Dynamical modeling of pro- and anti-inflammatory cytokines in the early stage of septic shock.

A dynamical model of the pathophysiological behaviors of IL18 and IL10 cytokines with their receptors is tested against data for the case of early sepsis. The proposed approach considers the surroundings (organs and bone marrow) and the different subsystems (cells and cyctokines). The interactions between blood cells, cytokines and the surroundings are described via mass balances. Cytokines are adsorbed onto associated receptors at the cell surface. The adsorption is described by the Langmuir model and gives rise to the production of more cytokines and associated receptors inside the cell. The quantities of pro and anti-inflammatory cytokines present in the body are combined to give global information via an inflammation level function which describes the patient's state. Data for parameter estimation comes from the Sepsis 48 H database. Comparisons between patient data and simulations are presented and are in good agreement. For the IL18/IL10 cytokine pair, 5 key parameters have been found. They are linked to pro-inflammatory IL18 cytokine and show that the early sepsis is driven by components of inflammatory character.

[Neuroendocrine carcinoma of the digestive tract: a literature review]. / Carcinome neuro-endocrine du tractus digestif : revue de la littérature.

Neuroendocrine carcinoma is a rare and agressive malignant tumor, mainly developing at the expense of the respiratory and of the digestive tract. Among the digestive tract, appendix, small bowel, and pancreas are the preferential sites of involvement, other locations have been more rarely reported. Neuroendocrine digestive tumors may present with various symptoms in relationship with their localization and a complex pathophysiology. Diagnosis is often made at an advanced stage, explaining partly the bad prognosis of these tumors. The optimal management of digestive neuroendocrine tumors is rendered difficult by their rarity and by a low number of randomized trials. We review the literature regarding epidemiologic and prognostic features of these rare tumors, their diagnostic and therapeutic care. Potential complications are also discussed.

[Single center experience of (18F)-fluorocholine positron emission tomography: analysis of its impact on salvage local therapy in patients with prostate adenocarcinoma]. / Expérience monocentrique de la tomographie par émission de positons à la (18F)-fluorocholine : analyse de son impact sur les indications de traitement local de rattrapage dans la prise en charge des adénocarcinomes prostatiques.

PURPOSE: To assess usefulness of ((18)F)-fluorocholine positron emission tomography (PET) for localizing relapse in patients with biochemical relapse from prostate adenocarcinoma and its impact on indications of salvage local therapy. PATIENTS AND METHODS: An ((18)F)-fluorocholine PET coupled with computed tomography was performed in 28 patients with biochemical progression from prostate adenocarcinoma. At the time of ((18)F)-fluorocholine PET, median prostate specific antigen (PSA) was 3.0 ng/mL (from 0.34 to 93 ng/mL) and 17 patients (60.7%) received hormone therapy. Eighteen patients from this cohort were potentially candidates to salvage radiotherapy. RESULTS: A pathologic uptake was shown in 11 patients (39.3%) and 17 patients (60.7%) had no pathologic uptake. Median PSA was 2.4 ng/mL (0.33 to 36 ng/mL) in case of negative ((18)F)-fluorocholine PET, versus 6.75 ng/mL (1.21 to 93 ng/mL) in case of pathologic uptake (P=0.04). Among the 17 patients candidates to salvage radiotherapy, ((18)F)-fluorocholine PET helped deciding for salvage radiotherapy in five patients, since it showed only centropelvic pathologic uptake (27.7%). In one patient, it showed metastatic and radiotherapy was contraindicated. After prostatectomy, ((18)F)-fluorocholine PET was positive in only one patient candidate to salvage radiotherapy (9.1%), showing anastomotic relapse. CONCLUSION: ((18)F)-fluorocholine was positive in about a third of patients with biochemical progression. Its clinical impact is being prospectively investigated.

[Positron emission tomography in the management of cervix cancer patients]. / Tomographie par émission de positons dans la prise en charge des cancers du col de l'utérus.

Since its introduction in clinical practice in the 1990's, positron emission tomography (PET), usually with (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), has become an important imaging modality in patients with cancer. For cervix carcinoma, FDG-PET is significantly more accurate than computed tomography (CT) and is recommended for loco-regional lymph node and extrapelvic staging. The metabolic dimension of the technique provides additional prognostic information. Ongoing studies now concentrate on more advanced clinical applications, such as the planning of radiotherapy, the response evaluation after the induction of therapy, the early detection of recurrence. Technical innovations, such as PET cameras with better spatial resolution and hybrid positron emission tomography/computed tomography (PET-CT), available now on the whole territory, provide both anatomic and metabolic information in the same procedure. From the point of view of biological metabolism, new radiopharmaceutical probes are being developed. Those hold promise for future refinements in this field. This article reviews the current applications of FDG-PET in patients with cervix cancer.

