Progression detection of stage I nonseminomatous testis cancer on surveillance: implications for the followup protocol

PURPOSE: To optimize followup in patients with stage I nonseminomatous testis cancer on surveillance we evaluated the contribution of each followup modality to the detection of progression as well as morbidity and mortality outcomes. MATERIALS AND METHODS: After orchiectomy 170 patients with clinical stage I nonseminoma were prospectively placed on a surveillance protocol. History, physical examination, serum tumor markers, abdominal and pelvic computerized tomography (CT), and chest x-ray were used for followup. The number of failures, methods and timing of progression detection, treatments required, mortality rate and subsequent contralateral primary tumors were recorded. RESULTS: The 170 surveillance patients were followed a median of 6.3 years. Within 2 years (median 6.9 months) postoperatively 48 patients (28.2%) had disease progression. History, physical examination, markers, CT and chest radiography provided the initial evidence of progression in 18 (37.5%), 34 (70.8%), 34 (70.8%), and 4 (8.3%) patients, respectively. Each modality was the only indicator of failure in 2 (4.2%), 4 (8.3%), 10 (20.8%) and 0 cases, respectively. Of the 170 patients 122 (71.8%) required no additional treatment beyond orchiectomy, 26 (15.3%) received 1 and 22 (12.9%) underwent more than 1 therapeutic modality. Only 1 patient (0.6%) died of disease. Contralateral tumors developed in 5 cases (2.9%) therapeutic a mean of 8.1 years after orchiectomy. CONCLUSIONS: In stage I nonseminoma patients, surveillance history, physical examination, tumor markers and abdominopelvic CT are necessary components of the followup protocol. Removal of routine chest x-ray from the protocol would not have changed progression detection. The initial surveillance visit must occur by 2 months postoperatively. Patients should be followed beyond 5 years and likely for life in addition to regular patient self-examination.     

Porous composites of hydroxyapatite‐filled poly[ethylene‐co‐(vinyl acetate)] for tissue engineering

A novel porous composite of hydroxyapatite/poly[ethylene‐co‐vinyl acetate)] (HAP/EVA) having better osteointegration was fabricated by gas foaming technique using a non toxic gas blowing agent intended for bone replacement applications. Combined techniques of scanning electronic microscopy (SEM) and X‐ray microcomputed tomography (µCT) analysis showed that the pore size and pore volume of the porous composite decrease with the increase of HAP content. The gravimetric analysis evidenced for good pore interconnectivity within the porous composites. Energy dispersive X‐ray analysis (EDX) studies inveterated the even scattering of Ca ions which in turn indicate the uniform dispersion of HAP particles in the composites. The significant gradation in Ca ion concentration seen in EDX studies is well accordance with the amount of HAP loading in the sample. Mechanical properties of the porous composite having different HAP content were measured to have the compressive strength varying from 1.06 to 2.2 MPa. Non‐cytotoxic character of the material was observed by the cytocompatibility studies. The metabolic activity of L929 cells seeded on the material assessed by [3‐(4,5‐dimethylthiazol)‐2‐yl]‐2,5‐diphenyltertrazolium bromide (MTT) assay was found to be 91.8%. The adhesion and migration of the cells inside the pore walls were visualized by confocal microscopy. Copyright © 2010 Society of Chemical Industry     

Interleukin-1 mediates a rapid inflammatory response after injection of adenoviral vectors into the brain

Adenovirus-mediated gene transfer into the brain is associated with significant inflammation and activation of anti-vector and anti-transgene immune responses that curtail the gene delivery of adenoviruses and therapeutic efficacy. Elucidating the molecular mediators of inflammatory and immune responses to adenoviruses injected into the brain should allow us to inhibit their inflammatory actions, thereby reducing vector clearance and enhance adenoviral-mediated gene transfer into the CNS. Cytokines are primary mediators of the immune response and are released during inflammation. Here we report for the first time that injection of replication-deficient adenovirus vectors into the cerebral ventricles of rats causes a rapid increase in body temperature. This fever response precedes any vector-encoded transgene expression and occurs with vectors encoding no transgene, as well as with vectors encoding a therapeutic transgene i.e., HSV1-thymidine kinase. No fever is detected after infection of the striatum, an important brain target in studies on neurodegeneration. After infection of the brain ventricles, CSF levels of immunoreactive tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta increase significantly (up to 300-fold). In the hypothalamus, the locus of thermoregulation in the brain, only IL-1beta and IL-6 are significantly elevated. A neutralizing TNF-alpha antibody has no effect on adenovirus-induced fever. However, pretreatment with either the IL-1 receptor antagonist or the cyclooxygenase inhibitor flurbiprofen completely abolishes adenovirus-induced fever, suggesting that IL-1 and prostaglandins are direct mediators of this response. These results are the first to demonstrate that IL-1, but not TNF-alpha, is the main mediator of a very early inflammatory response to adenovirus in the brain.     

Physical and functional interactions between the herpes simplex virus UL15 and UL28 DNA cleavage and packaging proteins

Herpes simplex virus (HSV) DNA is cleaved from concatemers and packaged into capsids in infected cell nuclei. This process requires seven viral proteins, including UL15 and UL28. UL15 expressed alone displays a nuclear localization, while UL28 remains cytoplasmic. Coexpression with UL15 enables UL28 to enter nuclei, suggesting an interaction between the two proteins. Additionally, UL28 copurified with UL15 from HSV-infected cells after ion-exchange and DNA affinity chromatography, and the complex sedimented as a 1:1 heterodimer upon sucrose gradient centrifugation. These findings are evidence of a physical interaction of UL15 and UL28 and a functional role for UL15 in directing UL28 to the nucleus.