Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment

The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumor progression and metastasis. Of particular interest in this setting is interleukin-1 (IL-1), a pleiotropic cytokine with numerous roles in both physiological and pathological states. It is known to be up regulated in many tumor types and has been implicated as a factor in tumor progression via the expression of metastatic and angiogenic genes and growth factors. A number of studies have reported that high IL-1 concentrations within the tumor microenvironment are associated with a more virulent tumor phenotype. Solid tumors in which IL-1 has been shown to be up regulated include breast, colon, lung, head and neck cancers, and melanomas, and patients with IL-1 producing tumors have generally bad prognoses. The exact mechanisms by which IL-1 promotes tumor growth remain unclear, though the protein is believed to act via induction of pro-metastatic genes such as matrix metalloproteinases and through the stimulation of adjacent cells to produce angiogenic proteins and growth factors such as VEGF, IL-8, IL-6, TNFα, and TGFβ. The IL-1 receptor antagonist (IL-1ra) is a naturally occurring inhibitor to IL-1 and acts by binding to the IL-1 receptor without activating it. The protein has been shown to decrease tumor growth, angiogenesis, and metastases in murine xenograft models. Our focus in this review is to summarize the known data on the role of IL-1 in tumor progression and metastasis and the use of IL-1 inhibition as a novel therapeutic approach in the treatment of solid organ malignancies.     

Brain protection at the blood-cerebrospinal fluid interface involves a glutathione-dependent metabolic barrier mechanism.

The choroid plexuses (CPs) form a protective interface between the blood and the ventricular cerebrospinal fluid (CSF). To probe into the pathways by which CPs provide brain protection, we sought to evaluate the efficiency of glutathione conjugation in this barrier as a mechanism to prevent the entry of blood-borne electrophilic, potentially toxic compounds into the CSF, and we investigated the fate of the resulting metabolites. Rat CPs, as well as human CPs from both fetal and adult brains, displayed high glutathione-S-transferase activities. Using an in vitro model of the blood-CSF barrier consisting of choroidal epithelial cells cultured in a two-chambered device, we showed that glutathione conjugation can efficiently prevent the entry of 1-chloro-2,4-dinitrobenzene (CDNB) into the CSF, a model for electrophilic compounds. The duration of this enzymatic protection was set by the concentration of CDNB to which the epithelium was exposed, and this barrier effect was impaired only on severe epithelial intracellular glutathione and cysteine depletion. The conjugate was excreted from the choroidal cells in a polarized manner, mostly at the blood-facing membrane, via a high-capacity transport process, which is not a rate-limiting step in this detoxification pathway, and which may involve transporters of the ATP-binding cassette c(Abcc) and/or solute carrier 21 (Slc21) families. Supplying the choroidal epithelium at the blood-facing membrane with a therapeutically relevant concentration of N-acetylcysteine sustained this neuroprotective effect. Thus, glutathione conjugation at the CP epithelium coupled with the basolateral efflux of the resulting metabolites form an efficient blood-CSF enzymatic barrier, which can be enhanced by pharmacologically increasing glutathione synthesis within the epithelial cells.     

Evaluation of a new generation of plastic evacuated blood-collection tubes in clinical chemistry, therapeutic drug monitoring, hormone and trace metal analysis.

Polyethylene terephthalate (PET) tubes have several advantages over glass tubes: they are unbreakable, lighter and more easily disposed of. Despite a steady increase in their use and an expansion of the range of available tubes, few studies validating their use have been published in the literature. This paper describes the various studies that have been performed to compare VENOJECT glass, VENOSAFE PET and VENOSAFE PET/heparin tubes for the assay of a panel of analytes in routine clinical chemistry, immunochemistry, hormone and tumor marker analysis and trace metal determination. These studies demonstrate that VENOSAFE PET tubes are a suitable alternative to glass tubes.     

Small cell lung cancer in Norway. Should more patients have been offered surgical therapy?

OBJECTIVE: The final outcome of patients with small cell lung cancer (SCLC) is poor with an overall 5-year survival rate of less than 10%. Therefore, the question of surgery in patients with a technically-operable solitary tumor has been raised. The purpose of this study was to identify the proportion of patients with operable SCLC and to assess the prognosis of different treatment strategies. For patients who were operated, we compared the resection specimens from patients with more than 5-year survival with those with shorter survival to see whether the specimens belonged to different subclasses of SCLC. METHODS: In Norway all clinical and pathologic departments submit reports on cancer patients to the Cancer Registry. The Registry also has a law-regulated authority to collect supplemental information regarding diagnosis, treatment and outcome for all cancer patients from the hospitals in charge. All reports on patients diagnosed as having SCLC in limited disease or unknown stage during the time interval 1993-1999 were reviewed. Patients with a T2-tumor, in whom a pneumonectomy would have to be performed, were classified as potentially operable. Five-year relative survival was calculated for patients diagnosed in 1993-1997. RESULTS: During the actual period 2442 individuals with SCLC were identified. The majority was treated with conventional chemotherapy or concurrent chemoradiotherapy while 38 underwent surgical therapy. Following reclassification of 697 patients reported to have limited disease or unknown stage 180 were judged to be in stage I. In addition to the 38 resected patients 14 were considered fit for surgery technically and medically while 97 were found to be potentially operable treatment modalities apart from surgery yielded a 5-year survival rate <7%. For stage I (N=96) the rate was 11.3% in conventionally treated patients compared to 44.9% for those who underwent surgical resection. By pathological review of surgical specimens a diagnosis of SCLC was confirmed in all patients treated by surgery in the groups with long and short survival. CONCLUSION: This investigation demonstrates that patients with SCLC having a peripherally located tumor should be referred to surgery, as long time survival is far better than for conventionally treated patients.     

Classification of patients with whiplash associated disorders (WAD): reliable and valid subgroups based on the Multidimensional Pain Inventory (MPI-S).

BACKGROUND: Classification of patients with chronic whiplash associated disorders (WAD) into homogenous subgroups is an important objective in order to tailor interventions and to control for subgroup differences when evaluating treatment outcome. AIMS: The aims of this study were to investigate if it was possible to replicate and describe the three cluster solution and profiles found in other pain groups and describe cluster profiles based on self-reported Multidimensional Pain Inventory-scores for patients with WAD three months after the injury, describe characteristics of the clusters in relation to disability, self-efficacy and coping at the same point in time and to validate the cluster solution by comparing clusters in disability, self-efficacy and coping over time. METHODS: Ninety-one WAD-patients three months after the accident took part in the study. The measures used were the Multidimensional Pain Inventory-Swedish version (MPI-S), The Self-Efficacy Scale, The Coping Strategies Questionnaire and The Pain Disability Index. Cluster analysis was conducted for the total sample MPI-S subscale scores. RESULTS: The adaptive copers cluster represented 42% of the sample, dysfunctional 34% of the sample, and interpersonally distressed 24% of the sample. The external validation of cluster solution showed that there were several significant differences between clusters in self-efficacy, disability and coping measures. There was also a significant interaction effect (clusterxtime) in disability (PDI). Patients in dysfunctional cluster reported a decreased disability over time. CONCLUSIONS: These results support the presence of different subgroups among patients with whiplash associated disorders. This classification can be seen as a complement to a classification based on medical condition.