Beyond second-line therapy in patients with metastatic colorectal cancer: a systematic review.

Background: The optimal chemotherapeutic regimen for use beyond the second line for patients with metastatic colorectal cancer (mCRC) remains unclear. Materials and methods: We systematically searched the Cochrane Database of Systematic Reviews, EMBASE and Medline for records published between January 2002 and May 2017, and cancer congress databases for records published between January 2014 and June 2017. Eligible studies evaluated the efficacy, safety and patient-reported outcomes of monotherapies or combination therapies at any dose and number of treatment cycles for use beyond the second line in patients with mCRC. Studies were assessed for design and quality, and a qualitative data synthesis was conducted to understand the impact of treatment on overall survival and other relevant cancer-related outcomes. Results: The search yielded 938 references of which 68 were included for qualitative synthesis. There was limited evidence to support rechallenge with chemotherapy, targeted therapy or both. Compared with placebo, an overall survival benefit for trifluridine/tipiracil (also known as TAS-102) or regorafenib has been shown for patients previously treated with conventional chemotherapy and targeted therapy. There was no evidence to suggest a difference in efficacy between these treatments. Patient choice and quality of life at this stage of treatment should also be considered when choosing an appropriate therapy. Conclusions: These findings support the introduction of an approved agent such as trifluridine/tipiracil or regorafenib beyond the second line before any rechallenge in patients with mCRC who have failed second-line treatment.

Activity of ebastine (10 and 20 mg) and cetirizine at 24 hours of a steady state treatment in the skin of healthy volunteers.

We have compared the inhibitory effects of ebastine (10 mg), ebastine (20 mg) and cetirizine (10 mg) on histamine-induced wheal and flare skin reactions 24 h following a 6-day-long treatment. This was a double-blind, randomised, crossover, placebo-controlled study involving 24 healthy volunteers (18-65 years) with negative skin prick tests and the absence of specific IgEs to common allergens. Subjects were randomised to receive each of the following treatments once daily for 6 days: ebastine (10 mg), ebastine (20 mg), cetirizine (10 mg) or placebo with a washout period of 5 days. Twenty-four hours after the last dose of each treatment, histamine skin prick tests were performed (0, 0.5, 1, 2.5, 5, 10, 20, 50, 100 and 200 mg/mL), and wheal and flare responses were measured. All active treatments produced significant inhibition of the wheal responses compared to placebo (P < 0.001). Wheal response inhibition was significantly better with 20 mg of ebastine compared with 10 mg of ebastine and 10 mg of cetirizine. In a comparison to histamine concentrations required to produce a wheal surface area of 10 mm2, 20 mg of ebastine was also significantly better than ebastine 10 mg and cetirizine (P < 0.001), and 10 mg ebastine was significantly better than cetirizine (P < 0.05). Highly significant (P < 0.001) effects on the flare response were observed with each active treatment compared to placebo, with no difference between groups. The frequency of adverse events, primarily somnolence, was similar among the four treatment groups. Our results clearly indicate that ebastine, at either recommended dosage of 10 and 20 mg, and cetirizine produced significant inhibition of the histamine-induced wheal and flare reaction compared to placebo for up to 24 h. A superior efficacy of 20 mg of ebastine is observed compared with 10 mg of ebastine and 10 mg of cetirizine on the skin wheal response 24 h after the last dose of a 6-day-long treatment. This study clearly proves ebastine to be an effective, truly once-daily antihistamine.

Local safety of intranasal triamcinolone acetonide: clinical and histological aspects of nasal mucosa in the long-term treatment of perennial allergic rhinitis.

Intranasal corticosteroids are increasingly used to treat allergic rhinitis and their long-term use is generally safe. However, the long-term safety of each molecule should be assessed. The main aim of this multicenter, prospective, randomized, open-label study was to evaluate the effect of triamcinolone acetonide aqueous intranasal spray on nasal mucosal thickness, macroscopic appearance, and mucociliary function. Patients with perennial allergic rhinitis were treated with triamcinolone acetonide 220 micrograms/day for six months. Nasal biopsies taken before and after treatment were compared with biopsies from patients who had been randomized to oral cetirizine 10 mg day or intranasal beclomethasone dipropionate 400 micrograms/day. In the evaluable population (n = 70), there were no significant differences between groups in terms of histologically evaluated thickness and endoscopically evaluated macroscopic appearance of the nasal mucosa, or indigocarmine saccharine test mucociliary function. In the intent-to-treat population (n = 92), there was no difference between treatment groups in the incidence of overall adverse events. This study indicates that sustained treatment with intranasal triamcinolone acetonide does not lead to atrophy of the nasal mucosa or impairment of mucociliary function.

