The role of cytotoxic T-lymphocytes in the prevention and immune surveillance of tumors— lessons from normal and immunodeficient mice

The idea of immunological surveillance against cancer has existed for nearly 100 years but as no conclusive evidence has yet been published the importance of the cellular immune defense in the detection and removal of incipient or existing tumors is still a hotly debated subject. However, in order to select a relevant immunotherapeutic strategy in the treatment of cancer, a fundamental understanding of the basic immunologic conditions under which a tumor develops and exists is a prerequisite. Therefore, a murine model was set up that we hoped would enable us to confirm or reject the theory of immunological surveillance. A large panel of methylcholanthrene induced tumors was established in T-cell immunodeficient nude mice and congenic normal mice to study the influence of the immune system on developing tumors. As nude mice developed tumors fastest and with the highest incidence, we concluded that in this model the immune system constituted a 'tumor-suppressive factor' delaying and sometimes abrogating tumor growth, i.e. performing immune surveillance. Immunogenicity of the tumors was assessed by transplantation back to normal histocompatible mice. Tumors originating from the immunodeficient nude mice turned out to be far more immunogenic than tumors from normal mice, resulting in a high rejection rate. CD8+ cytotoxic T cells were found to be indispensable for this rejection, leading to the conclusion that the cytotoxic T cells perform immune selection in normal mice, eliminating immunogenic tumor cell variants in the incipient tumor. In this review, we discuss the difficulties facing immunotherapy when conclusions are drawn from the presented observations and hypotheses.     

肝动脉注射阿霉素温度敏感脂质体的制剂研究

自Yatvin等创造温度敏感脂质体以来,许多研究结果证明它是靶治疗的良好载体。Chuang等认为根据荷瘤肝脏的血流分布,设想将温度敏感脂质体通过肝动脉注射滞留于肝动脉,结合人为控制释放脂质体中所包封的药物,有可能提高肝脏肿瘤中的药物浓     

A study of adaptive responses in cell signaling in migraine and cluster headache: correlations between headache type and changes in gene expression

The project was an investigation into whether changes in the expression of G-proteins underlie altered cell signaling in migraine and cluster headache. The basis for this assumption is that altered physiological responses are seen in migraineurs and that differences in cell signaling are detected biochemically in various cell types isolated from peripheral blood. Levels of three G-protein mRNAs—Gsα, Giα, and Gqα were quantified in lymphocytes from clinically well-defined migraine and cluster headache patients and correlated with headache type and influence of drug treatment. Giα mRNA was reduced by 50% in all migraine patients compared with control subjects; similarly in patients with or without aura, in patients with a migraine headache at the time of sampling, and patients in a quiescent state. No reduction in the levels of Gsα or Gqα mRNA were seen in migraine patients. A smaller reduction was seen in cluster headache patients, most marked in those without medication. Levels of Gsα. mRNA were significantly reduced in cluster headache patients compared with migraine patients. The marked down-regulation of Giα mRNA in migraine, whether quiescent or acute, indicates either an adaptive response to headache in this group of patients or that low levels of Giα mRNA make individuals more susceptible to migraine.     

A randomized, double-blind, parallel-group study comparing the analgesic effect of etoricoxib to placebo, naproxen sodium, and acetaminophen with codeine using the dental impaction pain model

OBJECTIVE: To compare the overall analgesic effect, including time to onset, peak and duration of effect for etoricoxib 120 mg, a new COX-2 selective inhibitor, in patients with acute pain to that of placebo. Naproxen sodium 550 mg and acetaminophen/codeine 600/60 mg were the active comparators. METHODS: A total of 201 patients with moderate to severe pain following surgical extraction of > or = 2 third molars, of which at least the mandibular tooth was impacted, were randomly allocated to receive single oral doses of placebo (n = 50), etoricoxib 120 mg (n = 50), naproxen sodium 550 mg (n = 51), or acetaminophen/codeine 600/60 mg (n = 50). The endpoints included total pain relief over 8 hours (TOPAR8, primary end point), sum of pain intensity difference over 8 hours, patient's global evaluation, onset, peak, and duration of analgesia. RESULTS: Etoricoxib 120 mg had a significantly greater least squares (LS) mean TOPAR8 score than placebo (20.9 vs 5.4; P < 0.001) and acetaminophen/codeine 600/60 mg (20.9 vs 11.5; P < 0.001), and a similar LS mean TOPAR8 score to naproxen sodium 550 mg (20.9 vs 21.3). All three active treatments had rapid onset of analgesia, median time approximately 30 minutes. The duration of analgesic effect, defined as median time to rescue medication use, was >24 hours for etoricoxib, 20.8 hours for naproxen sodium, 3.6 hours for acetaminophen/codeine, and 1.6 hours for placebo. DISCUSSION: Etoricoxib is a new COX-2 selective inhibitor under development for treatment of osteoarthritis, rheumatoid arthritis, and acute pain. In this study, etoricoxib 120 mg provided rapid and long-lasting pain relief to patients with moderate-to-severe postdental surgery pain. Etoricoxib was generally well tolerated.     

