Cytogenetic study in primary myelofibrosis at diagnosis: Clinical and histological association and impact on survival according to WHO 2017 classification in an Italian multicenter series.

We analyzed cytogenetic data at diagnosis in 395 primary myelofibrosis (PMF) patients to evaluate any possible association between karyotype and WHO 2017 classification and its impact on prognosis. All the cases were diagnosed and followed at five Italian Hematological Centers between November 1983 and December 2016. An abnormal karyotype (AK) was found in 69 patients and clustered differently according to bone marrow fibrosis grade as it was found in 31 (27.0%) cases with overt fibrotic and 38 (13.6%) with pre-fibrotic PMF (p = 0.001). Sex, anemia, thrombocytopenia, circulating blasts ≥1%, higher lactate dehydrogenase, and International Prognostic Scoring System risk classes were all significantly associated with karyotype. At a median follow-up of >6 years, 101 deaths were recorded. Survival was different between AK and normal karyotype (NK) patients with an estimated median overall survival (OS) of 11.6 and 25.7 years, respectively (p = 0.0148). In conclusion, in our cohort around 20% of patients had an AK, more frequently in subjects with an advanced bone marrow fibrosis grade and clinical-laboratory features indicative of a more aggressive disease. This study shows that an AK confers a more severe clinical phenotype and impacts adversely on OS, thus representing an additional parameter to be considered in the evaluation of PMF prognosis.

Integrating clinical, morphological, and molecular data to assess prognosis in patients with primary myelofibrosis at diagnosis: A practical approach.

Currently available prognostic scoring systems in primary myelofibrosis (PMF) do not integrate clinical, histological, and molecular data, or they also required information on "other" mutations that are available in the clinical practice only in a very limited number of laboratories. In the present multicenter study, including 401 PMF patients, an integrated International Prognostic Scoring System (I-IPSS) was developed by combining IPSS, grade of bone marrow fibrosis (GBMF), and driver mutations molecular status (MS) to define PMF prognosis at diagnosis. Four prognostic categories were identified: I-IPSS-low risk (113 patients), I-IPSS-intermediate-1 risk (56 patients), I-IPSS-intermediate-2 risk (154 patients), and I-IPSS-high risk (78 patients). Median overall survival was 26.7 years in I-IPSS-intermediate-1, 10.8 in I-IPSS-intermediate-2, and 6.4 in I-IPSS-high-risk patients (log-rank test <0.0001); instead, it was not reached in the I-IPSS-low-risk cohort because of the extremely low number of registered deaths. The addition of GBMF and MS to IPSS improved the efficacy for predicting the risk of death. Indeed, the sensitivity of I-IPSS was significantly higher (P < .05) than that of IPSS, considering both total deaths and 5- and 10-year mortality. This comprehensive approach allows clinicians to evaluate mutual interactions between IPSS, GBMF, and MS and identify high-risk patients with poor prognosis who may benefit from aggressive treatments. More importantly, this integrated score can be easily applicable worldwide as it only required information that represent the good clinical practice in the management of PMF patients.

The myeloproliferative neoplasms, unclassifiable: clinical and pathological considerations.

This corrects the article DOI: 10.1038/modpathol.2016.182.

The myeloproliferative neoplasms, unclassifiable: clinical and pathological considerations.

In this study, we investigate in detail the morphological, clinical and molecular features of 71 consecutive patients with a diagnosis of myeloproliferative neoplasms, unclassifiable. We performed a meticulous morphological analysis and found that most of the cases displayed a hypercellular bone marrow (70%) with normal erythropoiesis without left-shifting (59%), increased granulopoiesis with left-shifting (73%) and increased megakaryocytes with loose clustering (96%). Megakaryocytes displayed frequent giant forms with hyperlobulated or bulbous nuclei and/or other maturation defects. Interestingly, more than half of the cases displayed severe bone marrow fibrosis (59%). Median values of hemoglobin level and white blood cells count were all within the normal range; in contrast, median platelets count and lactate dehydrogenase were increased. Little less than half of the patients (44%) showed splenomegaly. JAK2V617F mutation was detected in 72% of all patients. Among the JAK2-negative cases, MPLW515L mutation was found in 17% and CALR mutations in 67% of the investigated cases, respectively. Finally, by multiple correspondence analysis of the morphological profiles, we found that all but four of the cases could be grouped in three morphological clusters with some features similar to those of the classic BCR-ABL1-negative myeloproliferative neoplasms. Analysis of the clinical parameters in these three clusters revealed discrepancies with the morphological profile in about 55% of the patients. In conclusion, we found that the category of myeloproliferative neoplasm, unclassifiable is heterogeneous but identification of different subgroups is possible and should be recommended for a better management of these patients.