[Radiotherapy of maxillary sinus carcinoma: state of art]. / Radiothérapie des carcinomes des sinus maxillaires: l'état de l'art.

Maxillary sinus carcinomas are rare malignancies of the face, characterized by high local relapsing rate. Modalities of treatment are without consensus and respective roles of radiation therapy and surgery remain controversial. As those malignancies are often diagnosed at locally advanced stage, radiation therapy may frequently be used for patients having unresectable advanced disease. Nevertheless, surgery remains treatment of choice for more localized malignancies, in association with systematic postoperative radiotherapy. For those patients whose prognosis remains pejorative, it is necessary to precise the role of radiotherapy in first intention for inoperable tumors, to define necessity for nodal treatment performing and evaluate the place of neoadjuvant or concomitant chemotherapy in a multimodal strategy.

The use of computed tomography in radiotherapy treatment planning for breast cancer. How does conventional radiotherapy planning compare with virtual?

PURPOSE: To compare, in terms of ballistics and dosimetry, a conventional and a virtual simulation in 14 patients without changing the set-up. PATIENTS AND METHODS: 14 women with breast cancer were treated with postoperative radiotherapy from October 2003 to November 2004. Whole breast irradiation alone was indicated (50 Gy at International Committee on Radiation Units [ICRU] point in 25 fractions over 5 weeks) with, in some cases, an additional boost of 16 Gy to the tumor bed--that was not taken into account in this study. After CT scan, tangential fields were conventionally simulated using a Mecaserto Phebus-type simulator-CT scan. The planning target volume (PTV) was the clinical target volume (CTV) expanded with an additional margin of 1 cm in all directions but towards the skin. Both the lungs and the heart were delineated as organs at risk. Dosimetries were computed for the two beams arrangements i.e. 2D conventional and 3D virtual. RESULTS: The mean age of 14 women was 51.4 years (range 26-65). Laterality was the left breast for 6 patients and the right for 8. Few differences were noticeable in terms of gantry angles. The 3D medial fields were more medial with a mean of 8 mm (range 0-15). The 3D lateral fields were more posterior with a mean difference of 8 mm (range 0-25). The dosimetry analysis showed that, with regard to conventional simulations, at least 95% of the CTV received in all cases > 95% of the prescribed dose. However, in 8 out of 14 patients (57%), 15% of the PTV received < 95% of the prescribed dose. The ICRU 50 quality criterion that at least 95% of the PTV (PTV(95%)) should receive at least 95% of the prescribed dose was never met with conventional simulation. In the case of virtual simulation, the ballistics of the treatment were designed to meet the ICRU quality criterion and thus the PTV95% was higher here than with the conventional simulation by a mean of 17.6% +/- 9.7%. The percentage of CTV receiving a dose higher than 107% of the prescribed dose was 21.3% +/- 12% with conventional and 24% +/- 11% with virtual simulation. CONCLUSION: The high incidence of breast cancer, the essential role of radiotherapy in its treatment and the potential ensuing toxicity explain why so many studies are devoted to the improvements brought to the techniques of this treatment. The virtual planning of the treatment, however, comes up against many difficulties. The countering of the CTV is complex and necessitates a combination of clinical examination and imagery. The choice of margins around the CTV has not been standardised and is largely dependent both on the equipment used and the quality control methods.

[Prostate cancer and disseminated intravascular coagulation: review of the literature]. / Cancer de prostate et coagulation intravasculaire disséminée: une revue de la littérature.

Disseminated intravascular coagulation is a rare complication of prostatic cancer evolution. Occurring on hormonorefractory phase, it remains most often infraclinic. Cases of acute, severe intravascular disseminated coagulation at first presentation are life-threatening because of hemorragic and thrombotic complications, justifying emergency medical treatment. In the light of a review of literature, we insist on epidemiological features, physiopathology and therapeutics of intravascular disseminated coagulation. In spite of a pejorative prognosis, this could help to achieve a period of remission.

[Cancer chemotherapy of the upper aerodigestive tract]. / Chimiothérapie des cancers des voies aérodigestives supérieures.

