Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Hand and forearm dermatoses among veterinarians.

BACKGROUND: Infectious and non-infectious hand and forearm dermatoses are frequent in daily veterinary medicine. In this specific occupation there is a serious impact of skin disease on the lives and careers of veterinarians. OBJECTIVE: In this study we clarify the different occupational dermatoses on hands and forearms among veterinarians, using data collected in different dermatological patch-test expert centres in Belgium and the Netherlands. METHODS: Instead of questioning veterinarians themselves, which has been done in different studies in the past, we contacted dermatologists in Belgium and the Netherlands, questioning them about their experiences with dermatoses among veterinarians. RESULTS: Seven dermatologists described a total of 58 veterinarians. Infectious dermatoses were described in 12 cases (20.7%). The non-infectious dermatoses (46 cases, 79.3%) can be classified as contact urticaria and as irritant or allergic contact dermatitis. CONCLUSION: While irritant contact dermatitis accounts for the vast majority of hand and forearm dermatoses among veterinarians, contact urticaria and allergic contact dermatitis also significantly contribute to the occupational morbidity. Repeated hand washing, occlusion under rubber gloves, contact with animal protein fluids during obstetric procedures and contact with antiseptic agents, systemic and topical corticosteroids and antibiotics are the most likely causes of hand and forearm dermatoses among veterinarians.

Allergen-induced interleukin-9 production in vitro: correlation with atopy in human adults and comparison with interleukin-5 and interleukin-13.

BACKGROUND: The contribution of IL-9 to human atopy is supported by genetic studies. However, IL-9 production in response to allergen in vitro has been reported only in children. OBJECTIVE: Study IL-9 induction by allergen in adults, compare it with IL-5 and IL-13 and evaluate its association with atopy. METHODS: Peripheral blood mononuclear cell (PBMC) from control adults and from atopic patients were cultured with various allergens or phytohaemagglutinin (PHA) and secreted IL-5, IL-9 and IL-13 were measured by ELISA. RESULTS: IL-9 was produced in response to Dermatophagoides pteronyssinus (Der p) by PBMC from Der p-hypersensitive adults at levels equivalent to those induced by PHA but with slower kinetics. The induction of IL-9 was allergen specific, reflecting donor RAST profile. In Der p-triggered reactions of non-atopic and atopic subjects, IL-9 showed the highest selectivity for atopics, IL-5 and IL-13 being produced more frequently in non-atopic donors. Significant correlations with specific IgE titres were found for IL-9 with all allergens tested (Der p and two peptides of Bet v 1 birch allergen). For IL-5 and IL-13, they were in the same range for Der p but more variable for birch allergens. Patterns of cytokine production by individual patients in response to allergen reflected these differences: for Der p, IL-5, IL-9 and IL-13 productions were strongly correlated but for birch IL-5 differed from the latter two. The in vitro production of IL-9 reflected clinical hypersensitivity profiles and was higher in individuals with asthma than in those with disease limited to rhinitis and/or conjunctivitis. CONCLUSIONS: Allergen-triggered IL-9 production in vitro is an excellent marker for atopy in adults given its virtual absence in allergen-stimulated PBMC from non-atopic individuals and its correlation with allergen-specific IgE and asthma.

Clinical and molecular abnormalities in lipoid proteinosis.

Lipoid proteinosis (hyalinosis cutis et mucosae) is a rare, autosomal recessive disease. The main clinicopathological features comprise skin and mucous membrane infiltration and scarring with deposition of hyaline material. In this report, we describe a 6-year-old boy in whom a diagnosis of lipoid proteinosis was first suspected when he presented with blisters and erosions at 4 years, a history of life-long dysphonia and a previous epileptic convulsion. The diagnosis was confirmed by histology and identification of a homozygous frameshift mutation, 501insC, in exon 6 of the gene encoding extracellular matrix protein 1, ECM1. Lipoid proteinosis may show protean clinical features and be difficult to diagnose on clinical grounds alone. This case report illustrates that lipoid proteinosis may show protean clinical features and yet remain undiagnosed for many years. Although the gold standard for definite diagnosis remains histology, molecular characterisation of the gene mutation will add to our understanding of genotype-phenotype correlation and perhaps to the development of a rationale for future therapeutics.

[Semiconstrained total elbow arthroplasty for severe post traumatic ankylosis of the elbow: a case-report]. / Arthroplastie totale semicontrainte pour ankylose sévère post-traumatique du coude: 'a propos d'un cas.

Post traumatic stiffness in young subjects has been long considered a bad indication for total elbow arthroplasty. We present the case of a 48 year old woman with an elbow fracture, operated in childhood who developed progressive painful stiffness. After treatment with a cemented semi constrained Coonrad-Morrey total arthroplasty, we have obtained a good result at over 4 years follow-up. The gain of ROM is 40 degrees, the analogue scale for pain is 2.5/10 and the Mayo Clinic Performance Index for the Elbow is 80/100. The subjective impression is excellent and there were no complications.

