Long-term prophylactic intravenous antibiotics after Kasai portoenterostomy for biliary atresia do not reduce the risks of post-operative cholangitis, a retrospective study.

BACKGROUND: Postoperative cholangitis (PC) is the most common and serious complication of biliary atresia (BA) patients post-Kasai portoenterostomy (KPE). The duration of prophylactic intravenous antibiotics (IVA) after KPE varies with no clear consensus. We conducted a retrospective cohort study to explore the effects of IVA duration on preventing post-operative cholangitis and analyze the risk factors for cholangitis and short-term prognosis. METHODS: All patients diagnosed with BA and received KPE in Guangzhou Women and Children's Hospital in 2018, were included in this study. The patients received prophylactic IVA after KPE. Firstly, the patients were divided into two groups based on the presence or absence of PC (PC and NPC group). The correlation between PC and the IVA duration was analyzed, followed by a comparison of short-term prognosis, outcome, and other risk factors between the groups. Next, the patients were divided based on the median IVA duration of 11 days (long IVA and short IVA group), followed by a comparison of the incidence of PC, short-term prognosis, outcome, and other risk factors between the two groups. RESULTS: Totally 89 patients were included in this study. Amount them, eleven patients who were lost during follow-up, were excluded from the study. The prophylactic IVA duration of the PC (n=52) and NPC (n=25) groups was 12.6±8.5 and 13.0±4.5 days, respectively (P=0.79). Further, the jaundice clearance rate of the two groups was similar (PC: 31/52, NPC: 13/25, P=0.53). There was no difference in the incidence and frequency of cholangitis between the short (n=42) and long (n=35) IVA groups (27/42, 25/35, P=0.51), and the duration of IVA had no effect on jaundice clearance (24/42, 20/35, P=1.00). The short IVA group had a significantly shorter hospital stay than the long IVA group (16.2±5.1, 25.3±8.3, P=8.95×10-8). Patients undergoing KPE at an older age were at a higher risk of cholangitis (NPC: 60.6±19.7, PC: 72.3±17.8, P=0.01). CONCLUSIONS: A long duration of IVA after KPE for BA may not be necessary. Early diagnosed patients had timely surgery had a lower incidence of PC. Our findings may help in promoting the scientific use of antibiotics and reducing the LHS.

Long non­coding RNA 00858 knockdown alleviates bladder cancer via regulation of the miR­3064­5p/CTGF axis.

The long non-coding RNA 00858 (LINC00858) has been reported to be an oncogene for various cancer diseases, including osteosarcoma and colorectal cancer. However, the expression pattern and function of LINC00858 in bladder cancer remain largely unknown. The expression level of LINC00858 was measured in tumor tissues and cell lines by RT-qPCR. The role of LINC00858 in bladder cancer cells were studied by gain- and loss-of-function strategies in vitro. Cell proliferation, migration and invasion were assessed by CCK-8, colony formation, wound healing and Transwell chamber assays. At the molecular level, dual luciferase reporter and RNA RIP assays were performed to identify the interaction among LINC00858, microRNA (miR)-3064-5p and cellular communication network factor 2 (CTGF). The results revealed that the expression level of LINC00858 was upregulated in bladder cancer tissues and cell lines including T24, J82 and 5637. Moreover, knockdown of LINC00858 suppressed cell proliferation, migration and invasion in vitro. Mechanistically, LINC00858 functioned as a competitive RNA to increase the expression level of oncogene CTGF by sequestering miR-3064-5p. In conclusion, LINC00858 knockdown inhibited the proliferation, migration and invasion of bladder cancer cells via regulation of the miR-3064-5p/CTGF axis.

Prenatal diagnosis and postnatal management of congenital mesoblastic nephroma: Experience at a single center in China.

OBJECTIVE: To review the prenatal and postnatal clinical characteristics and pathological subtypes, as well as the surgical outcome for congenital mesoblastic nephroma (CMN) cases. METHOD: A retrospective review was performed in 11 cases with CMN prenatally diagnosed at a single center between 2015 and 2019. The clinical characteristics, surgical outcome, histopathology, and follow-up were retrospectively obtained and reviewed. RESULTS: The median gestational age at which the sonographic diagnosis was made was 35 weeks. Polyhydramnios was found in four (36.4%) cases, and all resulted in a preterm birth. Nine infants had hypertension. Ten cases underwent radical nephrectomy, and one underwent radical nephrectomy and partial adrenalectomy. The pathological results showed that six tumors were classical variants, four mixed variants, and one was a cellular variant. Three cases presented as a stage I, eight as stage II, and no stage III or IV cases were diagnosed. All patients are alive so far. At a median follow-up of 14 months, no local recurrence, or remote metastases were found. CONCLUSION: The prognosis of prenatal CMN cases is excellent after early surgery.