Tumours of the upper aerodigestive tract represent the sixth most frequent kind of cancer in France and throughout the world. If the localised forms may be controlled in the long run in two thirds of cases by surgery or radiotherapy, only one third of locally advanced forms are accessible to a cure after association from radiotherapy and chemotherapy. Besides, with a median of survival less than six months, metastatic tumours present a catastrophic spontaneous prognosis among patients with a medical ground that is often heavily deteriorated by prolonged exposure to alcohol and tobacco. Thus, there is a necessity to implement adapted therapeutic strategies to each patient and based on satisfactory proof levels of effectiveness. Optimisation of existing chemotherapy protocols and development of new therapies, in particular of targeted therapies, remain an important objective in the hope to improve results of treatments in locally advanced and metastatic cancers of the oral cavity.

[Favorable outcome of gemcitabine-induced acute respiratory distress syndrome]. / Syndrome de détresse respiratoire aiguë à la gemcitabine d'évolution favorable.

Gemcitabine is a new important drug used to treat solid tumors including non-small cell lung cancer, pancreatic, bladder and breast cancers. Myelosuppression is the most common adverse effect. Pulmonary toxicity is rare and usually mild and self-limiting with acute dyspnea. Severe pneumonitis and potentially fatal acute respiratory distress syndrome (ARDS) have been described in patients treated for a non-small cell lung cancer. We report a case of gemcitabine-induced ARDS in a 72-year old patient treated with gemcitabine and cisplatin for a bladder cancer without lung metastasis. Administration of high doses of corticosteroids led to a prompt symptomatic improvement.

[Comparison of classic simulation and virtual simulation in breast irradiation: prospective study on 14 patients]. / Comparaison simulation classique-simulation virtuelle au cours d'une irradiation mammaire: étude prospective sur 14 patientes.

PURPOSE: To compare conventional 2D simulation and virtual simulation on 14 patients with breast cancer. PATIENTS AND METHODS: Patients were simulated for treatment using standard procedure. They subsequently underwent CT scan in the treatment position. The CTV was defined as breast tissue. The PTV was obtained by adding a 3D margin of 1 cm around CTV. Organs at risk (lungs and heart) were outlined. Ballistics and dose distribution obtained with the two planning methods were compared. RESULTS: With conventional simulation, 95% of CTV received 95% of the dose prescribed. Virtual simulation significantly improved dosimetric coverage of PTV without increasing irradiation volume of lung and heart. In 2D simulation, using three slices allowed optimisation by adjusting wedge angle. The five-slice plan was a much better predictor of the maximum dose regions when compared to the three-slice plan. Using entire CT data didn't give any benefit. CONCLUSION: Variations in CTV delineation and PTV definition limit interest of virtual simulation. In classic simulation, a 5 CT slice-plan can be used to optimise dose distribution.

[Combined chemotherapy and radiation therapy for intracranial germinomas. The Val-de-Grace hospital experience]. / Intérêt de la chimiothérapie néoadjuvante dans le traitement des séminomes purs intracérébraux: expérience de l'hôpital du Val-de-Grâce.

Optimal management of intracranial germinomas remains controversial. Focal irradiation to the primary tumor followed by prophylactic craniospinal radiotherapy represents the traditional treatment resulting in excellent long-term survival but potential late effects. To decrease late effects related to extensive fields of radiotherapy, combined chemotherapy and irradiation has been tested with reduced volumes and doses of radiation therapy. We report our experience about four patients successfully treated by neoadjuvant chemotherapy with carboplatin and etoposide followed by radiotherapy delivering 26 to 36 Gy to the whole brain and 36 to 50 Gy to the initial tumor volume.

A double-blind placebo-controlled evaluation of sublingual immunotherapy with a standardized ragweed extract in patients with seasonal rhinitis. Evidence for a dose-response relationship.

