Blocking FGF2 with a new specific monoclonal antibody impairs angiogenesis and experimental metastatic melanoma, suggesting a potential role in adjuvant settings

Compelling evidence suggests that fibroblast growth factor 2 (FGF2), overexpressed in melanomas, plays an important role in tumor growth, angiogenesis and metastasis. In this study, we evaluated the therapeutic use of a new anti-FGF2 monoclonal antibody (mAb), 3F12E7, using for that the B16-F10 melanoma model. The FGF2 neutralizing effect of this antibody was certified by in vitro assays, which allowed the further track of its possible in vivo application. 3F12E7 mAb could be retained in B16-F10 tumors, as shown by antibody low-pH elution and nuclear medicine studies, and also led to reduction in number and size of metastatic foci in lungs, when treatment starts one day after intravenous injection of B16-F10 cells. Such data were accompanied by decreased CD34(+) tumor vascular density and impaired subcutaneous tumor outgrowth. Treatments starting one week after melanoma cell intravenous injection did not reduce tumor burden, remaining the therapeutic effectiveness restricted to early-adopted regimens. Altogether, the presented anti-FGF2 3F12E7 mAb stands as a promising agent to treat metastatic melanoma tumors in adjuvant settings. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Lung clearance index: evidence for use in clinical trials in cystic fibrosis.

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.

Evidence of transmission of a Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus clone: a family affair.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) may represent a serious public health problem, owing to the spread of toxin-producing lineages. The presence of genes encoding for Panton-Valentine leukocidin (PVL) is an important virulence marker, as the clinical sequelae of PVL-positive infections are often described as more severe than those of PVL-negative S. aureus infections. To date, the presence of PVL has not appeared to be common in Italy; we describe the intrafamilial transmission of an epidemic PVL-producing CA-MRSA lineage, Southwest Pacific clone (SWP). Our data suggested that the strain circulated from the father, who was recurrently affected by a soft tissue infection, to the mother, who showed nasal colonization, and to their child, who was hospitalized with symptoms of necrotizing pneumonia. In this case, we found that a recurrent skin infection that is not normally taken into account may represent a serious threat if caused by a PVL-producing strain. Our findings may have considerable implications for strategies for infection control and treatment of methicillin-resistant S. aureus infections.

Molecular epidemiology of meticillin-resistant Staphylococcus aureus in Italian cystic fibrosis patients: a national overview.

BACKGROUND: The genetic background, transmissibility and virulence of MRSA have been poorly investigated in the cystic fibrosis (CF) population. The aim of this multicentre study was to analyse MRSA strains isolated from CF patients attending nine Italian CF care centres during a two-year period (2004-2005). All CF patients infected by MRSA were included. METHOD: Antibiotic susceptibility testing, SCCmec typing, Panton-Valentine Leukocidin (PVL) production, and Multi Locus Sequence Typing (MLST) analysis were carried out on collected isolates (one strain per patient). RESULTS: One hundred and seventy-eight strains isolated from 2360 patients attending the participating centres were analysed. We detected 56 (31.4%) SCCmec IV PVL-negative strains, with a resistance rate of 80.3% to clindamycin and of 14.5% to trimethoprim/sulphamethoxazole. MLST analysis showed that many isolates belonged to known epidemic lineages. The largest clone grouping of 29 isolates from 6 centres had the genetic background (ST8-MRSA-IV) of the American lineages USA300 and USA500, thus demonstrating the diffusion of these strains in a population considered at risk for hospital associated infections. CONCLUSIONS: Known MRSA epidemic clones such as USA600, USA800, USA1100, and UK EMRSA-3 were described for the first time in Italy. The diffusion of MRSA strains with high pathogenic potential in the CF population suggests that analysis of the MRSA strains involved in pulmonary infections of these patients is needed.

Case report: cystic fibrosis, lung transplantation, and the novel H1N1 flu.

