Cancer scene investigation: how a cold virus became a tumor killer

Oncolytic therapy is a novel anticancer treatment with attenuated lytic viruses such as adenovirus (Ad). These viruses kill the host cells through their lytic replication cycle and are thus distinct from classical gene therapy viruses, which serve as gene delivery agents and do not replicate. Oncolytic Ads are genetically engineered so as to replicate only in cancer cells. Their replication cycle leads to viral multiplication, the killing of the host cells and spreading of the infection throughout the tumor. Following success in preclinical studies, their anti-tumor potential is now being evaluated in the clinic. Three oncolytic Ads (dl1520, Ad5-CD/TKrep, and CV706) have completed Phase I and II clinical trials in cancer patients where their administration via multiple routes and in combination with chemo- or radiotherapies, has demonstrated overall safety. These viruses are being re-engineered to arm them with additional therapeutic genes, bolstering their oncolytic activity with a bystander effect. For example, Ad5-CD/TKrep delivers a therapeutic prodrug-activating (suicide) gene. These data indicate that oncolytic Ads are a promising novel cancer treatment approach that can be combined with other modalities, such as gene therapy and classical chemo- and radiotherapies. Further improvements to enhance their specificity, targeting and oncolytic activity are needed however, as these first-generation viruses showed modest anti-tumor activity. To improve their efficacy in the clinic, it will be important to devise and incorporate novel monitoring techniques in the clinical trials, such as analysis of viral replication in biopsies and through the use of creative noninvasive imaging technologies.     

Trefoil factor expression in biliary epithelium of graft-versus-host disease of the liver after allogeneic hematopoietic cell transplantation

BACKGROUND: The aims of this study were to determine the presence of trefoil factor family-3 (TFF3) expression in biliary epithelial cells (BECs) of chronic graft-versus-host disease (cGVHD) of the liver after allogeneic hematopoietic cell transplantation, to compare such expression in chronic liver diseases (CLD) with/without predominantly biliary disease, and to assess the effect of bile duct injury on the degree of TFF3 expression in BECs of cGVHD. METHODS: A total of 82 paraffin-embedded liver biopsy samples were reviewed. These samples were basically divided into two distinct groups according to the presence of ductal injury: group 1 with CLD and predominantly biliary disease (n=26: 17 cGVHD and 9 primary biliary cirrhosis [PBC]) and group 2 with CLD and predominantly parenchymal liver disease (n=56: 20 steatohepatitis and 36 chronic viral hepatitis). Group 2 was used as the controls. Immunohistochemistry was performed using a polyclonal anti-TFF3 antibody. Real-time quantitative PCR was used for the detection of TFF3 mRNA expression. RESULTS: Positive TFF3 immunohistochemical staining and the presence of TFF3 messenger RNA gene expression was demonstrably higher in group 1 than that in group 2 (P<0.0001 and P<0.05, respectively). No significant difference in terms of positive TFF3 stained BECs between GVHD and PBC samples was observed (P>0.05). The extent of TFF3 expression in GVHD samples with severe ductal injury were significantly more common than that of GVHD samples with mild/moderate ductal injury (P<0.0001). CONCLUSIONS: The expression of TFF3 in cGVHD of the liver is increased in response to bile duct damage and repair. Such expression seems to be related the severity of ductal injury.     

Elevated plasma concentrations of transforming growth factor-beta 1 in patients with unilateral ureteral obstruction