Correlation analysis of IL-11 polymorphisms and Hirschsprung disease subtype susceptibility in Southern Chinese Children.

BACKGROUND: Hirschsprung disease (HSCR) is a hereditary defect, which is characterized by the absence of enteric ganglia and is frequently concurrent with Hirschsprung-associated enterocolitis (HAEC). However, the pathogenesis for HSCR is complicated and remains unclear. Recent studies have shown that pro-inflammatory cytokines such as interleukin-11 (IL-11) are involved in the enteric nervous system's progress. It was found that IL-11 SNPs (rs8104023 and rs4252546) are associated with HSCR in the Korean population waiting for replication in an independent cohort. This study evaluated the relationship between IL-11 and the susceptibility of patients to HSCR by performing subphenotype interaction examination, HAEC pre-/post-surgical patient-only association analysis, and independence testing. METHODS: In this study, a cohort consisting of children from Southern China, comprising 1470 cases and 1473 controls, was chosen to examine the relationship between two polymorphisms (rs8104023 and rs4252546 in IL-11) and susceptibility to HSCR by replication research, subphenotype association analysis, and independence testing. RESULTS: The results showed that IL-11 gene polymorphisms (rs8104023 and rs4252546) are not associated with the risk of HSCR in the Chinese population. The results of both short-segment and long-segment (S-HSCR and L-HSCR) surgery (3.34 ≤ OR ≤ 4.05, 0.02 ≤ P ≤ 0.04) showed that single nucleotide polymorphisms (SNP) rs8104023 is associated with susceptibility to HAEC. CONCLUSIONS: This study explored the relationship between genetic polymorphisms and susceptibility to HAEC in HSCR subtypes for the first time. These findings should be replicated in a larger and multicentre study.

Comparison of outcomes following three surgical techniques for patients with severe jejunoileal atresia.

BACKGROUND: Severe jejunoileal atresia is associated with prolonged parenteral nutrition, higher mortality and secondary surgery. However, the ideal surgical management of this condition remains controversial. This study aimed to compare the outcomes of patients with severe jejunoileal atresia treated by three different procedures. METHODS: From January 2007 to December 2016, 105 neonates with severe jejunoileal atresia were retrospectively reviewed. Of these, 42 patients (40.0%) underwent the Bishop-Koop procedure (BK group), 49 (46.7%) underwent primary anastomosis (PA group) and 14 (13.3%) underwent Mikulicz double-barreled ileostomy (DB group). Demographics, treatment and outcomes including mortality, morbidity and nutrition status were reviewed and were compared among the three groups. RESULTS: The total mortality rate was 6.7%, showing no statistical difference among the three groups (P = 0.164). The BK group had the lowest post-operative complication rate (33.3% vs 65.3% for the PA group and 71.4% for the DB group, P = 0.003) and re-operation rate (4.8% vs 38.8% for the PA group and 14.3% for the DB group, P < 0.001). Compared with the BK group, the PA group showed a positive correlation with the complication rate and re-operation rate, with an odds ratio of 4.15 [95% confidence interval (CI): 1.57, 10.96] and 12.78 (95% CI: 2.58, 63.29), respectively. The DB group showed a positive correlation with the complication rate when compared with the BK group, with an odds ratio of 7.73 (95% CI: 1.67, 35.72). The weight-for-age Z-score at stoma closure was -1.22 (95% CI: -1.91, -0.54) in the BK group and -2.84 (95% CI: -4.28, -1.40) in the DB group (P = 0.039). CONCLUSIONS: The Bishop-Koop procedure for severe jejunoileal atresia had a low complication rate and re-operation rate, and the nutrition status at stoma closure was superior to double-barreled enterostomy. The Bishop-Koop procedure seems to be an appropriate choice for severe jejunoileal atresia.

Low expression of PDK1 inhibits renal cell carcinoma cell proliferation, migration, invasion and epithelial mesenchymal transition through inhibition of the PI3K-PDK1-Akt pathway.

