Ultraflex precision colonic stent placement as a bridge to surgery in patients with malignant colon obstruction

BACKGROUND: Emergency surgery for malignant colon obstruction entails relatively high morbidity and mortality rates and typically necessitates a 2-step resection. These problems might be potentially mitigated by placement of a self-expanding metal stent (SEMS) as a bridge to surgery. A nitinol colorectal SEMS may offer several advantages, but available evidence on the utility of this SEMS type remains highly limited. OBJECTIVE: Our purpose was to evaluate the effectiveness and safety as a bridge to surgery of a nitinol SEMS designed for colorectal use. DESIGN: Prospective and retrospective multicenter clinical study. SETTING: Sixteen European study centers. PATIENTS: Thirty-six patients with malignant colonic obstruction. INTERVENTIONS: Nitinol colorectal SEMS placement. MAIN OUTCOME MEASURES: Technical success in accurate SEMS placement with coverage of the entire stricture length, clinical success in alleviating colonic obstructive symptoms, and bridging to elective surgery. RESULTS: Technical success was achieved in 97% of patients with a 95% CI of 85% to 100% and clinical success in 81% (95% CI, 64%-92%). Elective surgery was performed in 94% (95% CI, 81%-99%) of patients at a median of 11 days (95% CI, 7-15 days) after SEMS placement. SEMS-related perforation occurred in 3 patients. LIMITATIONS: No control group was included in this nonrandomized cohort study. CONCLUSIONS: In this first comparatively large clinical study of a nitinol colorectal SEMS as a bridge to surgery, a high proportion of patients successfully proceeded to elective surgery after prior decompression by SEMS placement.     

Needle sharing: a longitudinal study of female injection drug users

The objective of this study was to examine the psychosocial risk and protective factors related to needle-sharing behavior among female intravenous drug users (IDUs) positive (N = 96) and negative (N = 128) for human immunodeficiency virus (HIV). Participants in this longitudinal study were interviewed individually at two points in time, with a 6-month interval between interviews. The interviewers used a structured questionnaire, which included psychosocial measures and questions about drug and sexual risk behaviors. Data were analyzed using Pearson correlations and hierarchical regression analyses. The findings supported a developmental model in which the psychosocial domains and HIV status predicted T1 (initial) needle-sharing behavior, which in turn was related to T2 (follow-up) needle-sharing behavior. In addition, the relationship between personality and peer risk factors and T2 needle sharing was buffered by family-related protective factors. While HIV-positive status had a direct effect on T1 needle sharing with strangers, its effect was mediated by all of the psychosocial variables in its relation to T1 needle sharing with familiar people. Comparisons of these results were made with a companion study of male IDUs. The results suggest several intervention and treatment approaches that can be implemented at different points in the developmental pathways leading to risky needle-sharing practices among female IDUs.     

Complications of diagnostic and therapeutic ERCP: a prospective multicenter study

OBJECTIVES: Diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP/ES) can be associated with unforeseeable complications, especially when involving postprocedural pancreatitis. The aim of the study was to investigate risk factors for complications of ERCP/ES in a prospective multicentric study. METHODS: One hundred fifty variables were prospectively collected at time of ERCP/ES and before hospital discharge over 2 years, in consecutive patients undergoing the procedure in nine endoscopic units in the Lombardy region of Italy. More than 150 ERCPs were performed in each center per year by a single operator or by a team of no more than three endoscopists. RESULTS: Two thousand four hundred sixty-two procedures were performed; 18 patients were discharged because the papilla of Vater was not reached (duodenal obstruction, previous gastrectomy, etc.). Two thousand four hundred forty-four procedures were considered in 2103 patients. Overall complications occurred in 121 patients (4.95% of cases): pancreatitis in 44 patients (1.8%), hemorrhage in 30 (1.13%), cholangitis in 14 (0.57%), perforation during ES in 14 (0.57%), and others in 14 (0.57%); deaths occurred in three patients (0.12%). In multivariate analysis, the following were significant risk factors: a) for pancreatitis, age (< or = 60 yr), use of precutting technique, and failed clearing of biliary stones, and b) for hemorrhage, precut sphincterotomy and obstruction of the orifice of the papilla of Vater. CONCLUSIONS: The results of our study further contribute to the assessment of risk factors for complications related to ERCP/ES. It is crucial to identify high risk patients to reduce complications of the procedures.     

Treatment of chronic idiopathic urticaria and positive autologous serum skin test with cyclosporine: clinical and immunological evaluation.