Prognostic significance of a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in primary myelofibrosis patients.

AIMS: To evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications. METHODS AND RESULTS: Reticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 baseline BMBs. Then, we assigned to each case a comprehensive score [reticulin, collagen, osteosclerosis (RCO) score, ranging from 0 to 9] that allowed us to distinguish two groups of patients, with low-grade (RCO score 0-4) and high-grade (RCO score 5-9) stromal changes. Of 122 patients, 88 displayed a low-grade and 34 a high-grade RCO score. The latter was associated more frequently with anaemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. The RCO score was correlated strictly with overall mortality (P = 0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low- and high-grade patients (log-rank test: P < 0.001). Moreover, it proved to be more accurate than the European Consensus on Grading of Bone Marrow Fibrosis (ECGMF grade) in identifying high-risk patients with poor prognosis. Finally, a combined analysis of RCO scores and IPSS risk categories in an integrated clinical-pathological evaluation was able to increase the positive predictive value (PPV) for mortality in high-risk patients. CONCLUSION: The comprehensive RCO score, obtained by histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis was prognostically significant and more accurate than ECGMF grade in identifying high-risk patients and improved PPV when applied in addition to IPSS.

Salmonella enterica Serotype Napoli is the First Cause of Invasive Nontyphoidal Salmonellosis in Lombardy, Italy (2010-2014), and Belongs to Typhi Subclade.

Salmonella enterica serotype Napoli (S. Napoli) is currently emerging in Europe and particularly in Italy, where in 2014 it caused a large outbreak associated with elevated rates of bacteremia. However, no study has yet investigated its invasive ability and phylogenetic classification. Here, we show that between 2010 and 2014, S. Napoli was the first cause of invasive salmonellosis affecting 40 cases out of 687 (invasive index: 5.8%), which is significantly higher than the invasive index of all the other nontyphoidal serotypes (2.0%, p < 0.05). Genomic and phylogenetic analyses of an invasive isolate revealed that S. Napoli belongs to Typhi subclade in clade A, Paratyphi A being the most related serotype and carrying almost identical pattern of typhoid-associated genes. This work presents evidence of invasive capacity of S. Napoli and argues for reconsideration of its nontyphoidal category.

Reproducibility of the WHO histological criteria for the diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms.

This study, performed on behalf of the Italian Registry of Thrombocythaemias (Registro Italiano Trombocitemie), aimed to test the inter-observer reproducibility of the histological parameters proposed by the WHO classification for the diagnosis of the Philadelphia chromosome-negative myeloproliferative neoplasms. A series of 103 bone marrow biopsy samples of Philadelphia chromosome-negative myeloproliferative neoplasms consecutively collected in 2004 were classified according to the WHO criteria as follows: essential thrombocythaemia (n=34), primary myelofibrosis (n=44) and polycythaemia vera (n=25). Two independent groups of pathologists reviewed the bone marrow biopsies. The first group was asked to reach a collegial 'consensus' diagnosis. The second group reviewed individually all the cases to recognize the main morphological parameters indicated by the WHO classification and report their results in a database. They were subsequently instructed to individually build a 'personal' diagnosis of myeloproliferative neoplasms subtype just assembling the parameters collected in the database. Our results indicate that high levels of agreement (≥70%) have been reached for about all of the morphological features. Moreover, among the 18 evaluated histological features, 11 resulted statistically more useful for the differential diagnosis among the different Philadelphia chromosome-negative myeloproliferative neoplasms. Finally, we found a high percentage of agreement (76%) between the 'personal' and 'consensus' diagnosis (Cohen's kappa statistic >0.40). In conclusion, our results support the use of the histological criteria proposed by the WHO classification for the Philadelphia chromosome-negative myeloproliferative neoplasms to ensure a more precise and early diagnosis for these patients.

Head-to-head comparison of single-breath and tidal-breath exhaled nitric oxide measurements.