As the most commonly occurring form of primary renal tumor, renal cell carcinoma (RCC) is a malignancy accompanied by a high mortality rate. 3-phosphoinositide-dependent protein kinase 1 (PDK1) has been established as a protein target and generated considerable interest in both the pharmaceutical and academia industry. The aim of the current study was to investigate the effect of si-PDK1 on the RCC cell apoptosis, proliferation, migration, invasion and epithelial mesenchymal transition (EMT) in connection with the PI3K-PDK1-Akt pathway. Microarray analysis from the GEO database was adopted to identify differentially expressed genes (DEGs) related to RCC, after which the positive expression of the PDK1 protein in tissue was determined accordingly. The optimal silencing si-RNA was subsequently selected and RCC cell lines 786-O and A498 were selected and transfected with either a si-PDK1 or activator of the PI3K-PDK1-Akt pathway for grouping purposes. The mRNA and protein expressions of PDK1, the PI3K-PDK1-Akt pathway-, EMT- and apoptosis-related genes were then evaluated. The effect of si-PDK1 on cell proliferation, apoptosis, invasion and migration was then analyzed. Through microarray analysis of GSE6344, GSE53757, GSE14762 and GSE781, PDK1 was examined. PDK1 was determined to be highly expressed in RCC tissues. Si-PDK1 exhibited marked reductions in relation to the mRNA and protein expression of PDK1, PI3K, AKT as well as Vimentin while elevated mRNA and protein expressions of E-cadherin were detected, which ultimately suggested that cell migration, proliferation and invasion had been inhibited coupled with enhanced levels of cell apoptosis. While a notable observation was made highlighting that the PI3K-PDK1-Akt pathway antagonized the effect of PDK1 silencing. Taken together, the key observations of this study provide evidence suggesting that high expressions of PDK1 are found in RCC, while highlighting that silencing PDK1 could inhibit RCC cell proliferation, migration, invasion and EMT by repressing the PI3K-PDK1-Akt pathway.

Fetal Lymphangioma: Prenatal diagnosis on ultrasound, treatment, and prognosis.

OBJECTIVE: To investigate the characteristics of fetal lymphangioma, including their location, imaging features, prenatal and differential diagnoses, treatment, and prognosis. STUDY DESIGN: Imaging data of 79 patients with fetal lymphangioma treated at our hospital were obtained. Imaging modalities included prenatal and post-natal magnetic resonance imaging (MRI), prenatal and post-natal color Doppler ultrasound, and post-natal contrast-enhanced computed tomography (CT). Modalities of delivery and treatment were selected according to the location and size of lymphangioma. RESULTS: Among the 133,322 fetuses of 130,202 pregnant women examined at our hospital, 5 fetuses were misdiagnosed and the diagnosis was missed in 5 fetuses prenatally. Finally, 79 had lymphangioma, confirmed by ultrasound, MRI, post-natal CT, and pathological results obtained postoperatively or on autopsy. The diagnostic coincidence rate of lymphangioma was 88.1% (74/84 cases). Of the 79 fetuses with a lymphangioma, septation of the mass was identified in 66 cases (83.54%), with no evidence of septation in the remaining 13 fetuses (16.46%). With regard to location, the lymphangioma was located in the neck in 50 fetuses (63.29%). Interventional sclerotherapy, using bleomycin, was performed in 22 neonates, of which 3 underwent ex utero intrapartum treatment (EXIT) due to evidence of airway or esophageal obstruction (16 patients underwent expectant management; 7 surgical operation). Thirty-two fetuses underwent medical termination and 2 fetuses died in-utero. Of the 16 patients who had expectant treatment, the lesions retroregressed during the intra-uterine period in 7 fetuses, before the post-natal age of 6 months in 4 neonates, and before the age of 2 years in 3 neonates. Of the 7 neonates who were treated surgically, relapse occurred in 1 case, which required re-operation. CONCLUSIONS: Prenatal ultrasound provides a clear differential diagnosis of fetal lymphangioma. Interventional therapy should be the first-choice treatment for neonates with a lymphangioma confirmed postnatally.

How to make an accurate diagnosis of fetal pyriform sinus fistula in utero: experience at a single medical center in mainland China.