This study evaluates the effectiveness and safety of cyclosporine (CsA) in the treatment of patients with chronic idiopathic urticaria with a positive autologous serum skin test (ASST), who fail to respond to conventional therapy, and requiring long-term oral steroid treatment. In a double-blind study, 40 adults were assigned randomly to receive CsA (5 mg/kg per day for 8 weeks and then 4 mg/kg per day for 8 weeks) or cetirizine (10 mg/day) and then they were followed up for 9 months. After 2 weeks, the study was opened because 16 patients (40%) had daily severe relapses requiring systemic steroids treatment. All of these patients had been receiving antihistamines and, therefore, all patients also were assigned to the CsA treatment regimen (5 mg/kg per day for 8 weeks and then 4 mg/kg per day for 8 weeks). The ASST and clinical severity score were evaluated before and after treatment. All of the 40 patients completed the 16-week CsA course without dropping out because of relevant side effects. In three patients, CsA was reduced by 0.5 mg/kg per day after the 1st month of treatment for a mild and reversible increase in serum creatinine. During CsA treatment, 20 patients had relapses resolving spontaneously (8 patients) or with antihistamines (12 patients). During the 9-month follow-up period, 22 patients had relapses resolving spontaneously (10 patients) or with antihistamines (12 patients). Only two patients failed to complete the study because of severe symptoms occurring after 4 and 7 days of follow-up and requiring long-term steroid treatment. After 9 months of follow-up, 16 patients were still in full remission. The clinical severity score of chronic idiopathic urticaria dropped significantly by the end of the 4th month of treatment (p = 0.002) as well as by the completion of follow-up (p = 0.007). The ASST was negative in 13 patients and positive in 3 of 16 patients, with total remission of symptoms. Significant score reduction also was observed in patients experiencing relapses that resolved spontaneously (p = 0.005) or with antihistamines (p = 0.03). These results show the long-term efficacy and tolerability of CsA in patients with severe chronic idiopathic urticaria, unresponsive to conventional treatments.     

Design of a superior cytokine antagonist for topical ophthalmic use

IL-1 is a key inflammatory and immune mediator in many diseases, including dry-eye disease, and its inhibition is clinically efficacious in rheumatoid arthritis and cryopyrin-associated periodic syndromes. To treat ocular surface disease with a topical biotherapeutic, the uniqueness of the site necessitates consideration of the agent’s size, target location, binding kinetics, and thermal stability. Here we chimerized two IL-1 receptor ligands, IL-1β and IL-1Ra, to create an optimized receptor antagonist, EBI-005, for topical ocular administration. EBI-005 binds its target, IL-1R1, 85-fold more tightly than IL-1Ra, and this increase translates to an ∼100-fold increase in potency in vivo. EBI-005 preserves the affinity bias of IL-1Ra for IL-1R1 over the decoy receptor (IL-1R2), and, surprisingly, is also more thermally stable than either parental molecule. This rationally designed antagonist represents a unique approach to therapeutic design that can potentially be exploited for other β-trefoil family proteins in the IL-1 and FGF families.The IL-1 cytokines (IL-1α and IL-1β) are master mediators of inflammatory responses (1). IL-1β also regulates immune function through its role in T helper 17 (Th17) cell differentiation and maintenance (2, 3). IL-1 action has been implicated in numerous human diseases, including rheumatoid arthritis, Muckle–Wells syndrome, gout, type 2 diabetes, and stroke (4). Several natural mechanisms directly oppose the actions of IL-1, including a soluble and cell surface decoy receptor (IL-1R2), a natural antagonist (IL-1Ra), and a soluble signaling receptor (IL-1R1) (5). Therapeutics that block IL-1 based on these mechanisms have been developed (6–8).Recently, a nonoptimized formulation of anakinra (methionyl-IL-1Ra; Kineret) was shown to provide clinical benefit in dry-eye disease (DED) (9). Moderate to severe DED is a chronic inflammatory condition of the corneal surface that results in pain, discomfort, and epitheliopathy (as measured by fluorescein staining). Inability to maintain a proper tear film over the cornea (owing to a variety of etiologies) results in desiccating stress, which drives an inflammatory cascade (10, 11). IL-1 plays a central role in the initiation and maintenance of this cascade, as well as in the pain mediated by the corneal neural plexus. IL-1α and IL-1β protein are elevated in the lacrimal gland, tears, and the ocular surface in all forms of dry-eye disease (12), and their mRNA is increased in both humans and in rodent disease models (13, 14). Genetic ablation of IL-1R1, the primary receptor for IL-1α and IL-1β, can block the development of corneal staining in a Sjögren syndrome corneal epitheliopathy model (15), and topically administered anakinra can improve surface epithliopathy in a mouse dry-eye model (14). IL-1β is essential for Th17 cell differentiation and maintenance, and Th17 cells are likely the main effector cells that induce epithelial damage (2, 3). Genetic and pharmacologic studies have shown that IL-1β mediates, and IL-1Ra blocks, normal, inflammatory, and neuropathic pain sensations (16–19).The development of a topical biotherapeutic agent for DED presents a protein engineering challenge, requiring optimization for the biology and topical route of administration. Given the rapid turnover of tear volume (10% min⁻¹) (20), blocking the tissue-associated receptor would be preferred over blocking tear-associated ligands, and the agent’s target affinity should be maximized to minimize clearance and the frequency of dosing. Considering the corneal epithelial barrier, smaller molecules would be preferable, and ideally the agent would have sufficient thermal stability to allow a room temperature formulation, to optimize patient compliance. We considered two designs for small, receptor-targeted agents: improved versions of IL-1Ra (∼17 kDa) and small-format (e.g., single-chain variable fragment) anti–IL-1R1 antibodies. Both designs can be expressed in Escherichia coli, but given the straightforward isolation of anakinra as a soluble protein after E. coli expression, and the fact that the existing clinical data are from the use of anakinra, we focused on improved receptor antagonists. Here we describe the creation of a unique type of chimeric molecule that meets the foregoing criteria.     

