SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis.

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

Longitudinal Evaluation of Bone Mineral Density and Bone Metabolism Markers in Patients with Indolent Systemic Mastocytosis Without Osteoporosis.

Systemic Mastocytosis has been long identified as a potential cause of osteoporosis; nevertheless, data regarding longitudinal variation of bone mineral density (BMD) in patients with indolent systemic mastocytosis (ISM) are missing . We studied BMD variation at lumbar spine and proximal hip after 30-month (±6 months) follow-up in a large cohort of patients (83) with ISM without osteoporosis, supplementated with vitamin D and/or calcium when needed. We also analyzed the correlation between variation of BMD, basal serum tryptase levels and bone turnover markers (BTM). Sixty-four percent of our population was male; mean age was 52.1 (±11.5) years. Vitamin D insufficiency (serum levels of 25-OH-vitamin D, 25OHD, lower than 75 nmol/L) was found in more than 70 % of patients. After a follow-up of 30 ± 6 months with only vitamin D (5000-7500 IU weekly of oral cholecalciferol) or calcium (500 mg/die) supplementation when needed, we observed 2.1 % increase in BMD at lumbar spine, with no significant changes at hip. At the end of follow-up, almost 60 % of patients showed 25OHD serum levels still lower than recommended, despite vitamin D supplementation. Reduction in BMD after follow-up significantly correlated with high C-telopeptide of type I collagen serum levels at the time of diagnosis. In patients with ISM without osteoporosis, a routinary BMD evaluation within a time <2 years is not justified, except in the presence of elevated BTM. In these patients, vitamin D supplementation is frequently needed.

Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis.

Mastocytosis is a rare condition characterized by abnormal mast cell proliferation and a broad spectrum of manifestations, including various organs and tissues. Osteoporosis is one of the most frequent manifestations of systemic mastocytosis, particularly in adults. Osteoporosis secondary to systemic mastocytosis is a cause of unexplained low bone mineral density that should be investigated when accompanied by suspicious clinical elements. Bone involvement is often complicated by a high recurrence of fragility fractures, mainly vertebral, leading to severe disability. The mechanism of bone loss is the result of different pathways, not yet fully discovered. The main actor is the osteoclast with a relative or absolute predominance of bone resorption. Among the stimuli that drive osteoclast activity, the most important one seems to be the RANK-RANKL signaling, but also histamine and other cytokines play a significant role in the process. The central role of osteoclasts made bisphosphonates, as anti-resorptive drugs, the most rational treatment for bone involvement in systemic mastocytosis. There are a few small studies supporting this approach, with large heterogeneity of drug and administration scheme. Currently, zoledronate has the best evidence in terms of gain in bone mineral density and bone turnover suppression, two surrogate markers of anti-fracture efficacy.

Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper.

Mastocytosis is a clonal disorder characterized by the proliferation and accumulation of mast cells (MC) in different tissues, with a preferential localization in skin and bone marrow (BM). The excess of MC in mastocytosis as well as the increased releasability of MC may lead to a higher frequency and severity of immediate hypersensitivity reactions. Mastocytosis in adults is associated with a history of anaphylaxis in 22-49%. Fatal anaphylaxis has been described particularly following hymenoptera stings, but also occasionally after the intake of drugs such as nonsteroidal anti-inflammatory drugs, opioids and drugs in the perioperative setting. However, data on the frequency of drug hypersensitivity in mastocytosis and vice versa are scarce and evidence for an association appears to be limited. Nevertheless, clonal MC disorders should be ruled out in cases of severe anaphylaxis: basal serum tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation.

Mastocytosis and allergic diseases.

Mastocytosis is a clonal disorder characterized by proliferation and accumulation of mast cells in various tissues, mainly skin and bone marrow. It can cause a wide variety of clinical manifestations-other than urticaria pigmentosa-that can lead to inappropriate release of mediators by mast cells. The most severe manifestation is anaphylaxis. The triggers of anaphylaxis in adults with mastocytosis are numerous, but Hymenoptera stings seem to be the most frequent, followed by foods and drugs. Therefore, to prevent severe reactions, it is very important to recognize and avoid potential triggers; in addition, venom-allergic patients must receive lifelong immunotherapy, which has proven very effective. Given that published data on drug anaphylaxis in patients with mast cell disorders are scarce, it is not currently possible to provide clear recommendations. The risk of systemic reactions during general anesthesia can be reduced by assessing risk on an individual basis (previous reaction to a drug or reaction during surgery) and by avoiding specific trigger factors (patient temperature changes, infusion of cold solution, tissue trauma, friction, and other mechanical factors).