BACKGROUND: There is a growing consensus on the benefits of sublingual-swallow immunotherapy in the treatment of allergic diseases. METHODS: This randomized, double-blind placebo-controlled study was undertaken to assess the efficacy and safety of sublingual immunotherapy with standardized ragweed pollen extract tablets, in patients with an allergic rhinitis. A total of 110 outpatients were randomized (immunotherapy [I]: 55; placebo [P]: 55), of whom 99 were analyzable for efficacy (I: 48; P: 51) and 106 analyzable for safety (I: 53; P: 53). After a 28-day progression phase, the patients received a maintenance treatment during 6.5 months. Efficacy variables included a global assessment of efficacy (patient/ investigator), symptoms and medication scores as well as the frequency of asthma attacks. RESULTS: In the active treatment group, 43 patients completed the study, versus 49 on placebo. During the whole period of pollination, the difference favoring immunotherapy was highly significant for the global assessment by the patient (p = 0.004) and by the investigator (p = 0.005). Adverse reactions were reported more often in the active treatment but mild or moderate, and they abated after dose adjustment. A subgroup analysis of those patients receiving the highest dose of immunotherapy (3 tablets 3 times a week) showed a highly significant response for rhinitis and conjunctivitis total scores by comparison to lower dosages. CONCLUSION: This study confirms the efficacy and safety of sublingual immunotherapy and strongly suggests a dose-response relationship.

Sublingual-swallow immunotherapy (SLIT) in patients with asthma due to house-dust mites: a double-blind, placebo-controlled study.

A double-blind, placebo-controlled study was carried out in 85 patients with a well-documented history of perennial asthma caused by house-dust mites. Patients received either placebo or sublingual immunotherapy (SLIT) with a standardized Dermatophagoides pteronyssinus (DP)-D. farinae (DF) 50/50 extract. After a run-in period, patients received increasing doses up to 300 IR every day for 4 weeks and then three times a week for the following 24 months. The cumulative dose was about 104000 IR, equivalent to 4.2 mg Der p 1 and 7.3 mg Der f 1. Symptom and medication scores and respiratory function were assessed throughout the trial. Serum specific IgE and IgG4 were determined before SLIT (t0) and after 6 (t1), 11 (t2), 17 (t3), and 25 months (t4) of SLIT. Mite exposure was evaluated at t0, t2, and t4 by semiquantitative guanine determinations. Patients aged 15 years and older were asked to assess their quality of life (QoL) by completing the SF20 (Short Form Health Status Survey) plus two items at t0, t2, and t4. Use of inhaled corticosteroids and beta2-agonists was significantly decreased after 25 months of treatment in both groups (P<0.03). SLIT patients showed significant improvements in respiratory function at t4 (% predicted FEV1 (P = 0.01), VC (P = 0.002), morning (P = 0.01) and evening (P = 0.03) PEFR), and reduction in daytime asthma score (P = 0.02). In the SLIT group, the post-treatment PD20 was 1.75 times higher than the baseline value. There was no change in PD20 in the placebo group. Compared to the placebo group, the SLIT group showed a significant increase in specific IgE DP(P = 0.05), IgE DF(P = 0.02), IgG4 DP(P = 0.001), and IgG4 DF (P = 0.001) levels after SLIT. QoL scores were similar in both groups at t0 and t2. At t4, all scores were better in the SLIT group than in the placebo group, with the differences being most marked for the general perception of health (P = 0.01) and physical pain (P = 0.02). Adverse events were similar in the two groups. This study shows that SLIT in house-dust-mite-related asthma has a good safety profile and improves respiratory function, bronchial hyperreactivity, and QoL.

Double-blind, randomised, placebo-controlled study of two concentrations of azelastine eye drops in seasonal allergic conjunctivitis or rhinoconjunctivitis.

This double-blind, randomised, placebo-controlled study was carried out to assess the efficacy and safety of 0.025% and 0.05% azelastine eye drops twice daily administered for 14 days to patients with seasonal allergic conjunctivitis or rhinoconjunctivitis. A total of 278 patients were recruited and 226 patients were evaluable for per protocol analysis. The target parameter was the response rate. Four eye symptoms, including the main symptom (itching) were recorded by patients in diaries and eight symptoms were assessed by physicians before and after seven and 14 days of treatment. Severity of symptoms was measured on a four-point scale. The response rates for itching (improvement of at least one score point within the first three days) according to patient assessment were 43% for placebo, 52% for 0.025% and 56% for 0.05% azelastine (NS). However, a more objective assessment of the three main eye symptoms by physicians showed a concentration-dependent improvement in response rate compared with placebo (a decrease of > or = 3 points from a baseline total score of > or = 6), which reached statistical significance for 0.05% azelastine on Day 7 (p < 0.002). In the evaluable patient population, the scores of the three main eye symptoms as well as of all eight recorded eye symptoms, as assessed by the physician, were significantly (p < 0.05) lower in the 0.05% azelastine eye drops group in comparison with the placebo group at Day 7. Inefficacy was the cause of withdrawal in five and three patients on 0.025% and 0.05% azelastine, respectively, and in six patients on placebo. Adverse drug effects, mainly a mild, transient irritation and a bitter or unpleasant taste, were reported by 14% (0.025%), 20% (0.05%) and 15% (placebo) of the patients. No serious side-effects occurred. Azelastine eye drops are effective and well tolerated at a concentration of 0.05% for the treatment of seasonal allergic conjunctivitis.