We measured plasma concentrations of TGF-beta 1 in patients with obstructive ureteral calculi and compared them with the plasma concentrations of healthy volunteers. The present study was a prospective study containing a homogenous group of patients with unilateral ureteral obstruction (UUO). The study consisted of patients with ureteral stones less than 7 mm in diameter that caused mild to moderate obstruction. All patients were referred by the emergency department of our hospital and examined between April 2003 and April 2004. The presence and characteristics of both stone and obstruction were determined by plain abdominal x-ray and gray-scale ultrasonography (US). Blood samples were collected from both patients and control individuals on admission and 1 week after conservative follow-up. The plasma TGF-beta 1 concentration was determined using a quantitative sandwich enzyme immunoassay specific for TGF-beta 1. There were 35 patients with 20 women and 15 men (average age 26.8±5.9 years), and 15 volunteers in the control group, with nine women and six men (average age 24.2±4.5 years). Average stone size was 5.6 mm±1.2 mm (range 3.5–7) for the patient group. US showed the presence of mild hydronephrosis in 24 and moderate hydronephrosis in 11 patients. Plasma concentrations of TGF-beta 1 in patients with ureteral obstruction (1,117±5.8 ng/ml, range 36–2,442 ng/ml) were significantly higher than those in the healthy control group (32±4 ng/ml) on admission (P<0.001). There was a significant increase in TGF-beta 1 plasma concentrations in the patient group (33,525±6.8 ng/ml, range 1,107–73,288 ng/ml) after 1 week follow-up (P<0.001). Ureteral obstruction increases plasma TGF-beta 1 concentrations in patients with ureteral stones as in UUO models in animal studies. A concomitant treatment with an anti-fibrotic agent may reduce the incidence of renal injury during obstruction.     

Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study

The objective of this prospective randomized placebo-controlled study was to determine the effectiveness of 400 mug oral and 400 mug vaginal misoprostol administration for cervical priming 3 h prior to manual vacuum aspiration (MVA) under local anesthesia for voluntary termination of pregnancy before 10 weeks of gestation in comparison with placebo oral or placebo vaginal administration (n=40 in each group). Postmedication cervical dilatation was similar in the oral (mean, 6.6+/-1.5) and vaginal (mean, 7.2+/-0.8) misoprostol groups but significantly higher compared with the oral (mean, 3.4+/-0.2) and vaginal (mean, 3.6+/-1.9) placebo groups. Duration of the procedure was also significantly shorter in the misoprostol groups in comparison with their placebo counterparts. Preoperative bleeding and side effects were more common in the misoprostol groups, but none required medical intervention. Intraoperative bleeding was less in the vaginal misoprostol group compared with the placebo groups. There was no significant difference in terms of visual analogue scores during the procedure, patient satisfaction, days of postoperative bleeding and rate of postoperative complications among the groups. Cervical priming with misoprostol administered orally or vaginally 3 h before MVA for termination of pregnancy under local anesthesia facilitates the procedure by decreasing the need for cervical dilatation and by shortening its duration without improving patients' pain perception and satisfaction mainly due to side effects.     

What Is The Role of Mechanical Bowel Preparation in Patients with Pilonidal Sinus Undergoing Surgery? Prospective, Randomized, Surgeon-blinded Trial

The aim of this study was to determine the effect of a mechanical bowel preparation on postoperative surgical wound infections in patients treated with identical antimicrobial prophylaxis undergoing wide excision and primary closure for chronic pilonidal sinus disease. Patients more than 18 years old were included in the study. All patients had intravenous antimicrobial prophylaxis at the time of anesthesia induction. In a prospective, randomized setting, patients were allocated to either the bowel preparation group or the no-bowel-preparation group. Mechanical bowel preparation was performed using an oral sodium phosphate solution. On the morning of the procedure a rectal enema was performed with the phosphate solution. The primary outcome measure was the rate of wound infection, but all postoperative complications and recurrences were recorded. All patients were actively observed for 1 year after discharge. The overall infection rate for the entire study population was 12.8% (13/101) including 14.3% (7/49) of those who had had the bowel preparation and 11.5% (6/52) of those with no bowel preparation. There was no statistically significant difference between groups (P = 0.680). The mean rate of recurrence for all 101 patients was 4.9% (5/101) at 19.2 months (range 12–32 months) of follow-up. The recurrence rate was 6.1% (3/49) in the bowel preparation group and 3.8% (2/52) in the no-bowel-preparation group (P = 1.000). Although the number of patients is small in this study, our results showed that the mechanical bowel preparation does not cause a decrease in the rate of surgical wound infections after excision and primary closure in patients with chronic pilonidal sinus disease.     