OBJECTIVE: The aim of this study was to make an accurate diagnosis of pyriform sinus fistula (PSF) for prenatal diagnosis. STUDY DESIGN: Medical records were reviewed for all 35 pyriform sinus fistula patients presenting between 2011 and 2017. Ultrasonography (US), fetal magnetic resonance imaging (MRI) and karyotyping were offered during gestation, while computer tomography (CT) and barium esophagography were performed after birth. RESULTS: Patients included 21 males (60%) and 14 females (40%) with a sex ratio of 1.5:1. The lesion was located on the left side in 32 (91.4%) cases, the right side in 2 (5.7%), and was bilateral (2.8%) in only one case. The sensitivity of CT, MRI, ultrasonography and barium esophagography were 100% (35/35), 69.2% (9/13), 22.9% (8/35), and 80% (20/25), respectively. If the diagnosis was correct, there was almost no recurrence after treatment. Karyotype analysis of all fetuses was normal. CONCLUSIONS: Pyriform sinus fistula is more commonly seen in the left side. Compared with ultrasonography, MRI has more advantages in prenatal diagnosis, and it is more accurate in postpartum CT examination. The outcome of children with pyriform sinus fistula may be guarded when it correct diagnosis.

Overexpression of PTK6 predicts poor prognosis in bladder cancer patients.

Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase and works as an oncogene in various cancers. Recently, PTK6 has been used as a therapeutic target for breast cancer patients in a clinical study. However, the prognostic value of PTK6 in bladder cancer (BC) remains vague. Therefore, we retrieved 3 independent investigations of Oncomine database and found that PTK6 is highly expressed in BC tissues compared with corresponding normal controls. Similar results were also observed in clinical specimens at both mRNA and protein levels. Immunohistochemical analysis indicated that PTK6 overexpression was highly related to the T classification, N classification, grade, recurrence, and poor prognosis of BC patients. Furthermore, we demonstrated that when PTK6 expression was knocked down by siRNAs, cell proliferation and migration were considerably inhibited in BC cell lines T24 and EJ. By these approaches, we are intended to elucidate PTK6 may be a reliable therapeutic target in BC and might benefit from PTK6 inhibitors in the future.

Trends of testis-sparing surgery for pediatric testicular tumors in South China.

BACKGROUND: Testis-sparing surgery is not popular in South China. This study aimed to investigate this procedure for pediatric testicular tumors. METHODS: Children with testicular benign tumors were retrospectively analyzed from January 2001 to June 2015 in the Sun Yat-sen University Cancer Center (SYSUCC) and the First Affiliated Hospital (SYSU-1st). Follow-up was performed until June 2016, and the proportions of TSS in the two hospitals during the different periods were compared. RESULTS: Forty-seven children with testicular benign tumors were enrolled, and 16 cases underwent testis-sparing surgery. All patients were cured and discharged, which included mature teratoma (n = 37), testicular adrenal rest tumors (n = 4), epidermal cysts (n = 3), granulomatous inflammation (n = 2) and adenomatoid tumors (n = 1). Inguinal testis-sparing surgery was performed in 16 children, and no recurrence was detected during follow-up. It was performed more frequently in SYSUCC than in SYSU-1st (P = 0.031), and the tumor size of these patients was smaller than those of patients who underwent radical orchiectomy (P = 0.044). Moreover, testis-sparing surgery has become more common in the past 5 years, although differences over time have not reached significance (P = 0.051). CONCLUSIONS: Testis-sparing surgery is reliable, and tumor size and special hospitals affect its success. Additionally, its use has become more popular in recent years. However, advocacy is still needed for the use of this technique in pediatric testicular benign tumors that are small sized.

Prenatal diagnosis and early postnatal management of pyriform sinus cyst: experience at a single medical center in mainland China.

OBJECTIVE: The aim of this study was to determine whether prenatal diagnosis of pyriform sinus cyst can improve the prognosis of this disorder. METHODS: A retrospective review was performed in 15 neonates with a pyriform sinus cyst seen at a single center between 2010 and 2014. Among the 15 cases, the diagnosis was made prenatally in eight cases (PreD), while the diagnosis was made postnatally in seven cases (PostD). Neonatal outcome was compared in the two subgroups. RESULTS: The mean gestational age at diagnosis of PreD was 27 ± 6.8 weeks, while the mean age at admission of PostD was 10.1 ± 8.8 days. Cervical mass, fever, respiratory distress, and hoarseness were common symptoms. The mean duration of postoperative mechanical ventilation was 11.5 ± 13.9 and 100.71 ± 80.0 h, respectively, in PreD and PostD (p < 0.01). The average postoperative length of stay and the length of hospital stay were 11.3 ± 3.34 and 19.6 ± 4.41 days in PreD, and 15.14 ± 8.28 and 24.14 ± 8.51 days in PostD, respectively. CONCLUSION: Prenatal diagnosis and timely postnatal sequential intervention were associated with less complications and shortened duration of postoperative mechanical ventilation. © 2016 John Wiley & Sons, Ltd.

