL13Rα2 in lung cancer remains unknown. We showed that IL13Rα2 overexpression was associated with late stages of disease progression and shorter disease-free survival (DFS) as well as overall survival (OS) in resected lung cancer patients. IL13Rα2 promoted the migration, invasion and anoikis resistance of lung cancer cells in vitro. Silencing of IL13Rα2 in lung cancer cells decreased invasion in vitro and lung metastasis in vivo. IL13Rα2 activated phosphatidylinositol 3 kinase (PI3K), Akt, and transcriptional coactivator with PDZ-binding motif (TAZ). Inhibition of PI3K attenuated activation of TAZ and its downstream target genes by IL13Rα2. We suggest that inhibition of IL13Rα2 is a potential therapeutic approach in lung cancer.

Phase II study of pazopanib as second-line treatment after sunitinib in patients with metastatic renal cell carcinoma: a Southern China Urology Cancer Consortium Trial.

This multicentre, single arm, phase II study was aimed to assess the efficacy and safety of pazopanib as second-line treatment after failure of sunitinib in patients with metastatic renal cell carcinoma (mRCC) and explore biomarkers for pazopanib response. Patients received pazopanib 800mgperday. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), overall survival (OS) and safety. Serum proteins (Delta-like ligand (DLL4), Notch1, hypoxia inducible factor-1α (HIF-1α), HIF-2α, vascular endothelial growth factor A (VEGFA) and platelet-derived growth factor receptor ß (PDGFRB)) levels were measured using enzyme-linked immunosorbent assay (ELISA). 86 patients with clear cell mRCC were enrolled from December 2009 to March 2012 from three centres in Southern China. Of 85 evaluable patients, the median PFS was 5.6months (95% confidence interval (CI), 4.1-6.7months) by independent review. No complete response (CR) was observed in all patients. 13 (15.3%; 95% confidence interval [CI], 11.2-23.9%) patients achieved partial responses (PR) (ORR 15.3%). Median OS was 18.1months (95% CI, 13.2-19.8months). The most common adverse events (AEs) were mild to moderate and clinically manageable, including hypertension (37.6%), diarrhoea (36.5%), increased AST (51.8%), and anaemia (60%). AEs resulted in dose reduction in 24.7% of patients. Multivariable analysis showed that higher baseline levels of DLL4 and VEGFA and lower baseline level of HIF-2α were associated with shorter PFS; only lower baseline level of HIF-2α was correlated with shorter OS. The lower expression level of DLL4 after pazopanib treatment was associated with higher response rate probability. In conclusion, pazopanib was clinically active and well tolerated as second-line treatment after sunitinib in mRCC patients. Baseline levels of serum DLL4, VEGFA and HIF-2α may have potential utility as biomarkers of clinical efficacy in this setting (chiCTR-TRC-13004016).

Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivo.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) occurs in non-small cell lung cancer (NSCLC) patients who initially respond to TKI treatment but whose cancer then progresses. Recent studies have shown that Notch signal is associated with drug resistance. However, the exact mechanism of Notch during acquisition of resistance to EGFR-TKI in human lung cancer remains unclear. In the present study, we showed that the expression of Notch-1 was highly upregulated in EGFR-TKI acquired resistant lung cancer cells. More importantly, Notch-1 contributed to the acquisition of the epithelial-mesenchymal transition (EMT) phenotype, which was critically associated with acquired resistance to EGFR-TKI. Silencing of Notch-1 using siRNA resulted in mesenchymal-epithelial transition (MET), which was associated with impaired invasion and anchorage-independent growth of lung cancer and resensitisation to gefitinib in acquired resistant NSCLC cells. Finally, gefitinib treatment of Balb/c nu/nu with acquired resistant lung cancer xenografts in combination with Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) resulted in effective tumour growth retardation, with decreased proliferative activity and increased apoptotic activity. Collectively, these data suggest that Notch-1 might play a novel role in acquired resistance to gefitinib, which could be reversed by inhibiting Notch-1.

SIRT1 regulates endothelial Notch signaling in lung cancer.