BACKGROUND: Exhaled nitric oxide (eNO) is an endogenous gas involved in airway pathophysiology and is determined in orally exhaled air by various techniques. However, traditional single-breath technique (eNO(SB)) requires active cooperation and is not always easily practicable (especially in young children); simpler techniques including tidal breathing measurements (eNO(TB)) are not standardized. The aim of this study was to evaluate the possible correlation and correspondence between eNO(SB) and eNO(TB) and the impact of potential confounders in children with chronic adenotonsillar disease. METHODS: Eighty-six children (mean age 8.7 ± 3.2 y) underwent eNO assessment by means of eNO(SB) and eNO(TB). The correlation among eNO(TB), eNO(SB), and other potential confounders (i.e., gender, age, weight, height, BMI, and passive smoking exposure) were studied. RESULTS: The analyses showed a poor correspondence between eNO(SB) and eNO(TB), with the latter underestimating (P < 0.001) mean eNO values: 6.4 parts per billion (ppb) (95% confidence interval (CI): 8.4-11.4 ppb) vs. 9.8 ppb (95% CI: 5.6-7.3 ppb). A greater correlation was found between eNO(SB) and eNO(TB) in children younger than 6 y. Only eNO(SB) and age predicted eNO(TB) (R2 = 43.6%). CONCLUSION: eNO(TB) is not a good predictor of eNO(SB) in children. Constant-flow eNO(SB) is the technique of choice for eNO assessment in young children.

The European Consensus on grading of bone marrow fibrosis allows a better prognostication of patients with primary myelofibrosis.

We investigated the relationship between the International Prognostic Scoring System of the International Working Group for Myelofibrosis Research and Treatment and the European Consensus on grading of bone marrow fibrosis (MF) in patients with primary myelofibrosis. We compared them in 196 consecutive primary myelofibrosis patients (median follow-up 45.7 months; range 7.4-159). International Prognostic Scoring System classified 42 cases as low risk, 73 as intermediate risk-1, 69 as intermediate risk-2, and 12 as high risk; European Consensus on grading of bone marrow fibrosis classified 83 cases as MF-0, 58 as MF-1, 41 as MF-2, and 14 as MF-3. By the time of the analysis, 30 patients (15.3%) had died. Overall median survival was 3.8 years (95% confidence interval: 3.3-4.3). Multivariate analysis confirmed that both scoring systems independently predicted survival, with hazard ratios similar to those provided by univariate analysis (respectively, 2.40 (95% confidence interval: 1.47-3.91) and 2.58 (95% confidence interval: 1.72-3.89) but the likelihood ratio increased from 19.6 of the International Prognostic Scoring System or 29.0 of the European Consensus on grading of bone MF to 42.3 when both measures were considered together. Analysis of the overall survival curves documented that patients classified as having the most favourable rate with both prognostic scores (ie low risk and MF-0) survive longer than those with only one favourable score (ie low risk but MF >0 or MF-0, but International Prognostic Scoring System >low risk). In contrast, those patients classified as having the most unfavourable rate for both scores (high risk and MF-3) have a shorter survival than those with only one unfavourable score (ie high risk but MF<3 or MF-3, but International Prognostic Scoring System

Transoral removal of hiloparenchymal submandibular calculi: a long-term clinical experience.

Traditional management of hiloparenchymal submandibular calculi is based on sialadenectomy. Recently, different minimally invasive and conservative techniques have been developed for the treatment of the submandibular calculi. We aimed to investigate the effectiveness of transoral surgical removal of large hiloparenchymal calculi by monitoring the trend for recurrence with clinical and ultrasonographic follow-up. A consecutive series of 84 patients with large (>7 mm) hilar or hiloparenchymal submandibular calculi underwent the transoral surgical removal under general anaesthesia. A video-assisted endoscopic procedure was performed in eight patients. All the patients underwent diagnostic ultrasonography and colour Doppler ultrasonography and clinical evaluation to define the exact location (hilar vs. parenchymal) and the diameter of the stone. The surgical procedure was successful in all but one of the patients. Stone recurrence was observed in 16 patients but obstructive symptoms were observed in only 12 patients during a median follow-up time of 52 months. The risk for recurrence was higher in patients who previously underwent extracorporeal shockwave lithotripsy. Conservative transoral removal of large hiloparenchymal submandibular calculi is a safe and effective surgical procedure. Future studies with longer follow-up will confirm the risk for recurrence of calculi.