Mastocytosis and allergic diseases

Mastocytosis is a clonal disorder characterized by proliferation and accumulation of mast cells in various tissues, mainly skin and bone marrow. It can cause a wide variety of clinical manifestations-other than urticaria pigmentosa-that can lead to inappropriate release of mediators by mast cells. The most severe manifestation is anaphylaxis. The triggers of anaphylaxis in adults with mastocytosis are numerous, but Hymenoptera stings seem to be the most frequent, followed by foods and drugs. Therefore, to prevent severe reactions, it is very important to recognize and avoid potential triggers; in addition, venom-allergic patients must receive lifelong immunotherapy, which has proven very effective. Given that published data on drug anaphylaxis in patients with mast cell disorders are scarce, it is not currently possible to provide clear recommendations. The risk of systemic reactions during general anesthesia can be reduced by assessing risk on an individual basis (previous reaction to a drug or reaction during surgery) and by avoiding specific trigger factors (patient temperature changes, infusion of cold solution, tissue trauma, friction, and other mechanical factors) (AU)

La mastocitosis es una enfermedad clonal caracterizada por la proliferacion y acumulo de mastocitos (MC) en diferentes tejidos, sobre todo en la piel y en la medula osea (MO), que da lugar a una amplia variedad de manifestaciones clinicas, entre ellas la urticaria pigmentosa, siempre debidas a la inapropiada liberacion de mediadores de MC, siendo la mas grave de ellas la anafilaxia. Los desencadenantes de la anafilaxia en adultos con mastocitosis son numerosos, pero la picadura de himenopteros parece ser la mas frecuente, seguida de algunos alimentos y medicamentos. En la prevencion de las reacciones graves es muy importante reconocer y evitar el posible agente desencadenante, siendo tambien importante que los pacientes con alergia a venenos sigan un tratamiento largo con inmunoterapia que se ha demostrado efectivo en dichos pacientes. Los datos publicados sobre anafilaxia por medicamentos en pacientes con mastocitosis son escasos y no es posible dar unas claras recomendaciones sobre este tema. El riesgo de reacciones sistemicas durante la anestesia general puede reducirse haciendo un seguimiento de los riesgos personales de cada paciente (con reacciones previas a medicamentos o durante una cirugia), y evitando los factores desencadenantes (cambios de temperatura, infusion con soluciones frias, friccion y otros agentes mecánicos (AU)

Nurses' preferred end-of-life treatment choices in five countries.

BACKGROUND: Previous research has focused on physician's perspectives of end-of-life (EOL) decision making as well as patient and family EOL decision making. There is a lack of research pertaining to the EOL treatment preferences of nurses and especially nurses working in a variety of care settings. AIM: The aim of this study was to compare nurses' EOL treatment preferences in Hong Kong, Ireland, Israel, Italy and the USA. METHODS: A comparative descriptive design was used with a convenience sample of nurses (n = 1089). A survey questionnaire using EOL hypothetical clinical case scenarios was used to collect data between June 2011 and July 2012. RESULTS: Nurses in every country consistently chose a more aggressive option for patients than for themselves or for a parent. The treatment preferences of nurses varied from country to country. Lack of knowledge of patients' wishes and duty of care were the main influencing factors on treatment preferences. STUDY LIMITATIONS: The study was limited to the hypothetical nature of the scenarios; however, the study highlights numerous future research questions. CONCLUSIONS: This study is the first to examine and compare nurses' preferred EOL treatment choices in five countries from three different continents. The findings of this study raise several important questions for healthcare researchers, for policy development, and highlight the need for further international collaboration.

Validation of a stoma-specific quality of life questionnaire in a sample of patients with colostomy or ileostomy.

AIM: The aim of this study was to determine how socio-demographic and clinical variables affect quality of life (QoL) and to assess the validity of a 20-item scale in a sample of Italian subjects with colostomy, ileostomy and multiple stomata. METHOD: A cross-sectional multicentre survey was carried out in Italy between 2009 and 2010 in 73 stoma centres coordinated by the University of Padova. Patients aged 18 years old and above with a history of nontemporary stoma were included in the study. The Stoma Care QoL scale was measured and validated using a Rasch model. Socio-demographic and clinical characteristics were considered in the analyses. RESULTS: Two hundred and fifty-one patients were recruited for the study; the mean age was 62 years, 58% were men, 72% had colostomy and 25% ileostomy; approximately 70% of patients had intestinal cancer requiring a stoma, 13% a complication and 10% an inflammatory disease. No significant differences were observed throughout strata in the Stoma Care QoL scale index, except for geographical area, where subjects from south Italy showed a significantly lower index than subjects living in other parts of Italy (P < 0.01). Colostomy and ileostomy patients reported very similar QoL. Cronbach's alpha for the Stoma Care QoL scale was 0.90 (95% CI 0.88-0.92). Rasch analysis supported the viability of the Stoma Care QoL scale questionnaire and showed acceptable goodness-of-fit. Three under-fitted items were observed. CONCLUSION: The study confirms the validity of the 20-item Stoma Care QoL scale questionnaire as a research tool for stoma patients but the number of items could be reduced.