The H1N1 pandemic flu is a significant risk factor for both patients with chronic disease who need organ transplantation and transplant recipients. This population needs special care regarding comorbidities and related complications. MB, a 38-year-old Italian cystic fibrosis male patient with lung and pancreatic involvement, was referred to our division in July 2009 for fever-associated arthromyalgia, headache, and rhinitis. Lung transplantation had been performed in September 2005, and he was subsequently treated with immunosuppressive therapy: tacrolimus, everolimus, and prednisolone. In the past, chronic respiratory colonization with Pseudomonas aeruginosa and intermittent infection with Aspergillus flavus, chronic renal failure, hypertension, and diabetes mellitus complicated his clinical history. He started antiviral treatment with oseltamivir despite no travel history and no respiratory symptoms. H1N1 swab was positive. Three days later, the patient was admitted to the hospital for the persistence of fever and the onset of cough. Chest x-ray showed a left lower pneumonia, which was confirmed by computerized tomography. Broad-spectrum antibiotic therapy led to an improvement of the clinical condition. The patient was discharged 8 days later; a control swab was negative. This case report suggests some general considerations regarding solid organ recipients: 1) Flu-related complications require early treatment (both antiviral and antibiotic); 2) active microbiologic surveillance is important to prevent lethal infections (ie, invasive aspergillosis); 3) evaluation of immunosuppressant blood levels is necessary for drug-drug interactions. Active prevention is the best option for decreasing morbidity and mortality in the transplanted patient.

The costs of treatment of early and chronic Pseudomonas aeruginosa infection in cystic fibrosis patients.

The aim of cystic fibrosis (CF) care is to improve both the life expectancy and quality of life of patients. However, rising costs and limited resources of health services must be taken into account. There are many different antibiotic strategies for therapy of Pseudomonas aeruginosa infection in CF patients. In this 5-year retrospective study we found that the cost of treatment of initial infection is considerably lower than the cost of treating chronic P. aeruginosa infections. The percentage distribution of costs of antibiotic treatment in relationship to the administration route was considerably different between outpatients and inpatients. We observed an increase in antibiotic costs with the age of the patient and the decrease in FEV(1)values. The implementation of early eradication treatment, in addition to decreasing the prevalence of patients chronically infected by P. aeruginosa, might also bring about a notable decrease in costs.

Bone mineral density in cystic fibrosis patients under the age of 18 years.

AIM: The increase in life expectancy of cystic fibrosis (CF) patients has brought about a rise in new clinical problems in these patients, such as a decrease in bone mineral density (BMD). The cause of diminished BMD in CF is multi-factorial. METHODS: The aim of this cross-sectional study, conducted on 39 CF patients under the age of 18 years, was to evaluate the degree of bone mineralization and the prevalence of low BMD in these patients during a follow-up at the Cystic Fibrosis Regional Center of Tuscany, using a dual energy X-ray absorptiometry (DXA) scan, and to then study the factors correlated with low BMD. RESULTS: Areas BMD values (g/cm2) and Z-score values were determined. Eighteen patients (46%) out of the our sample had decreased BMD, while 21 patients (54%) had normal values. A statistically significant association was found between BMD Z-score values and pancreatic insufficiency, BMI<5th percentile and DeltaF508 homozygosis. Subjects treated with oral steroid therapy had a 3.9 times greater risk of developing osteoporosis compared to non-treated subjects (95% C.I.: 1.07-22.6; R.R. 4.9). An association was found between BMD Z-score values and FEV1 values (r=0.29; P=0.06), physical activity total score values (r=0.22; P=0.19) and the Chrispin-Norman chest radiographic score (r=-0.31; P=0.06). CONCLUSION: Early identification of reduced bone mass values would permit early intervention to prevent the development of osteoporosis. Maintaining pulmonary function, guaranteeing optimal nutritional status, following an adequate program of physical activity and controlling steroid intake could maintain BMD over time.

Isolation measures for prevention of infection with respiratory pathogens in cystic fibrosis: a systematic review.

Respiratory infections are the most important cause of morbidity and mortality in patients with cystic fibrosis (CF). These infections are typically caused by a limited number of respiratory pathogens, particularly Burkholderia cepacia complex (BCC) and Pseudomonas aeruginosa (PA). Since the 1980s, several outbreaks of unique strains of PA and BCC among CF patients attending the same CF care centres have been described, leading to a sharp decline in the patients' health. One of the measures adopted in CF centres to interrupt ongoing outbreaks is the separation of patients with a respiratory tract culture that is positive for PA or BCC from patients who are not infected. This type of measure has been implemented routinely in many CF centres to prevent cross-transmission of PA and BCC. The aim of this review was to determine what evidence is available to support the efficacy of isolation (or segregation) practices in preventing, delaying or reducing the risk for CF patients of acquiring PA and BCC. A systematic review of scientific literature from 1980 to 31 December 2004 was performed. Existing guidelines regarding infection control in CF were also analysed. In total, 398 relevant papers were retrieved. Only 10 well-designed studies were found that evaluated the efficacy of isolation practices in preventing the transmission of respiratory pathogens in CF care centres (one prospective controlled study, one retrospective cohort study, five 'before-after' studies and three cross-sectional studies. No systematic reviews or randomized controlled trials exist on this subject. In the absence of studies with an experimental, controlled design, the efficacy of isolation practices in preventing the transmission of respiratory pathogens in CF remains unproven. However, notwithstanding the considerable limits represented by the study designs, which were mainly retrospective, the observational studies reviewed seem to support the implementation of isolation (or segregation) measures to reduce the risk of transmission of BCC and PA in CF patients.