Standardized Indications to Assist in the Safe Thoracoscopic Repair of Congenital Diaphragmatic Hernia in Neonates.

BACKGROUND: To analyze the early outcome of thoracoscopic repair (TR) of neonatal congenital diaphragmatic hernia (CDH) with standardized indications. METHODS: Clinical data of 14 neonates with CDH who underwent TR from September 2013 to August 2014 were retrospectively analyzed. SELECTION CRITERIA: weight beyond 2.0 kg; liver in the abdomen; no intestinal obstruction; no severe cardiopulmonary anomalies; not required high-frequency oscillatory ventilation or extracorporeal membrane oxygenation. Timing of surgery: mean arterial blood pressure normal for gestational age; preductal saturation levels of 85%-95% on fractional inspired oxygen below 50%; lactate below 3 mmol/L; urine output more than 2 mL/kg/h. Fourteen cases in the historical control group who underwent open repair (OR) with the same physiological status were reviewed for comparison. RESULTS: Demographic features were similar between the TR group and OR group. The TR group had a higher intraoperative mean PaCO2 (48 ± 8 mmHg versus 39 ± 6 mmHg, P = .0024) and mean arterial pH (7.30 ± 0.06 versus 7.39 ± 0.06, P = .0005), but no differences in lactate (0.93 ± 0.16 mmol/L versus 0.98 ± 0.14 mmol/L, P = .3869). Longer operation time was found in the TR group (116 ± 27 minutes versus 74 ± 25 minutes, P = .0002). No recurrence was observed in groups within the first year of life follow-up. CONCLUSIONS: With selection criteria and timing, TR of CDH in neonates can be performed safely and successfully.

Comparison of tubularized incised plate urethroplasty combined with a meatus-based ventral dartos flap or dorsal dartos flap in hypospadias.

PURPOSE: Tubularized incised plate urethroplasty (TIPU) is the preferred surgical option for distal and mid-shaft hypospadias repair. Neourethra dartos flap coverage is routinely used as a protective layer with good results. We modified meatus-based ventral dartos flap (MBVDF) to TIPU by dissecting the proximal mid-ventral dartos attached urethra and leaving the subcutaneous fascia connecting the meatus, and retrospectively compared the outcomes of using MBVDF with single dorsal dartos flap (DDF) on the complication rates of TIPU. METHODS: We present 2 surgeons' experiences with 356 patients with distal and mid-shaft hypospadias between January 2010 and December 2014. Patients were divided into two groups. Group DDF included 185 patients (mean age 29 months) underwent TIPU with DDF rotated laterally covering the suture lines of the neourethra. Group MBVDF included 171 patients (mean age 26 months) underwent TIPU with MBVDF covering the suture lines of the neourethra. Statistical analysis of patient basic information and complications was performed by two independent sample t test and Chi square test or Fisher's exact test. RESULTS: There were no statistical differences in age, type of hypospadias, and follow-up time between the two groups. The mean operative time in the group MBVDF (68.93 ± 8.32 min) was significantly shorter than in the group DDF (73.60 ± 9.06 min). Ventral skin necrosis (2.7%) and penile rotation (3.8%) in group DDF was significantly higher than group MBVDF which did not occur. The differences in other complication rates including fistula rate (2.7 vs 2.9%) between the groups were not statistically significant. CONCLUSION: DDF and MBVDF with TIPU are similarly effective methods for decreasing fistula in hypospadias repair. MBVDF with TIPU may be an easier method and can avoid ventral skin necrosis and penile rotation.

Intussusception patients older than 1 year tend to have early recurrence after pneumatic enema reduction.