Clinical Impact of Tumour Involvement of the Anastomotic Doughnut in Oesophagogastric Cancer Surgery

INTRODUCTION

Published colorectal cancer surgery data suggest no role for the analysis of the anastomotic doughnuts following anterior resection. The usefulness of routine histological analysis of the upper gastrointestinal doughnut is not clear. Our study assessed the impact of cancer involvement of the doughnut on clinical practice. Factors associated with doughnut involvement and the effect on patients'' survival were also analysed.

PATIENTS AND METHODS

The clinicopathological details of 462 patients who underwent potentially curative oesophagogastrectomy for cancer with a stapled anastomosis between 1994 and 2006 in two specialist centres were retrospectively analysed. Univariate, multivariate and survival analyses were carried out.

RESULTS

Approximately 5% of doughnuts (22 of 462) were histologically involved with cancer. Microscopic involvement of the proximal resection margin, local lymph node metastasis and lymphatic invasion within the main resected specimen were independently associated with doughnut involvement (all P < 0.05). However, these three factors taken together failed to predict doughnut involvement. Doughnut involvement was an independent adverse prognostic factor for overall survival (P = 0.0013).

CONCLUSIONS

In contrast to findings in colorectal surgery, doughnut involvement with cancer appears to have useful prognostic information following oesophagogastrectomy. Routine histological analysis of upper gastrointestinal doughnuts is justified. Doughnut involvement could potentially strengthen the indications for adjuvant therapy in the future.     

Hospital treatment -is it affordable? A structured cost analysis of vaginal deliveries and planned caesarean sections

Introduction

The analysis of cost effectiveness in hospitals is as difficult as treating the patients properly. We are yet not able to answer the simple question of what costs are caused by a certain diagnosis and its treatment during an average hospital stay.

Methods

To answer some issues of the global problem of cost effectiveness during hospitalisation, we analysed the costs and the cost structure of a normal obstetrical hospital stay during an uncomplicated vaginal delivery and a planned caesarean section. Cost data was collected and summarized from the patients file, the hospital''s computer system gathering all cost centres, known material expenses and expenses of non obstetrical medical services.

Results

For vaginal deliveries/planned caesareans we can calculate with a surplus of about 83 €/1432 €. About 45% of the summarized costs are calculated on a reliable database.

Discussion

The introduction of the DRG based clearing system in Germany has aggravated the discussion on cost effectiveness. Our meticulous work-up of expenses excluded personal precautionary costs and personnel costs of documentation because no tools are described to depict such costs. If we would add these costs to the known expenses of our study, we strongly suspect that hospital treatment of vaginal deliveries or planned caesarean sections is not cost effective.     

Increased urinary nitric oxide oxidation products in children with active coeliac disease

BACKGROUND: Nitric oxide (NO) production catalyzed by iNOS (inducible NO synthase) is thought to take place mainly in macrophages after activation by inflammatory mediators. NO is subsequently oxidized to nitrite and nitrate, which are excreted in urine. The concentration of inflammatory mediators in small bowel biopsy specimens from patients with coeliac disease is increased. The latter could induce increased NO production by stimulation of intestinal macrophage iNOS, resulting in high levels of urinary NO oxidation products, nitrite and nitrate (NOx). AIM: In the present study we evaluated the urinary NOx/creatinine ratios in children with active coeliac disease (n = 22), coeliac disease patients on a gluten-free diet (n = 9), healthy (n = 11) and sick control children (n = 18). METHODS: The Griess reagent method was used for measuring urinary NOx. RESULTS: Median NOx/creatinine ratios of active coeliac disease patients, coeliac disease patients on a gluten-free diet, healthy and sick control patients were 1.21, 0.19, 0.10 and 0.13 mmol/mmol, respectively. All active coeliac disease patients showed increased NOx/ creatinine ratios. Urinary NOx/creatinine ratios of the active coeliac disease patients were significantly higher than those of healthy controls (p < 0.0001), sick controls (p < 0.0001) and coeliac disease patients on a gluten-free diet (p < 0.0001). CONCLUSION: The urinary NOx/creatinine ratio is increased in patients with active coeliac disease and reverts to normal on a gluten-free diet.     