[Toxicoderma caused by prednisone and prednisolone. Value of skin tests in the screening of cross sensitivity]. / Toxidermie à la prednisone et prednisolone. Intérêt des tests cutanés dans la recherche de réactions croisées.

INTRODUCTION: Allergic reactions to general corticosteroid therapy are uncommon. CASE REPORT: We report a patient with systemic lupus erythematousus who developed skin rash after initiation of prednisone then prednisolone therapy. Histology evidence suggested leukocytoclastic vasculitis. The skin tests (prick tests, intradermoreactions and patch-tests) using a battery of injectable corticosteroids showed a highly positive reaction to prednisolone, methylprednisolone and dexamethasone on the intradermo-reactions 24 hours later. Histology examination of a positive-response showed leukocytoclastic vasculitis associated with eczematiform alterations of the epidermis compatible with a drug reaction. The skin tests however were negative for betamethasone, triamcinolone, paramethasone and hydrocorticose. The patient was treated with betamethasone and no skin reaction was observed. DISCUSSION: Skin tests, particularly intradermo-reactions read 24 hours later would appear to be useful in identifying possible cross-sensitivity.

Allergic sensitization and clinical reactions to latex, food and pollen in adult patients.

BACKGROUND: Many latex-allergic patients are sensitized to one or more foods. Patients allergic to tree and/or grass pollens are also often sensitized to plant-derived foods. Atopy, defined in most studies as sensitivity to an aeroallergen, is a risk factor for latex allergy. The relative importance of pollen sensitivity, a sign of atopy, as a risk factor for food allergy in latex-allergic patients has not, however, been examined. OBJECTIVE: To investigate the relationship between pollen sensitivity and sensitivity to food in latex-allergic patients. METHODS: Forty-four latex-allergic patients (Groups 1 and 2), 24 of whom were also allergic to tree and/or grass pollen (Group 1) and 25 pollinosis patients who were not allergic to latex (Group 3) were studied. We obtained a history of reactions to food and skin tested them with 12 fresh-frozen fruits. RESULTS: All 12 foods induced a skin test reaction in at least one patient in each of the three Groups. There were, however, twice as many positive skin test reactions to food in patients with pollinosis, whether or not they were allergic to latex, as there were in patients allergic to latex but not to pollen. Latex-allergic patients were most likely to have a positive skin test and a history of a reaction to avocado or banana whereas patients with pollinosis only were most likely to have a positive skin test and a history of a reaction to apple, peach or celery. CONCLUSIONS: These results suggest that concomitant allergy to pollen is an important risk factor in determining which plant-derived foods sensitize latex-allergic patients.

Duration of the antihistaminic effect after discontinuation of ebastine.

BACKGROUND: The inhibitory effect of antihistamines on allergen-induced skin reactions can impair the results of allergen skin testing, which are necessary for the diagnosis of atopic diseases. This study was designed to determine the time period required for the inhibitory effect of ebastine on allergen-induced skin reactivity to disappear completely. METHODS: This was a double-blind, placebo-controlled, parallel-group study including 23 out of 27 randomized patients. They received either ebastine 20 mg or placebo once daily for 7 days. At the end of treatment, allergen challenge was performed daily for 7 days. Histamine challenge was performed on day 1 (6 and 24 h) and day 5 after treatment. The wheal and flare surface areas were measured and analyzed. RESULTS: Highly significant inhibition of the wheal and flare response induced by allergen was observed after ebastine treatment on days 1 and 2 as compared with placebo (P < 0.01 for both). The inhibition was reduced, although still significant, by day 3 (P < 0.05). No significant difference was observed by day 4 between the ebastine and the placebo groups. The effects of histamine challenge were significantly reduced in the ebastine compared with the placebo group at day 1 (6 and 24 h), and were similar at day 5 after treatment. CONCLUSION: Our results show that the wheal and flare response to allergen after ebastine discontinuation returns to placebo values after 4 days. Therefore, patients using ebastine need to be antihistamine-free for 4 days before the skin prick test. This is valuable information for the allergologist seeking to diagnose allergen sensitivity.

Chronic generalized eczema caused by multiple dye sensitization.

Textile dye sensitization is rare; its low incidence (1.4% to 5.8%) is most likely because dye contact allergy is not suspected and therefore not tested. The greatest number of positive test results are obtained for disperse dyes. We report an uncommon observation of severe and chronic textile dye dermatitis with positive patch test results to Disperse Blue 106, Disperse Blue 124, Disperse Brown 1, Disperse Yellow 3, and p-aminophenol.p-aminophenol, Disperse Blue 124, and Disperse Blue 106 are derived from p-phenylenediamine, but this allergen seems to be unreliable as a detector of textile dye allergy. The admittedly allergic capacity of disperse dyes and the increasing fabrication of synthetic fibers (acrylics and polyesters) usually colored with this group of dyes could induce more frequent textile sensitization.