The role of basophil activation test in special populations with mastocytosis and reactions to hymenoptera sting.

BACKGROUND: Systemic mastocytosis (SM) may be associated with hymenoptera allergy. In such cases, immunotherapy is a life-saving treatment, but a circumstantiated diagnosis is needed for its prescription. Patients with SM and previous reactions to stings, but with negative tests represent a diagnostic dilemma. The basophil activation test (BAT) may be helpful in refining the diagnosis. OBJECTIVE: We assessed the usefulness of BAT in subpopulations of mastocytosis patients, including those with negative tests for insect allergy. METHODS: Within a population of patients with mastocytosis and previous stings, we studied by BAT and augmented intradermal test (IDT) (10 µg/ml) two groups: (1) with reactions to stings and negative tests; (2) without reactions and negative tests. Basophil activation test was performed with different venoms, assessing at flow cytometry basophils' activation. RESULTS: Sixty-three patients had mastocytosis and 52 had reactions to previous hymenoptera stings. Of them, seven proved negative to diagnostic tests. In six of seven of those patients, BAT was negative with all venoms, and in one, basophils resulted activated also with the negative control. In six patients without previous reactions and negative tests, BAT was totally negative in five of six patients and weakly positive to Hornet in one. Finally, the IDT at 10 µg/ml venom produced nonspecific positive results in most cases. CONCLUSION: In patients with mastocytosis, the negative results of standard tests are reliable, because BAT and IDT at higher concentration do not add useful information.

Managing distressed and disturbed patients: the thoughts and feelings experienced by Italian nurses.

This paper reports on a qualitative study to identify Italian nurses' feelings and emotions towards the management of distressed and disturbed psychiatric patients in acute inpatient settings. Four focus groups were carried out involving 33 nurses from seven acute psychiatric services in a region of Italy. Data were analysed using content analysis. Findings highlight that fear is the prevailing feeling experienced by nurses in the management of distressed patients. This includes both fear of being physically harmed and concerns about doing harm or damage to patients. The unpredictability of aggressive behaviour from unknown patients was described as especially frightening. Known patients, namely those previously admitted to the unit, induced less fear, as their behaviour was considered more predictable. Patients with dual diagnosis were also a worry for many nurses, who considered themselves lacking in the personal relational skills needed to manage an individual in crisis. Nurses reported that they try to understand the reasons for a patient's aggressive behaviour and are empathetic to his or her suffering. When such empathy is lacking, nurses experience conflicting feelings of counter-aggressiveness. The paper concludes by emphasizing the need to increase availability of education related to patient management, in particular team working and its internal relationships.

How much specific is the association between hymenoptera venom allergy and mastocytosis?

BACKGROUND: The preferential association of mastocytosis with hymenoptera sting reactions is well known, but there is no data on the prevalence of clonal mast cell disorders in subjects with severe systemic reactions due to foods or drugs. METHODS: Patients with food- or drug-induced severe systemic reactions, including anaphylaxis, and increased serum tryptase were studied for the presence of mastocytosis, and compared with a population of patients with hymenoptera allergy. The aetiological role of foods or drugs was assessed according to current recommendations. Systemic reactions were graded in severity according to the procedure described by Mueller. Serum tryptase was considered increased if the level was >11.4 ng/ml. Subjects with increased tryptase had dermatological evaluation and Bone marrow(BM) aspirate-biopsy, which included histology/cytology, flow cytometry and detection of KIT mutations. RESULTS: A total of 137 subjects (57 male, mean age 42 years) were studied. Of them, 86 proved positive for drugs and 51 for foods. Overall, out of 137 patients, only nine (6.6%) had a basal tryptase >11.4 ng/ml, and only two (1.5%) were diagnosed with mastocytosis. This was clearly different from patients with hymenoptera allergy, where 13.9% had elevated tryptase and 11.1% had a clonal mast cell disorder. CONCLUSION: The association of clonal mast cell disorders with hymenoptera allergy seems to be more specific than that with food- or drug-induced systemic reactions.

ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor.

Zeta-associated protein-70 (ZAP-70), mostly assessed by flow-cytometry (FC), recently emerged as reliable prognostic factor in chronic lymphocytic leukaemia (CLL) at presentation. We evaluated ZAP-70 expression in 156 CLL patients by immunohistochemistry (IHC) on formalin-fixed bone marrow (BM) biopsies at diagnosis. At presentation, 117 patients (75%) were with Binet stage A, 27 (17%) stage B and 12 (8%) stage C. Median follow-up was 61 months (range 6-242). ZAP-70 was expressed in neoplastic lymphocytes of 69 patients (44%). Concordance between ZAP-70 by IHC and ZAP-70 by FC, immunoglobulin heavy chain variable genes (IGHV) mutational status and CD38 expression was found in 41/46 (89%), 41/49 (80%) and in 60/88 (68%) tested cases, respectively. ZAP-70 expression significantly correlated with advanced Binet stage (B-C), diffuse BM infiltration, increased lactate dehydrogenase (LDH) and beta2-microglobulin serum levels and lymphocyte doubling time <12 months. ZAP-70 positivity was significantly related to poorer time to progression (median 16 months vs 158 of ZAP-70-negative cases) (P<0.0001) and overall survival (median 106 months vs not reached) (P=0.0002); this correlation was confirmed at multivariate analysis. ZAP-70 expression correlated with poorer outcome also when evaluated only in the 117 stage A patients. In conclusion, immunohistological detection of ZAP-70 on formalin-fixed BM biopsies at diagnosis appears a useful methodological approach to identify patients with poor prognosis in CLL.

Restauración de la audición con prótesis implantables. B.A.H.A., implante coclear e implante auditivo de tronco cerebral / Restoration of hearing with implantable prosthesis

The authors' present an experience with restoration of hearing with implantable prothesis

Restauración de la audición con prótesis implantables. B.A.H.A., implante coclear e implante auditivo de tronco cerebral / Restoration of hearing with implantable prosthesis

The authors present an experience with restoration of hearing with implantable prothesis (AU)

Serum levels of soluble CD30 improve International Prognostic Score in predicting the outcome of advanced Hodgkin's lymphoma.

BACKGROUND: The International Prognostic Score (IPS) and circulating levels of the soluble form of CD30 molecule (sCD30) have both been associated with poor outcome in patients with advanced Hodgkin's lymphoma (HL). The aim of this study was to assess the prognostic power of the combined evaluation of sCD30 and IPS in these patients. PATIENTS AND METHODS: We included 101 patients with advanced HL, treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or MOPP (mechlorethamine, vincristine, procarbazine and prednisone)/ABVD chemotherapy with or without radiotherapy. All were tested for pre-treatment sCD30 levels. RESULTS: Six-year estimated overall survival (OS) and failure-free survival (FFS) was 89% +/- 3% and 75% +/- 4%, respectively. Thirty-three patients (33%) had IPS >2; their FFS was 60% compared with 82% in the remaining patients (P = 0.027). Serum sCD30 levels were > or =100 U/ml in 41 (41%) patients; their FFS at 6 years was 58%, compared with 87% in patients with sCD30 <100 U/ml (P = 0.003). In the 18 patients with both sCD30 > or =100 U/ml and IPS >2, FFS was significantly worse (44%) than in patients with low sCD30 and low IPS (89%) (P <0.001) or with only one of the two adverse prognostic factors (73%) (P = 0.03). CONCLUSIONS: In our study, the combination of IPS >2 and serum sCD30 levels > or =100 U/ml identifies a sizeable subgroup (18%) of advanced HL patients with very poor FFS, who might take advantage of intensified up-front treatment strategies.

An international psychometric testing of the care dependency scale.

In an international study, psychometric properties of the Care Dependency Scale (CDS) were examined by analysing data gathered in Dutch, Canadian, Italian and Norwegian nursing homes. For that purpose, from these countries a convenience sample was developed consisting of 525 patients with dementia. The English, Italian and Norwegian research instruments were translations of the original Dutch CDS. Psychometric evaluations of the CDS were carried out for each country separately as well as for the four countries combined. High alpha coefficients between 0.94 and 0.97 were calculated. Subsequent test-retest and inter-rater reliability revealed moderate to substantial Kappa values. Factor analysis resulted in a one-factor solution. The scalability of the CDS was demonstrated by means of Mokken scale analysis. One of the main outcomes of the cross-cultural comparison was that the findings in the four countries show more similarities than differences, so that the scale can be used appropriately in nursing home practice.