BACKGROUND: Sirtuin 1 (SIRT1) acts as a key regulator of vascular endothelial homeostasis, angiogenesis, and endothelial dysfunction. However, the underlying mechanism for SIRT1-mediated lung carcinoma angiogenesis remains unknown. Herein, we report that the nicotinamide adenine dinucleotide 1 (NAD1)-dependent deacetylase SIRT1 can function as an intrinsic negative modulator of Delta-like ligand 4 (DLL4)/Notch signaling in Lewis lung carcinoma (LLC) xenograft-derived vascular endothelial cells (lung cancer-derived ECs). PRINCIPAL FINDINGS: SIRT1 negatively regulates Notch1 intracellular domain (N1IC) and Notch1 target genes HEY1 and HEY2 in response to Delta-like ligand 4 (DLL4) stimulation. Furthermore, SIRT1 deacetylated and repressed N1IC expression. Quantitative chromatin immunoprecipitation (qChIP) analysis and gene reporter assay demonstrated that SIRT1 bound to one highly conserved region, which was located at approximately -500 bp upstream of the transcriptional start site of Notch1,and repressed Notch1 transcription. Inhibition of endothelial cell growth and sprouting angiogenesis by DLL4/Notch signaling was enhanced in SIRT1-silenced lung cancer-derived EC and rescued by Notch inhibitor DAPT. In vivo, an increase in proangiogenic activity was observed in Matrigel plugs from endothelial-specific SIRT1 knock-in mice. SIRT1 also enhanced tumor neovascularization and tumor growth of LLC xenografts. CONCLUSIONS: Our results show that SIRT1 facilitates endothelial cell branching and proliferation to increase vessel density and promote lung tumor growth through down-regulation of DLL4/Notch signaling and deacetylation of N1IC. Thus, targeting SIRT1 activity or/and gene expression may represent a novel mechanism in the treatment of lung cancer.

Prognostic significance of TAZ expression in resected non-small cell lung cancer.

INTRODUCTION: Transcriptional coactivator with PDZ-binding motif (TAZ) is known to bind to a variety of transcription factors to control cell differentiation and organ development. Recently, TAZ has been identified as an oncogene and has an important role in tumorigenicity of non-small cell lung cancer (NSCLC). Therefore, TAZ may present a novel target for the future diagnosis, prognosis, and therapy for lung cancer. We investigated the relationship between TAZ expression and clinicopathological parameters and determined its prognostic significance concerning survival in patients with resected NSCLC. METHODS: TAZ expression was immunohistochemically studied in 181 consecutive patients with NSCLC and 20 cases of normal lung tissue. The association between expression of TAZ and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of TAZ expression on survival. RESULTS: TAZ expression was observed in 121 of the 181 (66.8%) NSCLC. TAZ had nuclear and cytoplasmic expression. Clinicopathologically, TAZ expression was significantly associated with lung adenocarcinoma (p = 0. 002), poorer differentiation (p = 0.001), p-tumor, node, metastasis stage (p = 0.001), lymph node metastasis (p = 0.032), intratumoral vascular invasion (p = 0.004), pleural invasion (p = 0.003), adjuvant chemotherapy (p = 0.044), and poorer prognosis (p = 0.002). Multivariable analysis confirmed that TAZ expression increased the hazard of death after adjusting for other clinicopathological factors (hazard ratio, 2.56; 95% confidence interval, 1.39-4.66; p = 0.01). Overall survival was significantly prolonged in TAZ negative group when compared with TAZ positive group (61.8 versus 47.1 months; p < 0.0001), as was disease-free survival (44.3 versus 25.1 months; p < 0.0001). Adjuvant chemotherapy prolonged overall survival among resected NSCLC patients with TAZ positive expression (p = 0.001). CONCLUSIONS: This study suggests that TAZ expression is a prognostic indicator of poorer survival probability for patients with resected NSCLC.

Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells.

Despite an initial response to EGFR tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer, most patients eventually become resistant and result in treatment failure. Recent studies have shown that epithelial to mesenchymal transition (EMT) is associated with drug resistance and cancer cell metastasis. Strong multiple gene signature data indicate that EMT acts as a determinant of insensitivity to EGFR-TKI. However, the exact mechanism for the acquisition of the EMT phenotype in EGFR-TKI resistant lung cancer cells remains unclear. In the present study, we showed that the expression of Notch-1 was highly upregulated in gefitinib-resistant PC9/AB2 lung cancer cells. Notch-1 receptor intracellular domain (N1IC), the activated form of the Notch-1 receptor, promoted the EMT phenotype in PC9 cells. Silencing of Notch-1 using siRNA reversed the EMT phenotype and restored sensitivity to gefitinib in PC9/AB2 cells. Moreover, Notch-1 reduction was also involved in inhibition of anoikis as well as colony-formation activity of PC9/AB2 cells. Taken together, these results provide strong molecular evidence that gefitinib-acquired resistance in lung cancer cells undergoing EMT occurs through activation of Notch-1 signaling. Thus, inhibition of Notch-1 can be a novel strategy for the reversal of the EMT phenotype thereby potentially increasing therapeutic drug sensitivity to lung cancer cells.

[Low serum fetuin A is a risk factor of coronary artery calcification in patients starting hemodialysis].