Clinical and pathologic methods to assess the long-term safety of nasal corticosteroids. French Triamcinolone Acetonide Study Group.

BACKGROUND: The main objective of this long-term prospective local safety study was to evaluate endoscopic and histologic changes in nasal epithelium after 6-month treatment with triamcinolone acetonide (TAA). We describe here a method to measure quantitatively epithelium thickness. Results were compared with those seen with the use of cetirizine (an antihistamine) and another oral intranasal corticosteroid, beclomethasone dipropionate (BDP). METHODS: Patients were examined by an ENT specialist who first performed an endoscopic evaluation of the nasal cavities, assessing any morphologic abnormalities and the aspect of the mucosa. Biopsies were taken from the inferior turbinate before and after 24 weeks of treatment. Biopsies were immediately fixed in cold acetone (-20 degrees C) and embedded in glycolmethacrylate; sections of 2 microm were cut on an ultramicrotome. Morphometric evaluations were done in a blinded fashion by computerized image analysis to measure an epithelial area over a minimum length of 50 microm. The thickness was ascertained by the ratio of area to length. RESULTS: 1) For all three treatment groups, the nasal epithelium thickness decreased slightly from pretreatment to the end of treatment. 2) No statistically significant differences between the three treatment groups were found in epithelium thickness. 3) Macroscopically, nasal tissues in all treated groups were normal. CONCLUSIONS: These results clearly indicate that long-term treatment with TAA has no atrophic effect on nasal mucosa.

Control and exacerbation of asthma: a survey of more than 3000 French physicians.

BACKGROUND: Asthma control and prevention of exacerbations are primary objectives for asthma care. However there is a lack of universal definition of these notions which may therefore have a different meaning according to the physician's practice. METHODS: In the present survey, 1805 general practitioners, 551 pulmonologists, 176 allergologists and 470 resuscitation/emergency care physicians were randomly selected in fall 2001 and asked to answer one question on asthma control and three questions on asthma exacerbation. RESULTS: Regarding asthma control, the presence of minimum symptoms was the primary criterion for asthma specialists (pulmonologists and allergologists), while a normal respiratory function was first considered by nonspecialist physicians (general practitioners and emergency care physicians). The first criterion of mild exacerbation for asthma specialists was the occurrence during at least 2 days of an increase in the frequency of dyspnoea and/or the use of short-acting bronchodilators. For nonspecialist physicians, dyspnoea affecting daily activities and/or sleeping was the preferred notion. Hospitalization was unanimously recognized as the first criterion for severe exacerbations. A decrease in peak expiratory flow of more than 30% below the baseline value on two consecutive days and an episode requiring systemic corticosteroids were the next criteria. CONCLUSIONS: This survey emphasizes the complexity of the notions of asthma control and exacerbation and provides novel informations to orient continuing education programmes.

Implementation of guidelines for seasonal allergic rhinitis: a randomized controlled trial.

BACKGROUND: Allergic rhinitis is a common disease altering quality of life. Its treatment is well established and guidelines have been proposed. However, their efficacy has never been tested. The aim of the study was to validate the guidelines of the International Consensus on Rhinitis in the treatment of seasonal allergic rhinitis. METHODS: A multicenter, multinational, open label, parallel, randomized study compared two therapeutic strategies in seasonal allergic rhinitis during a 3-week treatment. General practitioners were randomized into two groups. In the first group of 224 patients, doctors followed guidelines from the International Consensus on Rhinitis. Depending on the severity of nasal and ocular symptoms defined using visual analogue scales, patients received ebastine (an oral antihistamine), triamcinolone acetonide (a topical corticosteroid) and/or ophthalmic nedocromil sodium (a topical ocular cromone). In the second group of 241 patients, general practitioners had a free choice of treatment. The primary efficacy end points were quality of life measured using the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ) and the symptom-medication scores assessed daily with an electronic dairy system. RESULTS: Adjusted mean total symptom scores over 21 days were 4.93 in the guidelines strategy group compared with 7.48 in the free-choice treatment group (P = 0.0001). Mean total scores in the RQLQ decreased by 2.19 in the guidelines group compared with a decrease of 1.79 in the free-choice treatment group (P = 0.0001). At 21 days, the least square mean difference in improvement in overall scores for RQLQ in the guidelines group compared with the free-choice treatment group was 0.53, which was greater than the minimal important difference. CONCLUSIONS: Patients with seasonal allergic rhinitis often present severe symptoms which are not well recognized or controlled by physicians using their own criteria of severity and treatment. Using a simple method for the evaluation of the severity and a simple therapeutic scheme based on International Guidelines, patients with seasonal allergic rhinitis presented a significant improvement by comparison with those receiving a non-standardized treatment.