PURPOSE: To identify age risk factors of early recurrent intussusception after pneumatic enema reduction. Management opinions are proposed. METHODS: Two thousand two hundred and ninety-five intussusception patients' medical records from January 2009 to December 2011 were retrospectively reviewed and analyzed. RESULTS: Of the 2295 patients, the intussusception of 1917 of them was initially reduced by pneumatic enema, with 127 cases recurring within 72 h. The early recurrence rate is 6.62%. The early recurrence rate of patients younger than 1 year old is 2.1% (22/1032), while the rate for those older than 1 year is 11.9% (105/885). The difference is significant (P = 0.0001). There were no significant differences between age groups older than 1 year. One hundred and seventeen cases of recurrence happened within 48 h, which accounted for 92.1% of all early recurrence. Recurrence patients were treated again with pneumatic enema, with a successful reduction in 93.7%. They were followed up for 2-4 years; the long-term recurrent rate was 11.8% (14/119). No patient had poor prognosis because of delayed treatment. CONCLUSION: Intussusception patients older than 1 year tend to have greater early recurrence rate after pneumatic enema reduction; 92.1% of the early recurrent cases happened in 48 h. There is no need to hospitalize patients after pneumatic enema reduction. A repeat pneumatic enema is a good choice before surgical approach.

Communicating bronchopulmonary foregut malformation type IA: radiologic anatomy and clinical dilemmas.

BACKGROUND: Communicating bronchopulmonary foregut malformation (CBPFM) type IA is extremely rare and is associated with a high mortality rate. This malformation manifests with communication between the lung and the foregut, and this can lead to esophageal atresia and tracheoesophageal fistula (EA-TEF) to the distal pouch. PURPOSE: To detail radiographic findings of CBPFM type IA cases and to summarize an appropriate therapeutic strategy for the management of this disorder. METHODS: Medical data for two patients with CBPFM type IA were retrospectively reviewed with regard to radiographic characteristics, therapy, and outcome. RESULTS: Both cases were initially misdiagnosed due to the presence of EA-TEF. Unusual atelectasis of the lateral lung was observed in chest radiographs, while non-aerated hypoplastic right lung and agenesis of the right main bronchus were detected by computed tomography. A final diagnosis was made by esophagogram. Only one patient survived following surgery. CONCLUSION: CBPFM type IA is a rare condition and is extremely difficult to diagnose. However, CBPFM type IA should be suspected in patients manifesting EA and atelectasis of a unilateral lung on a chest radiograph. The decision to perform a pneumonectomy or bronchoplasty depends on the degree of exiting permitted due to pulmonary damage assessed by computed tomography.

[Treatment strategy and prognosis analysis in children with type I esophageal atresia].

OBJECTIVE: To analyze the postoperative short-term and long-term outcomes in the management of type I esophageal atresia, and to explore the ideal operative strategy. METHODS: Clinical data of 22 patients with type I esophageal atresia treated from January 2005 to September 2012 were retrospectively reviewed. Of 22 patients, 6 patients gave up the treatment. Two underwent primary repair after birth. Of 14 patients undergoing cervical esophagostomy and gastrostomy, 8 patients received esophageal replacement. Postoperative short-term and long-term complications, nutritional state and neurodevelopment were studied on above 10 children with radical operations. RESULTS: Of 10 patients with radical operation, the short-term complications were hydrothorax in 1 case, anastomotic leakage in 4, dumping syndrome in 1, anastomotic stricture in 1. The long-term complications were esophageal stricture in 2 cases, and repeated respiratory infection in 3. These complications could be managed successfully. The postoperative follow-up duration ranged from 2 to 62 months. Two cases were lost during follow-up after 2 years. Weight-for-age was normal in 2 patients, mild malnutrition in 5 patients, and moderate malnutrition in 1 patients. Neurodevelopment is significantly delayed as compared to normal children. CONCLUSIONS: Operative strategy should be chosen according to the distance between proximal and distal esophagus in the treatment of type I esophageal atresia. The efficacy of radical operation is relative satisfactory in terms of short-term and long-term complications and the quality of life.

Immunotherapy of tumors with protein vaccine based on chicken homologous Tie-2.