Comparison of rofecoxib and oxycodone plus acetaminophen in the treatment of acute pain: a randomized, double-blind, placebo-controlled study in patients with moderate to severe postoperative pain in the third molar extraction model

BACKGROUND: Opiates, acetaminophen, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2-selective inhibitors such as rofecoxib are used in the treatment of acute pain because of their anti-inflammatory and/or analgesic properties. Rofecoxib has demonstrated an improved gastrointestinal safety profile compared with nonselective NSAIDs. OBJECTIVE: The aim of this study was to compare the analgesic efficacy and tolerability profile of rofecoxib 50 mg with those of the centrally acting, nonsalicylate, opiate/nonopiate analgesic combination oxycodone/acetominophen 5/325 in patients with pain after dental surgery. METHODS: In this randomized, double-blind, placebo- and active comparator-controlled study, patients experiencing moderate to severe postoperative pain after extraction of > or =2 third molars (including > or =1 mandibular impaction) received a single oral dose of rofecoxib 50 mg, oxycodone/acetaminophen 5/325 mg, or placebo. End points included total pain relief over 6 hours (TOPAR6, the primary end point) and 4 hours (TOPAR4), patient's global assessment of treatment at 6 hours (GLOBAL6) and 24 hours (GLOBAL24), summed pain intensity difference over 6 hours (SPID6), onset of analgesic effect (time to perceptible/meaningful pain relief, using a 2-stopwatch method), peak pain relief (PEAKPR), peak pain intensity difference (PEAKPID), and duration of analgesic effect (time to use of rescue analgesia). RESULTS: Two hundred twelve patients (63% female, 37% male; 76% white, 24% other; mean [SD] age, 20.9 [4.4] years; age range, 16-41 years) were enrolled in the study and received a single oral dose of rofecoxib 50 mg (n = 90), oxycodone/acetaminophen 5/325 mg (n = 91), or placebo (n = 31). The analgesic effect of rofecoxib was significantly greater than that of oxycodone/acetaminophen at P < 0.001 for TOPAR6, TOPAR4, GLOBAL6, GLOBAL24, and SPID6; at P < 0.010 for PEAKPR and PEAKPID; and at P < 0.001 for median time to use of rescue analgesia. Significantly fewer patients in the rofecoxib group (72.2%) took rescue analgesia within 24 hours postdose compared with the oxycodone/acetaminophen group (94.5%; P < 0.001) and the placebo group (96.8%; P < 0.02). Both active treatments were similar with respect to onset of analgesic effect. Both were generally well tolerated; the overall incidence of adverse experiences in the rofecoxib, oxycodone/acetaminophen, and placebo groups was 51.1%, 64.8%, and 48.4%, respectively. Rofecoxib was associated with a significantly lower incidence of nausea (18.9% vs 39.6%; P < 0.001) and vomiting (6.7% vs 23.1%; P < 0.001) compared with oxycodone/acetaminophen. CONCLUSIONS: In study patients with moderate to severe pain after dental surgery, rofecoxib 50 mg had a greater analgesic effect than oxycodone/acetaminophen 5/325 mg and was associated with less nausea and vomiting.     

Severe perinatal thrombosis in double and triple heterozygous offspring of a family segregating two independent protein S mutations and a protein C mutation

Molecular genetic and phenotypic analyses were performed in a highly unusual case of combined protein S and protein C deficiency manifesting in a family in which a child had died perinatally from renal vein thrombosis. Antenatal diagnosis in a second pregnancy was initially performed by indirect restriction fragment length polymorphism (RFLP) tracking using a neutral dimorphism within the PROS gene and served to exclude severe protein S deficiency. Am umbilical vein blood sample at 22 weeks gestation showed isolated protein C deficiency. This pregnancy proceeded to a full-term delivery without thrombotic complications. Molecular genetic analysis of the PROC and PROS gene segregating in the family then yielded one PROC gene lesion in the father and two PROS gene lesions, one in each parent. These lesions were shown to segregate with the respective deficiency states through the family pedigree. Analysis of DNA from paraffin-embedded liver tissue taken from the deceased child showed the presence of both PROS mutations, as well as the PROC mutation. Genotypic analysis of the second child showed a PROC mutation, but neither PROS mutation consistent with its possession of normal protein S levels and a low/borderline protein C level. Antenatal diagnosis was then performed in a third pregnancy by direct mutation detection. However, although the fetus carried only the paternal PROS and PROC gene lesions, the child developed renal thrombosis in utero. It may be that a further genetic lesion at a third locus still remains to be defined. Alternatively, the intrauterine development of thrombosis in this infant could have been caused, at least in part by a transplacental thrombotic stimulus arising in the protein S-deficient maternal circulation. This analysis may, therefore, serve as a warning against extrapolating too readily from genotype to phenotype in families with a complex thrombotic disorder.