Effects of erythropoietin on hyperoxic lung injury in neonatal rats

Pulmonary oxygen toxicity is believed to play a prominent role in the lung injury that leads to the development of bronchopulmonary dysplasia (BPD). To determine whether human recombinant erythropoietin (rhEPO) treatment reduces the risk of developing BPD, we investigated the effect of rhEPO treatment on the histopathologic changes seen in hyperoxia-induced lung injury of BPD. Twenty-five rat pups were divided into four groups: air-exposed control group (n = 5), hyperoxia-exposed placebo group (n = 7), hyperoxia-exposed rhEPO-treated group (n = 6), and air-exposed rhEPO-treated group (n = 7). Measurement of alveolar surface area, quantification of secondary crest formation, microvessel count, evaluation of alveolar septal fibrosis, and smooth muscle actin immunostaining were performed to assess hyperoxia-induced changes in lung morphology. Treatment of hyperoxia-exposed animals with rhEPO resulted in a significant increase in the mean alveolar area, number of secondary crests formed, and the microvessel count in comparison with hyperoxia-exposed placebo-treated animals. There was significantly less fibrosis in rhEPO-treated animals. However, treatment of hyperoxia-exposed animals with rhEPO did not result in a significant change in smooth muscle content compared with hyperoxia-exposed placebo treated animals. Our results suggest treatment with rhEPO during hyperoxia exposure is associated with improved alveolar structure, enhanced vascularity, and decreased fibrosis. Therefore, we conclude that treatment of preterm infants with EPO might reduce the risk of developing BPD.     

Idiopathic hypertrophic cranial pachymeningitis with perifocal brain edema

Idiopathic hypertrophic cranial pachymeningitis (IHCP) consists of meningeal thickening due to chronic inflammation for which no cause such as infection, specific granulomatous disease, or malignancy is demonstrable. We present a case of IHCP with perifocal brain edema suggesting mass lesion with its magnetic resonance imaging (MRI) and pathologic findings. A 36-year-old woman was admitted to our hospital in August 2001 with a complaint of motor weakness in her left leg for 1 month. Magnetic resonance imaging with gadolinium revealed enhancement of the thickened dura mater and perifocal edema in the right frontoparietal region suggesting a mass lesion. Histological examination of the biopsy specimen revealed a dense fibrous cellular tissue. There was no obvious inflammatory infiltrate but in some areas between fibrous bundles one or two lymphocytes were detected. According to our knowledge, our patient is the second report in the literature of IHCP with focal edema causing a mass effect.     

Global fibrinolytic capacity in children on dialysis

Disturbances of coagulation and fibrinolysis have been reported in patients with chronic uremia. Studies of different coagulation and fibrinolysis parameters in regularly dialyzed patients have yielded conflicting results. Global fibrinolytic capacity (GFC) examines the function of the entire fibrinolytic system. This assay is a sensitive and reliable method for evaluating the fibrinolytic function of plasma in vitro. In this study, GFC was used as a screening test to investigate the effects of two different dialysis modalities on the fibrinolytic system on children on long-term dialysis. MATERIALS AND METHODS: The study included 12 children (age range, 11-20 years; mean age, 15.9+/-3.3 years) who were undergoing regular hemodialysis (HD) and 12 children (age range, 10-15 years; mean age, 13.1+/-1.7 years) who were undergoing continuous ambulatory peritoneal dialysis (CAPD). Thirteen healthy age- and sex-matched subjects served as controls. Each sample was investigated for complete blood count and serum levels of C-reactive protein, serum electrolytes, total cholesterol, triglyceride, fibrinogen, total protein and albumin. A GFC assay was also done in each case. RESULTS: The mean GFC in the CAPD group was lower than that in the HD and control groups (p<0.05). There was no significant difference between the mean GFC values of HD patients and controls. The mean serum albumin level was lower in CAPD patients than in HD patients (p<0.05), and there was also a positive correlation between serum albumin level and GFC in patient groups(r=0.52, p<0.05). Global fibrinolytic capacity was positively correlated with hemoglobin level and negatively correlated with weekly erythropoietin dose per kg body weight (r=0.56 and r=-0.49, respectively; p<0.05). CONCLUSION: The results suggest that CAPD patients have decreased fibrinolytic capacity compared to HD patients. Hypoalbuminemia and erythropoietin treatment may contribute to suppression of fibrinolytic function CAPD patients.