PURPOSE: Tie-2 is an endothelium-specific receptor tyrosine kinase known to play a key role in tumor angiogenesis. The present study explores the feasibility of immunotherapy of tumors by using a protein vaccine based on chicken Tie-2 as a model antigen to break the immune tolerance against Tie-2 in a cross-reaction between the xenogeneic homologous and self-Tie-2. EXPERIMENTAL DESIGN AND RESULTS: In this study, a chicken homologous Tie-2 protein vaccine (chTie-2) and a corresponding mouse Tie-2 vaccine as a control were prepared and the antitumor effect of these vaccines was tested in two tumor models (murine B16F10 melanoma and murine H22 hepatoma). Immunotherapy with chTie-2 was found effective in two tumor models. Autoantibodies against mouse Tie-2 were detected in sera of mice immunized with chTie-2 through Western blot analysis and ELISA assay. Anti-Tie-2 antibody-producing B cells were detectable by ELISPOT. Histologic examination revealed that autoantibodies were deposited on the endothelial cells of tumor tissues. Purified immunoglobulins from chTie-2-immunized mice could induce the apoptosis of human umbilical vein endothelial cells in vitro. Importantly, adoptive transfer of purified immunoglobulins led to antitumor effect in vivo; apparently, angiogenesis was significantly inhibited in these tumors. Furthermore, the antitumor activity and production of autoantibodies could be abrogated by depletion of CD4+ T lymphocytes. CONCLUSIONS: Our findings may provide a vaccine strategy for cancer therapy and show the potential utilization of interference with Tie-2 pathway.

Enhanced antitumor effect of the combination of tumstatin gene therapy and gemcitabine in murine models.

Targeting tumor endothelium is an important strategy for cancer therapy. We evaluated the effectiveness of gene therapy, that is, intramuscular delivery of plasmid DNA encoding tumstatin (pSecTag2B-tum), combined with gemcitabine administration in vitro and in vivo, using colon carcinoma (CT26) and Lewis lung carcinoma (LLC) murine models. The in vitro growth-inhibitory and proapoptotic effects of gemcitabine and/or tumstatin on human umbilical vein endothelial cells (HUVECs) and mouse endothelial cells (SVEC4-10), respectively, were assessed. in vitro, conditioned medium from pSecTag2B-tum-transfected COS cells inhibited the growth of endothelial cells but not of CT26 or LLC cells, whereas gemcitabine inhibited the growth of both endothelial cells and CT26 and LLC cells. Mice bearing subcutaneously established CT26 or LLC tumors received pSecTag2B-tum alone or in combination with gemcitabine to assess tumor growth inhibition. in vivo, combined treatment with pSecTag2B-tum and gemcitabine significantly decreased tumor growth through increased inhibition of tumor angiogenesis and increased tumor cell apoptosis compared with either agent alone. Enhanced antiproliferative and proapoptotic activity of the combination therapy on tumor-associated endothelial cells was calculated to be significant. This study suggests that combined treatment by the intramuscular delivery of plasmid DNA encoding tumstatin and gemcitabine augments tumor growth inhibition by suppressing angiogenesis and enhancing apoptosis in murine models. A combination of these agents could be used in future studies and translated into the clinical setting.

Improved therapeutic effectiveness by combining recombinant CXC chemokine ligand 10 with Cisplatin in solid tumors.

PURPOSE: CXC chemokine ligand 10 (CXCL10) is a potent inhibitor of angiogenesis. We wonder whether the combination of CXCL10 with cisplatin would improve the therapeutic antitumor efficacy. EXPERIMENT DESIGN: We evaluated the antitumor activity of the combination therapy in the immunocompetent C57BL/6 and BALB/c mice bearing LL/2 Lewis lung cancer and CT26 colon adenocarcinoma, respectively. Mice were treated with either CXCL10 s.c. at 25 mug per kg per day once daily for 30 days, cisplatin cycled twice (5 mg/kg i.p. on days 14 and 21 after the initiation of CXCL10), or both agents together. Tumor volume and survival time were observed. Antiangiogenesis of CXCL10 in vivo were determined by alginate capsule models and CD31 immunohistochemistry. Histologic analysis and assessment of apoptotic cells were also conducted in tumor tissues. RESULTS: CXCL10 + cisplatin reduced tumor growth in LL/2 and CT26 tumor model, respectively, more effectively, although cisplatin or CXCL10 individually resulted in suppression of tumor growth and improved survival time of tumor-bearing mice. CXCL10 successfully inhibited angiogenesis as assessed by alginate model and CD31 (P < 0.05). Histologic analysis of tumors exhibited that CXCL10 in combination with cisplatin led to the increased rate of apoptosis, tumor necrosis, and elevated lymphocyte infiltration. CONCLUSIONS: Our data suggest that the combination of CXCL10, a well-tolerated angiogenesis inhibitor, with cisplatin can enhance the antitumor activity. The present findings may be of importance to the further exploration of the potential application of this combined approach in the treatment of lung and colon carcinoma.