[Intracarpal ligament injuries associated with wrist fractures: a prospective radioclinical study of 40 patients]. / Les lésions ligamentaires intracarpiennes associées aux fractures du poignet: étude prospective radio-clinique sur 40 cas.

PURPOSE OF THE STUDY: We performed a prospective study to search for arthrographic signs in favor of intracarpal ligament lesions occurring concomitantly with wrist fractures. We looked for a relationship between type of fracture and displacement and examined their impact on early functional outcome. MATERIAL AND METHODS: The series included 40 patients treated over a 1-year period. All 40 patients had a displaced wrist fracture requiring surgical treatment. A three-phase arthrography was performed during the initial operation in order to search for injuries involving the scapho-lunate, luno-pyramidal or triangular complex ligaments. A second arthrography was performed at the time the osteosynthesis material was removed. All patients were followed one year postperatively. Functional outcome was recorded at one year. RESULTS: Abnormal images were found in 57% of the patients at the first arthrography. Injury to the triangular complex predominated, followed by combined injuries. There was no statistical correlation between type of fracture, degree of displacement, and presence of ligament lesions (p > 0.05). Lesions of the triangular fibrocartilaginous complex (TFCC) were significantly increased (p = 0.04) in the event of intra-articular fracture. Age and gender did not influence ligament injury. At one year, the functional outcome was statistically comparable between patients with and without ligament injury. At the second arthrography, we observed only five cases where cure of the luno-pyramidal ligament had been achieved. DISCUSSION: Intracarpal ligament injuries associated with wrist fractures are frequent. Age had no effect on occurrence of ligament injury in our series, similar to findings reported by others. Likewise, the type of fracture had no effect. Data in the literature show that intra-articular fractures and highly-displaced fractures aggravate ligament injury. Our functional results at one year did not demonstrate any significant difference in patients with and without ligament injury. A 3 or 5-year follow-up might provide further insight. Nevertheless, neglected scapho-lunate lesions still have a bad reputation in the literature, leading us to search for such lesions and to provide adapted treatment in all patients aged less than 50 years presenting a displaced fracture of the wrist.

Adverse skin reactions to anti-TNF-alpha monoclonal antibody therapy.

Various adverse cutaneous reactions to anti-TNF-alpha monoclonal antibody have been reported. In clinical studies with infliximab (Remicade) adverse drug reactions were most frequently reported in the respiratory system and in the skin and appendages. We describe here 6 patients receiving anti- TNF-alpha therapy (infliximab) for Crohn's disease or rheumatoid arthritis who consulted our out-patient department for adverse cutaneous reactions between November 1999 and February 2002. The following diagnoses were made: leukocytoclastic vasculitis, lichenoid drug reaction, perniosis-like eruption (2 patients), superficial granuloma annulare and acute folliculitis.

An unusual case of palmoplantar keratoderma.

A 55-year-old woman with palmoplantar keratoderma presented an associated hyperhidrosis with distinct odour and maceration. She had had the lesions for about 20 years and this seemed to be an isolated case in her family. This case appeared very unusual because there were no signs of acanthokeratolysis in the biopsies. Two months of treatment with acitretin (Neotigason; 25 mg daily), produced a spectacular result: clearance of all the lesions on both hands and a strong diminution of the lesions on the soles. The Unna-Thost variant of palmoplantar keratoderma usually appears in the first few months of life, and it rarely appears in the third decade. The condition is inherited as an autosomal dominant with high penetrance and expressivity. Our subject appeared to be an exception to these two facts.

Relevance and reproducibility of patch-test reactions to corticosteroids.

We present our patch test findings with dermatocorticosteroids during the period 1995-1999. We retrospectively studied the % of doubtful and positive reactions to each allergen in our corticosteroid series and assessed the relevance of these reactions. To assess reproducibility, we retested 15 patients with doubtful or positive reactions in 1999. The % of + or ++ reactions on D2-D3 and D7 ranged from 0.0% to 0.9% for most of the compounds tested. Hydrocortisone acetate 1% alc.abs./DMSO 50/50 showed a much higher % of positive reactions. Most of these reactions were not relevant and therefore probably due to the irritant nature of the vehicle. An overall reproducibility of 47.2% was obtained. 100.0% of the non-reproducible patch test reactions were not relevant. Definite relevance was much higher in the reproducible + or ++ reactions than in the reproducible doubtful reactions: 100.0% and 18.2%, respectively. We conclude that the mean % of + and ++ reactions to the corticosteroid series on D2-D3 is 0.5%, with an overall reproducibility of 47.2%. Tixocortol pivalate and budesonide proved to be important markers for dermatocorticosteroid allergy.

The risk of active sensitization to PPD.