Prevalence and correlates of vertebral fractures in adults with cystic fibrosis.

INTRODUCTION: Osteoporosis associated with cystic fibrosis (CF) is becoming increasingly important as the life expectancy of patients continues to increase. MATERIALS AND METHODS: We studied 191 adults with CF (18-50 years old; 100 men, 91 women). Total body, lumbar spine, and total proximal femur bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry, and lateral spinal radiographs were taken for assessment of vertebral fractures. A range of anthropometric, clinical and biochemical variables were evaluated as potential correlates. RESULTS: BMD T score values at the lumbar spine lower than -2.5 SD were observed in 27.3% and 11.2% of male and female patients, respectively. These proportions fell to 14% and 9.9% for total hip and 10.4% and 12.1% for total body, in men and women, respectively. Vertebral deformities were identified in 26.7% of the patients with a slightly higher prevalence in males (32%) than in females (21%, P = 0.058). Multiple vertebral deformities were observed in 12% and 7.7% of men and women, respectively. BMD values were significantly related to body weight, FEV1, age of puberty and occasionally to cumulative steroid dose in both genders. BMD values were also significantly related with serum albumin, IgG and cholinesterase. Serum estradiol levels were found below the normal range in 23% of the women and 27% of the men, and was significantly related to femur BMD values in both women and men. Significantly lower serum estradiol and free testosterone levels were observed in men with vertebral fractures. Serum osteocalcin was below the normal range in 36% and urinary deoxypyridinoline above the normal range in 51% of the patients. CONCLUSIONS: This study indicates that osteoporosis is a common complication of CF, being related to disease progression and apparently due to both excess bone resorption and inadequate bone formation. Estradiol deficiency may have a significant role in the pathogenesis in both genders. Vertebral fracture prevalence is high and greater than expected from prevalent BMD values.

Non-invasive proportional assist and pressure support ventilation in patients with cystic fibrosis and chronic respiratory failure.

BACKGROUND: Patients with advanced cystic fibrosis can benefit from non-invasive positive pressure ventilation (NPPV) for the treatment of acute decompensation as well as for the management of chronic respiratory failure. This study was undertaken to compare the physiological effects of non-invasive proportional assist ventilation (PAV) and pressure support ventilation (PSV) on ventilatory pattern, transcutaneous blood gas tensions, and diaphragmatic effort in stable patients with cystic fibrosis and chronic CO2 retention. METHODS: In 12 patients two periods of spontaneous breathing were followed randomly by PSV (12 (3) cm H2O) and PAV (flow assist 4.9 (1.3) cm H2O/l.s, volume assist 18.9 (5.1) cm H2O/l) set for the patient's comfort and administered for 40 minutes with 2 cm H2O continuous positive airway pressure. Ventilatory pattern, transcutaneous blood gas tensions, and surface diaphragmatic electromyography were measured in the last 10 minutes of each application. RESULTS: On average, both PSV and PAV improved ventilation (+30%), tidal volume (+30%), and transcutaneous CO2 (-7%) while reducing diaphragmatic activity (-30% with PSV, -20% with PAV). Mean inspiratory airway pressure was lower during PAV than during PSV (9.7 (1.9) and 12.9 (2.7) cm H2O, respectively; p<0.05). The mean coefficient of variation of tidal volume was about 20% (range 11-39%) during spontaneous breathing and did not change with either PAV or PSV. CONCLUSIONS: These results show that short term administration of nasal PAV and PSV to patients with stable cystic fibrosis with chronic respiratory insufficiency is well tolerated, improves ventilation and blood gas tensions, and unloads the diaphragm.

Early bronchopulmonary involvement in Crohn disease: a case report.