Pp65 antigenemia, plasma real-time PCR and DBS test in symptomatic and asymptomatic cytomegalovirus congenitally infected newborns.

BACKGROUND: Many congenitally cytomegalovirus-infected (cCMV) neonates are at risk for severe consequences, even if they are asymptomatic at birth. The assessment of the viral load in neonatal blood could help in identifying the babies at risk of sequelae. METHODS: In the present study, we elaborated the results obtained on blood samples collected in the first two weeks of life from 22 symptomatic and 48 asymptomatic newborns with cCMV diagnosed through urine testing. We evaluated the performances of two quantitative methods (pp65 antigenemia test and plasma Real-time PCR) and the semi-quantitative results of dried blood sample (DBS) test in the aim of identifying a valid method for measuring viral load. RESULTS: Plasma qPCR and DBS tests were positive in 100% of cases, antigenemia in 81%. Only the latter test gave quantitatively different results in symptomatic versus asymptomatic children. qPCR values of 103 copies/ml were found in 52% of newborn. "Strong" DBS test positivity cases had higher median values of both pp65 positive PBL and DNA copies/ml than cases with a "weak" positivity. CONCLUSIONS: As expected antigenemia test was less sensitive than molecular tests and DBS test performed better on samples with higher rates of pp65 positive PBL and higher numbers of DNA copies/ml. The prognostic significance of the results of these tests will be evaluated on completion of the ongoing collection of follow-up data of these children.

Prothrombotic gene mutations in patients with sudden sensorineural hearing loss and cardiovascular thrombotic disease.

OBJECTIVES: Impaired cochlear perfusion seems to be an important event in sudden sensorineural hearing loss. Prothrombotic gene mutations have been related to vascular disorders and sudden hearing loss. We assessed the prothrombotic risk in 10 patients with sudden sensorineural hearing loss who had previously experienced cardiovascular events to support its vascular pathogenesis. METHODS: Ten patients underwent hematologic tests (MTHFR C677T/A1298C, prothrombin G20210A, platelet GlyIIIaA1/A2, and V Leiden G1691A genotyping; fibrinogenemia; cholesterolemia: homocysteinemia; folatemia). The results were compared with those of 100 previously investigated patients with sudden hearing loss alone and those of 200 healthy controls. DNA was isolated from peripheral blood leukocytes, and the gene mutations were investigated by polymerase chain reaction and a LightCycler DNA analyzer. RESULTS: Two patients had 2 mutant alleles, 6 had 3, and 2 had 4. The mean homocysteine, cholesterol, and fibrinogen levels were above the upper limit of normal; the mean folate levels were slightly above the lower limit of normal. Multiple mutations were more frequent in the patient group than in the previously analyzed patients and healthy controls. CONCLUSIONS: The association between inherited and acquired prothrombotic factors in patients with sudden sensorineural hearing loss and thrombotic diseases in other sites suggests that a multifactorial mechanism may underlie microvascular cochlear impairment. Hematologic investigation, including MTHFR, prothrombin, platelet, and V Leiden genotyping, may help to detect patients at potential risk of recurrent hearing loss and multiple microvascular diseases, and could be usefully performed in otherwise idiopathic sudden sensorineural hearing loss.

Cystic Fibrosis Mortality in Childhood. Data from European Cystic Fibrosis Society Patient Registry.

Data collected in the European Cystic Fibrosis Society Patient Registry (ECFSPR) database were used to investigate whether risk factors for death in childhood and adolescents CF patients have different impact in countries of different income. In this way, it is possible to recognize where interventions could improve the quality of care and survival in these patients. We matched deceased and alive patients by age, country, year of follow-up. Multivariable logistic models were developed. In the years of this study, the ECFSPR collected information on 24,416 patients younger than 18 years: 7830 patients were from countries with low/middle income and 16,586 from countries with high income; among these the dead are 102 and 107 (p < 0.001), respectively. The use of oxygen, forced expiratory volume in one second (FEV1) below 40% and BMI standard deviation score (SDS) below -2 represent risk factors for death. However, some patients from countries with high income remain alive even if their values of FEV1% and BMI-SDS were low, and some deceased patients from countries with high income had high values of FEV1% (>60%). Evaluation of mortality in pediatric age may reflect the availability of resources for CF diagnosis and treatment in some countries.