RU 41740 (Biostim) stimulates the production of granulocyte macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro.

1. In this study, we observed the effects of RU 41740 (Biostim) on the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-8 (IL-8) in human bronchial epithelial cells in vitro. 2. Cytokine production was assessed by enzyme-linked immunosorbent assay. 3. We report that epithelial cells spontaneously released both cytokines and that RU 41740 induced a significant increase in production of IL-8 and GM-CSF. 4. This is the first observation of a stimulatory effect of an immunostimulating compound used in humans on cytokine production by epithelial cells.

Uptake of 12-HETE by human bronchial epithelial cells (HBEC): effects on HBEC cytokine production.

12-HETE, the major lipoxygenase end-product of platelets and macrophages, may be released in contact of bronchial epithelium in inflammatory diseases of the lung. We have studied the outcome of 12-HETE in presence of human bronchial epithelial cells (HBEC). When HBEC were incubated with [3H]12-HETE for 30 minutes, 27.5% of total radioactivity was found in HBEC and 72.5% in supernatants. Unesterified 12-HETE accounted for 22.4% of total radioactivity, 4.5% being recovered in phospholipids, preferentially in phosphatidylcholine and phosphatidylethanolamine. No incorporation in neutral lipids was detected. 72.9% of the incubated radioactivity was recovered in un identified metabolites. As 12-HETE has been shown to modulate the expression and production of various proteins, the consequence of the 12-HETE uptake on the release of GM-CSF and IL8 by HBEC was assessed. HBEC from control subjects were cultured for 24 hours with 12-HETE (10(-9) to 10(-7)M) in the presence or absence of TNF alpha. Detectable amounts of both cytokines were released in the supernatant in basal conditions at 24hr, and TNF alpha increased significantly the release of GM-CSF. 12-HETE at 10(-7)M weakly but significantly decreased the TNF-induced release of GM-CSF from HBEC. Thus the uptake of 12-HETE could affect the epithelial cell function in some situations.

Antihistamines and production of granulocyte-macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro: evaluation of the effects of loratadine and cetirizine.

1. In this study, we compared the effects of two antihistamine drugs on the production of granulocyte-macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro. 2. Cytokine production was assessed by the use of an enzyme-linked immunosorbent assay. 3. Epithelial cells spontaneously released both cytokines and tumor necrosis factor alone induced a significant increase in this production but loratadine and cetirizine had no effect at the various concentrations studied. 4. The antihistamines have no effect and this suggests that histamine plays no role in cytokine production under these conditions.

Increased respiratory burst and phosphodiesterase activity in alveolar eosinophils in chronic eosinophilic pneumonia.

A 43 year old woman presented with chronic eosinophilic pneumonia characterised by a high alveolar eosinophilic count, which allowed biochemical study of these cells. Alveolar eosinophils spontaneously produced high amounts of oxygen free radicals and exhibited an increased level of cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) activity compared to blood eosinophils from control or allergic subjects. This activity was preferentially located in the plasma membrane, whilst the PDE activity of blood eosinophils from asthmatics or controls predominated in the cytosol. Because of the potential role of phosphodiesterase during eosinophil activation and recruitment, phosphodiesterase inhibitors may be useful in the treatment of eosinophilic pneumonia.

[Corticoid resistance in asthma]. / La corticorésistance dans l'asthme.

Incorrect application of corticosteroid treatment, whether due to non-compliance, misinterpretation of etiological factors, or inadapted treatment, can lead to the difficult problem of corticoresistance. The expression of the phenomenon are varied and may concern all or part of the effector cells responsible for the inflammatory reaction. The underlying mechanism is still poorly understood but appears to involve a generally acquired, though sometimes inborn or genetically induced, desensitization of the receptor cells. Several substitute treatments have been proposed including methotrexate, gold salts, cyclosporin A, but the results have not been very promising.