Level of HER2/neu amplification in primary tumours and metastases in HER2-positive breast cancer and survival after trastuzumab therapy

BackgroundThe level of HER2/neu amplification may vary widely in breast cancers with HER2/neu alteration. The clinical significance of this phenomenon is still unclear. This study was aimed to explore the level of HER2/neu amplification in primary tumours and metastases in HER2-positive metastatic breast cancer (MBC) and its potential impact on survival after a trastuzumab-containing therapy.MethodsWe retrospectively identified MBC patients treated with a trastuzumab-containing therapy and performed dual-colour FISH on tumour samples from either primary tumour and/or metastasis in a central laboratory.ResultsWe retrieved 110 tumour samples from 91 patients and included 79 tumour samples (primary = 56; metastasis = 23) from 63 patients in the final analysis. We found higher level of HER2/neu amplification in the metastases than in the primary tumours (median HER2/CEP17 ratio: 10.5 vs 7.0, respectively). In 69% of patients (n = 16) with two tumour samples, the level of HER2/neu amplification was higher in the metastasis than in the paired primary tumour (median HER2/CEP17 ratio: 10.9 vs 8.3, respectively, p = 0.004). The incremental gain in level of HER2/neu amplification was associated with significantly shorter OS after trastuzumab-containing therapy (p = 0.023, HR 1.014, CI95%: 1.002–1.025).ConclusionsThe level of HER2/neu amplification tends to increase from the primary tumour to the paired metastases in a significant proportion of patients with HER2-positive MBC. This phenomenon, although still not completely understood, could lead to a shorter OS after trastuzumab therapy.     

Effects of FCE 20700, a new PGE2 derivative,on gastric acid secretion and cytoprotective processes in man

Summary The pharmacodynamic effects of FCE20700, a new PGE₂ derivative, have been investigated in 6 healthy volunteers given single intragastric (i.g.) and intraduodenal (i.d.) doses of 1 and 2 mg and placebo, according to a double-blind, within — subjects design. For 30–270 min following i.g. administration the effect of FCE20700 on peptone-stimulated gastric acid secretion (AS) was assessed by i.g. titration, and serum gastrin (G) levels were also determined. For the same period after i.d. dosing the effect of the compound on pentagastrin-stimulated AS and on mucoproteins and bicarbonate content in the gastric juice was measured. Blood pressure (BP), heart rate and possible side-effects were monitored. Following i.g. administration there was a moderate, dose-related, significant inhibition of AS; significant inhibition of G levels was observed only after the highest dose. After i.d. administration there was a very modest through dose-related and significant inhibition of AS; a brief maximal increase in mucoproteins and in bicarbonate levels was apparent after the 1 mg dose. After i.d. but not after i.g. administration of 2 mg there was a modest but significant decrease in BP. No side-effects of clinical relevance were reported. The results appear to suggest a major activity of FCE20700 on cytoprotection rather than in inhibiting gastric acid secretion. The observed change in BP may indicate that after i.d. administration there will be some systemic effects of FCE20700.