[Care dependency of nursing home patients with dementia: assessment from European perspective]. / Zorgafhankelijkheid van verpleeghuispatiënten met dementie: gemeten in Europees perspectief.

In an international, study psychometric properties of the Care Dependency Scale (in Dutch shortened as: ZAS) were examined by analysing data gathered in nursing homes in Germany, Finland, Italy, The Netherlands, Norway and Wales (UK). For that purpose, from these countries a convenience sample was developed consisting of 832 patients with dementia. The English, Finnish, German, Italian and Norwegian research instruments were translations of the original Dutch ZAS. Psychometric evaluations of the ZAS were carried out for each country separately as well as for the countries combined. High alpha coefficients between 0.93 and 0.97 were calculated. Subsequent interrater and test-retest reliability revealed moderate to substantial kappa values. Factor analysis resulted in a one-factor solution. One of the main outcomes of the cross-cultural comparison was that the findings in the six countries show more similarities than differences, so that the scale can be used appropriately in nursing home practice and for international comparison of care dependency.

Nursing research in Italy.

Nursing in Italy is achieving a higher academic status as a result of decades of efforts in scientific knowledge development. Beginning in the 1980s, Italian nurses, supported by researchers from allied disciplines, have begun to design and implement research at the local, regional, and national level. This study is the first effort ever made to identify the main characteristics of Italian nursing research published in Italian journals. The review covers 14 years (1983-1997). Overall, 240 studies from 11 journals, research reports from books, and several conference proceedings have been considered. Inclusion criteria were based on quality of research design, considering components such as sampling, sample size, and method of data analysis. Each article was analyzed according to an interpretive scheme focusing on method of analysis, scientific merit, and authorship. Of the 240 studies reviewed, journal articles selected from ten Italian journals accounted for 175 (73%), or the majority, of reviewed sources. Sixty-five (26%) research reports complete the remaining number. The major areas of research identified include nursing practice (43%), nursing education (6%), nursing administration and professional issues (34%), and knowledge and perceptions in society and nursing (17%). The majority of the research studies utilized survey models (47%), including several retrospective and longitudinal studies, followed by exploratory or descriptive (36%) and quasi-experimental (17%) designs. Many reports failed to identify the method of sampling used in the research design. However, of those that did, convenience samples were most often used. Random sampling was rarely reported. The majority of studies employed only descriptive statistics (i.e., frequency distribution, central tendency, variability, contingency tables, and correlation). Only few studies made use of advanced statistics for testing hypotheses (parametric and non-parametric tests) among which only a low percentage cited reliability testing. In 42% of the studies, the authors were represented by a group of nurses. Nurses and physicians worked together to author another 30% of the studies. The remaining studies were authored by either individual nurses (24%) or nurses and nonmedical professionals (4%). Much of the reviewed research has been carried out by nurses who have little or no research training.

Estimated 6-year event-free survival of 55% in 60 consecutive adult acute lymphoblastic leukemia patients treated with an intensive phase II protocol based on high induction dose of daunorubicin.

On the basis of a previous experience suggesting that daunorubicin dose in induction was an independent prognostic factor in adult ALL, we designed a chemotherapeutic regimen (ALLVR589) characterized by high doses of daunorubicin (270 mg/m2) in induction and by high-dose Ara-C in post-remission. The protocol was otherwise conventional: induction and post-remission therapy were followed by chemo-radio prophylaxis of the central nervous system (CNS) and periodical reinductions over a 3-year maintenance period. Sixty consecutive patients (male 42, female 18, median age 34 years, range 14-71; B-lineage, 35; T-lineage, 25; Ph' and bcr/abl positive, 7) recruited between 1989 and 1996, were evaluated for treatment outcome. Complete remissions were 56 (93%), one patient had refractory disease, early deaths were five (8%); 19/56 (34%) patients relapsed, five of whom were Ph'+. Median time to relapse was 11 months (range 3-47); 68% of relapses occurred within 12 months from CR. No CNS relapses were observed. After a median follow-up of 44 months (1-100), 33/60 (55%) patients remain event-free; 23/60 (38%) are off-therapy in continuous CR (median follow-up from diagnosis: 63 months; range 38-100). These results suggest that increasing DNM dosage in induction is one of the possible approaches to improve the outcome of adult ALL by decreasing the relapse occurrence.