Para-phenylenediamine (PPD) and para-aminoazobenzene are strong sensitizers. By the patch test procedure, the patient may be sensitized to these agents. Combined testing of para-compounds may increase the risk of active sensitization. We studied the % of positive patch test reactions and their relevance. In order to assess the risk of active sensitization, we compared the % of relevant reactions of both early (2/3 days) and late (7 days) reactions. We also compared the percentage of positive patch test reactions to PPD and their relevance if simultaneously tested with para-aminoazobenzene. We studied the patch test reactions to PPD in the routine series in 2058 patients. In a group of 678 patients we tested PPD and para-aminoazobenzene simultaneously. 4.3% and 3.1% of the patients reacted to PPD, respectively, with and without simultaneous testing with para-aminoazobenzene. We estimated the reactions as relevant in 21.1% and 39.7%, respectively, with and without simultaneous testing with para-aminoazobenzene. We considered none of the late reactions as relevant. We found a high proportion of relevant patch test reactions to PPD, but sensitization to PPD by the patch test procedure is a risk. We state that routine series should not contain PPD. The high number of irrelevant late positive reactions strongly suggests active sensitization. Moreover, PPD is not a ubiquitous allergen and can be tested on a non-routine basis if industrial exposure to para-compounds is suspected or if a specific localization (e.g., head or feet) prompts the testing of PPD. Testing PPD combined with para-aminoazobenzene does lead to a slight increase in positive reactions to PPD (p<0.25) and to an increase in irrelevant reactions (p<0.10).

The relevance of skin prick tests for Pityrosporum ovale in patients with head and neck dermatitis.

BACKGROUND: Patients with atopic dermatitis often develop immunoglobulin E antibodies against the yeast Pityrosporum ovale. This organism may produce positive skin prick reactions in a higher rate in patients with atopic dermatitis of the head, scalp, and neck region. METHODS: We investigated whether positive prick tests to P. ovale were associated with a specific localization in the head and neck region. A total of 589 consecutive patients were prick tested with a P. ovale extract from ALK Abelló. RESULTS: Thirty-seven patients (6.3%) showed a positive reaction to the P. ovale extract. We could not find significant differences in the localizations of the dermatitis and the pattern of reaction to the tested intracutaneous allergens between the 37 patients positive to P. ovale and the control group of 55 subjects with negative reactions. In a subgroup, we found an elevated level of P. ovale-specific IgE in 100.0% of the patients with head and neck dermatitis, compared with 13.6% in the atopic dermatitis patients with lesions in any other localization. CONCLUSIONS: Our results clearly show that P. ovale-specific IgE is strongly related to the head and neck localization of atopic dermatitis, but RAST seems more sensitive than a prick test with the extract we used.

Limited effects of placental and pituitary growth hormone on cytokine expression in vitro.

The hypothesis that growth hormone (GH) can affect immune responses in man has been evaluated by monitoring cytokine expression in cultures from peripheral blood mononuclear cells, by enzyme-linked immunosorbent assay (ELISA) and ribonuclease protection assay, and in tonsillar cells by ELISA. In addition to pituitary GH (GH-N), the placental form (GH-V), differing from pituitary GH by 13 amino acids has also been tested. Only few effects reached statistical significance and were in no case greater than 15%. Pituitary GH slightly reduced IL-5 production and stimulated IFN-gamma production. The latter effect was also observed with prolactin and could thus be induced through the prolactin receptor. It is proposed that GH has no strong effects on the parameters investigated, possibly as a result of redundancy in the cytokine network. Alternatively, effects on leukocytes are mediated by other tissues such as the liver or are clear only in response to stronger challenges.

Effects of selected herbicides on cytokine production in vitro.

To evaluate possible deleterious effects of commonly used herbicides on leukocytes, cytokine production was selected as a sensitive indicator. After in vitro exposure of human peripheral blood mononuclear cells from normal donors, the production of all 3 cytokines tested--interferon-gamma (a type 1 cytokine), interleukin-5 (a type 2 cytokine) and tumor necrosis factor-alpha (an inflammatory cytokine)--was impaired by up to 70, 50 and 70% respectively in a concentration-dependent manner in cultures exposed to atrazine (0.03-3 microM in 1% dimethylsulfoxide, DMSO). The effect paralleled that seen with dexamethasone, a known immunosuppressive agent. Other pesticides also dissolved in DMSO--mecoprop, simazine or MCPA (each up to 1 microM)--or dissolved in phosphate-buffered saline--diuron (up to 1 microM), isoproturon (up to 3 microM), metoxuron (up to 8 microM) or metamitron (up to 80 microM)--showed no concentration-related effects on cytokine production. There was, however, an inhibition of IFN-gamma and TNF-alpha production by simazine, metoxuron and mecoprop and of all three cytokines tested by diuron. MCPA (0.01 and 0.1 microM) stimulated the production of TNF-alpha. Thus, exposure to herbicides leading to plasma levels in the micromolar range induces imbalance in cytokine production.