Effect of allergic bronchopulmonary aspergillosis on FEV1 in children and adolescents with cystic fibrosis: a European Cystic Fibrosis Society Patient Registry analysis.

OBJECTIVE: To evaluate the effect of allergic bronchopulmonary aspergillosis (ABPA) on FEV1 percent predicted in children and adolescents with cystic fibrosis. DESIGN: Longitudinal data analysis (2008-2010). SETTING: Patients participating in the European Cystic Fibrosis Society Patient Registry. PARTICIPANTS: 3350 patients aged 6-17 years. MAIN OUTCOME MEASURE: FEV1 percent predicted was the main outcome measure (one measurement per year per child). To describe the effect of ABPA (main explanatory variable) on FEV1 while controlling for other prognostic factors, a linear mixed effects regression model was applied. RESULTS: In 2008, the mean (±SD) FEV1 percent predicted was 78.6 (±20.6) in patients with ABPA (n=346) and 88 (±19.8) in those without ABPA (n=2806). After considering other variables, FEV1 in subjects with ABPA on entry to the study was 1.47 percentage points lower than FEV1 in patients of similar age without ABPA (p=0.003). There was no FEV1 decline associated with ABPA over the subsequent study years as the interaction of ABPA with age was not significant (p>0.05). For patients aged 11.82 years (population mean age), poor body mass index had the greatest impact on FEV1 in 2008, followed by high-risk genotype (two severe mutations), female gender, diabetes mellitus, chronic Pseudomonas aeruginosa infection and ABPA in descending order of effect size. CONCLUSIONS: In contrast to the common clinical belief of ABPA having a serious impact on lung function, the difference in FEV1 between young patients with and without the complication was found to be modest when the effect of other prognostic factors was considered.

D-dimer is not a long-term prognostic marker following acute cerebral ischemia.

Recent evidence indicates a possible role of D-dimer in the early diagnosis of ischemic stroke subtypes. Whether D-dimer can also predict the long-term outcome following ischemic stroke is controversial. To define the prognostic role of D-dimer, patients hospitalized after an acute ischemic cerebrovascular event underwent D-dimer measurement (Liatest D-D; normal level < 0.50 microg/ml) on admission and were followed up for recurrent cerebrovascular events, occurrence of other cardiovascular events, and mortality. We enrolled 96 patients (mean age 74.9 years, 42 men). Mean follow-up was 61.5 months; 47 (48.5%) patients died, 23 (48.9%) because of a vascular event. There was no difference in mean D-dimer levels between dead patients and survivors (1.68 and 1.63 microg/ml, P = NS), but the mortality risk was higher with D-dimer of at least 0.50 microg/ml (odds ratio, 5.32; 95% confidence interval, 1.79-15.84). After adjustment for age and stroke subtype, the odds ratio was not significant. Mean D-dimer was similar between patients with and without a new vascular event (1.43 and 1.68 microg/ml, P = NS), and D-dimer of at least 0.50 microg/ml was not predictive of an increased risk of subsequent events. D-dimer levels measured in the acute phase after an acute cerebrovascular event probably do not predict the long-term clinical outcome.

Discrepancies between bone marrow histopathology and clinical phenotype in BCR-ABL1-negative myeloproliferative neoplasms associated with splanchnic vein thrombosis.

We examined a consecutive series of 29 patients with myeloproliferative neoplasms (MPNs) associated with splanchnic vein thrombosis (SVT) in order to evaluate their bone marrow morphology and identify possible associations between histological findings and clinical features. Eleven patients showed the morphological features of polycythemia vera (PV), 11 of primary myelofibrosis (PMF) and six of essential thrombocythemia (ET). Molecular analyses identified the JAK2 V617F mutation in 27 patients; one of the JAK2-negative patients carried the MPL W515K mutation, the other was "triple-negative" (no JAK2, MPL or CALR mutation). On the basis of the WHO classification, three patients were classified as having PV, 11 as having PMF, and two as having ET; the remaining 13 cases fell into the MPN-unclassifiable category as there were discrepancies between their morphological and clinical features. In conclusion, our findings suggest that bone marrow histology should always be considered a key component of the diagnostic algorithm in patients with SVT, but that it is not enough to distinguish the different entities. This is particularly important because diagnoses of PV, PMF or ET have very different prognoses and obviously imply different therapies. It is therefore necessary to adopt a comprehensive approach that considers morphological, clinical and molecular data.