OBJECTIVE: To examine the relationship between reduction of serum fetuin A and coronary artery calcification (CAC) in patients starting hemodialysis. METHODS: Twenty-nine patients on chronic hemodialysis (duration of hemodialysis less than 6 months) were enrolled in this study. Serum fetuin A and such potential CAC-related risk factors as C-reactive protein (CRP), Ca, P, iPTH, body mass index (BMI) were examined. CAC was detected by multislice spiral CT scan (MSCT) and quantified by the modified Agaston's scoring system. All the 29 patients were followed up for 18 months to appraise the cardiovascular events defined as cardiac failure, angina pectoris or myocardial infarction. RESULTS: Eleven patients (78.57%) were found to have CAC as detected by MSCT in low serum fetuin A (below the average serum concentration of 0.71 g/L) group, a rate significantly higher than that in high serum fetuin A group (7 patients, 46.67%, P<0.05). Serum fetuin A in these 29 patients was related with CAC score (Pearson correlation coefficient of -0.734, P=0.001) and stepwise regression analysis indicated that serum fetuin A (standardized beta=-0.568, P=0.003) and age (standardized beta=0.416, P=0.019) were independently correlated to CAC. Such factors as CRP, Ca, P, iPTH, Chol, TG, HDL-C, LDL-C, BMI and blood pressure were excluded from the regression equation. Reduction of serum fetuin A was associated with cardiovascular events (Spearman's rho -0.758, P<0.01). No significant difference was found between low and high serum fetuin A groups by Kaplan-Meier survival analysis (P=0.065). CONCLUSION: Reduced serum fetuin A may be a potential risk factor of coronary artery calcification, and can contribute to cardiovascular events in patients starting hemodialysis.

[Risk factors of hypertension in IgA nephropathy].

OBJECTIVE: To explore the risk factors of hypertension in patients with IgA nephropathy in South China. METHODS: The clinical and renal pathological data of 280 primary IgA nephropathy patients diagnosed by biopsy were analyzed to extinguish the risk factors of hypertension. RESULTS: A total of 96 patients were suffered with hypertension (34.3%). A single-variable analysis showed that the age (>or= 40 years), body weight (>or= 60 kg), absence of macrohematuria, duration of disease (>or= 60 months), blood urea nitrogen >or= 8 mmol/L, serum creatinine (>or= 133 micromol/L), hyperuricaemia, degree of 24 h-proteinuria (>or= 1.5 g), segmental glomerular lesions (>or= 25%), globe glomerular sclerosis (>or= 10%), tubular atrophy (>or= 25%), interstitial fibrosis (>or= 25%), interstitial inflammation (>or= 25%) and arteriole hypertrophy (>or= 10%) were all risk factors related to hypertension; multivariate logistic regression analysis showed that serum creatinine, age, arteriole hypertrophy, body weight and 24 h-proteinuria were the independent risk factors. CONCLUSION: Many factors were related the hypertension in patients with IgA nephropathy, while serum creatinine, age, arteriole hypertrophy, body weight and 24 h-proteinuria were the independent risk factors of hypertension.

[Efficacy and safety of coupled plasma filtration adsorption combined with continuous veno-venous hemofiltration for multiple organ dysfunction syndrome patients with acute liver failure].

OBJECTIVE: To evaluate efficacy and safety of coupled plasma filtration adsorption (CPFA) combined with continuous veno-venous hemofiltration (CVVH) for the treatment of multiple organ dysfunction syndrome (MODS) patients with acute liver failure (ALF), and to evaluate the effect of CPFA plus CVVF on inflammatory mediators in these patients. METHODS: A total of 38 cases of 11 MODS patients with ALF (male 6, female 5) were treated with CPFA plus CVVH, and the following clinical indicators including changes in mean arterial pressure (MAP), oxygen index (PaO(2)/FiO(2)), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6, IL-8, biochemical parameters of liver and kidney function, parameters of systemic inflammatory response syndrome (SIRS) score, and acute physiology and chronic health evaluation II (APACHE II) score were determined before and after the treatment. The degree of improvement in clinical symptoms, feasibility, tolerance toward CPFA plus CVVH, therapy-related adverse reactions and security were simultaneously evaluated. RESULTS: MAP increased by 12 mmHg (1 mmHg=0.133 kPa), and PaO(2)/FiO(2) increased by 40 mmHg after the application of CPFA plus CVVH (both P<0.05), along with significant decrease in TNF-alpha, IL-1 beta, IL-6, IL-8 and markedly lowered levels of serum total bilirubin (IBIL), direct bilirubin (DBIL), blood urea nitrogen (BUN), serum creatinine (SCr) and blood ammonia (all P<0.05). Besides, clinical symptoms, including urinary volume, mental disturbance, jaundice, debility, nausea, vomiting, fever, abdominal distention, anepithymia, and SIRS, APACHE II scores were improved significantly after the CPFA plus CVVH (all P<0.05). No therapy-related adverse reactions, including severe haemorrhage, shock, hypersensitivity, were noted, and patients tolerated well toward CPFA plus CVVH. The total survival rate of patients was 45.5% (5/11 cases) at the end of the treatment. CONCLUSION: Our data indicate that CPFA combined with CVVH is an effective and safe method to improve the prognosis of MODS patients with ALF, the mechanism of which may be related to its effective removal of inflammatory cytokines.