[The Italian registry for cystic fibrosis: what has changed in the last decade]. / Registro italiano fibrosi cistica: che cosa è cambiato nell'ultimo decennio.

Cystic Fibrosis is the most common life-shortening autosomal recessive disease of Caucasian population. The clinical expression of the disease is heterogeneous and the treatment of CF patients requires high qualification of medical and paramedical staff. In 1992 and 1993, in Italy, two national laws (104/92 and 548/93) were enacted in favour of people affected by CF. Data gathered in the Italian Registry for CF (started on 1.1.1988) allow us to monitor changes occurred in the age structure of patients and diagnosis methods. This also thanks to the laws mentioned above. Data here presented refer to 4,209 patients, 1,964 of whom were alive on 1.1.1988, and 2,245 were diagnosed afterwards. A remarkable increase in early diagnosis (within the 3rd month of life) was noticed (from 41% to 65%), together with an increasing percentage of subjects who underwent a neonatal screening program (+34%). An increase in late diagnoses is also apparent: the frequency for patients diagnosed after 18 years of life ranged from 8% to 12%. The proportion of adult patients is more than doubled between 1988 (17%) and 2000 (41%) and the number of patients over 30 is now about 400. 512 patients died during the study period. Median age at death increased from 14 (1988) to 22 (2000) years. This trend can be observed also for patients diagnosed within the first year of life. All these changes have contributed in modifying age structure of CF population. In late 80's, the latter was mostly composed by children, while now 50% of patients are adolescents or adults. Therefore, it is now necessary to involve specialists of adult diseases in CF care.

[Epidemiologic study Salus domestica: evaluation of health damage in a sample of women living near the Malpensa 2000 airport]. / Studio epidemiologico Salus domestica: valutazione dei danni di salute in un campione di donne residenti nei pressi dell'aeroporto Malpensa 2000.

The opening of the new Malpensa 2000 Airport worried people living in the neighbouring towns about possible effects of acoustic and air pollution on health status. For this reason, Varese Health Unit set up a study involving housewives and General Practitioners. This study has been carried out in 3 Areas: A Area, bordering the airport, B Area, at intermediate distance, and C Area, at long distance. On the whole, 932 housewives (18 to 64 years old) and 92 General Practitioners, were involved. The questionnaire, distributed to housewives between May 1st and November 30th 2000, was filled out in the doctor's surgery who furthermore added clinical data. Chi-square statistics were calculated to test the association between living area and personal data, behavioural and environmental characteristics, and reported disorders. To describe possible interrelationships between living Area and the answers supplied by housewives and General Practitioners the multiple correspondence multivariate analysis technique was applied. The housewives living next to the airport (A area) frequently report insomnia, nocturnal waking, anxiety and difficulty in hearing words. The multivariate analysis has shown a relationship between recently increasing noise noted by the housewives, and the area where they live, as well as a noticeable coherence between the answers given by the housewives and those given by the General Practitioners, who reported higher frequencies of cephalgy, allergies, anxiety neurosis, medical consultation, benzodiazepine's and sleeping disorder's prescriptions in A Area compared to C Area. The airport's presence seems to be associated with the onset of subjective disorders in neighbouring population. Some of these disorders, in particular neuropsychological ones, are clinically confirmed by General Practitioners, and are consistent with different noise exposure levels.

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation.

Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr(F508del) homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

Absence of a gender gap in survival. An analysis of the Italian registry for cystic fibrosis in the paediatric age.

BACKGROUND: The existence of gender-related differences since childhood in survival of cystic fibrosis (CF) patients has been recently challenged. METHODS: We evaluated the effect of gender on survival of 2293 CF patients born after 01/01/1988, followed up by 29 CF centres until 31/12/2004 and recorded in the Italian Registry for CF (IRCF). RESULTS: We observed similar annual mortality rates in females (3.59‰) and males (4.00‰), similar survival curves (log-rank test p=0.64) and similar hazards of death (hazard ratio adjusted for presence of symptoms at diagnosis, meconium ileus, F508del mutation and age at diagnosis: 1.29, 95%CI: 0.60; 2.76). However, excess mortality due to CF was higher for females (5.9) than males (5.1). CONCLUSIONS: In our population CF females do not experience higher mortality than males but, due to the disease, they lose the expected survival advantage occurring in the general population at this age. We do not exclude, however, that differences in mortality will establish after adolescence.