BACKGROUND: Bronchopulmonary manifestations of Crohn disease have been rarely described in children, including both subclinical pulmonary involvement and severe lung disease. CASE PRESENTATION: A 6.5-year-old girl is described with early recurrent bronchopulmonary symptoms both at presentation and in the quiescent phase of Crohn disease. Pulmonary function tests (lung volumes and flows, bronchial reactivity and carbon monoxide diffusing capacity) were normal. Bronchoalveolar cytology showed increased (30%) lymphocyte counts and bronchial biopsy revealed thickening of basal membrane and active chronic inflammation. CONCLUSIONS: Clinical and histological findings in our young patient suggest involvement of both distal and central airways in an early phase of lung disease. The pathogenesis of Crohn disease-associated lung disorders is discussed with reference to the available literature. A low threshold for pulmonary evaluation seems to be advisable in all children with CD.

Prevalence of urinary incontinence in women with cystic fibrosis.

OBJECTIVE: To determine the prevalence of urinary incontinence (UI) in female patients (aged > or = 15 years) attending a cystic fibrosis (CF) centre, in whom stress UI could be common, as chronic coughing and sputum production are frequent symptoms associated with progressive lung disease in these patients. PATIENTS AND METHODS: An anonymous questionnaire was completed by 176 women with CF (mean age 24.6 years, SD 5.8) during routine assessments as outpatients. RESULTS: In all, 72 patients (41%) were classified as never incontinent; occasional UI was reported in 61 women (35%). Regular UI, occurring twice or more a month for at least two consecutive months in the last year, was reported in 43 patients (24%). Regular UI was associated with increasing age and a lower mean (SD) forced expiratory volume/s (of that predicted) than in women with no urinary symptoms, at 26.9 (6.5) years and 53.5 (23.5)%, and 23.1 (5.4) years and 65.5 (23.2)%, respectively (P < 0.01 and P < 0.05, respectively). All incontinent women recorded stress UI; coughing, laughing and physical activity were associated with UI in 92%, 33% and 21% of the patients, respectively. CONCLUSION: Stress UI is a common symptom in women with CF. As urine loss can be under-reported to the healthcare providers, women should be asked about incontinence as part of their routine follow-up. Pelvic floor muscle exercises are effective in treating stress UI and should be considered for those with CF and regular UI.

Travel-associated Burkholderia pseudomallei infection (Melioidosis) in a patient with cystic fibrosis: a case report.

In September 1997, a 25-year-old Italian woman with cystic fibrosis (CF) spent 3 weeks in Thailand. In August 1998, her pulmonary function rapidly declined, with productive cough and intermittent fever. Chest x-ray films revealed diffuse, small, patchy opacities in the upper lobes. Burkholderia pseudomallei (BP) was isolated from specimens of the patient's sputum and was identified by means of 16S rDNA sequencing. The diagnosis of melioidosis was serologically confirmed. Continuous therapy with ceftazidime and co-trimoxazole and maintenance with co-trimoxazole, doxycycline, and chloramphenicol resulted in eradication of BP. We present the issue of whether patients with CF represent a population particularly at risk for melioidosis.

[Italian Cystic Fibrosis Registry: 10 years of activity]. / Registro Italiano Fibrosi Cistica: 10 anni di attività.

Cystic Fibrosis (CF) is a recessive autosomic genetic disease with an incidence in mediterranean countries of about 1:3500 born alive. In Italy the considerable genetic variability makes it difficult to identify all the homozygous subjects and, consequently, to estimate the incidence of the disease in healthy carriers. The disease is evolutive and affects various systems, most of all the respiratory and gastrointestinal systems. Not many years ago, when the clinical definition of CF was first introduced, average survival did not exceed the pediatric age. Nowadays with ever advancing diagnostic and therapeutical techniques many CF patients survive until an adult age. It is therefore necessary to plan adequate health service interventions so as to satisfy as much as possible the needs of both the patients and their families. To this end data collected since 1.1.1988 by the Italian registry for CF (year of birth, sex, region of birth and residence, diagnosis procedures, results of sweat test, pancreatic insufficiency, DNA analysis, status: alive, dead, lost to follow up) of all the patients, diagnosed in the 18 Reference Centres and the 3 local Centres for CF, have proved to be extremely useful. Since the birth of the Registry on 31.12.1997, data relating to 2458 patients alive on 1.1.1988 and 1159 born during the last ten years, for a total of 3617 subjects (1756 females and 1861 males), have been recorded. As already mentioned a considerable increase in life expectancy of CF patients (from 1988 to 1990 the average age of death was 14 years, from 1994 to 1997 it was 19) and a consequent increase in the percentage of adult patients have been observed.

Effect of different inspiratory maneuvers on FEV1 in patients with cystic fibrosis.

The time course of inspiration has been shown to have a significant influence on the subsequent maximal expiratory flows and timed forced expiratory volumes in healthy adults and those with COPD. The purpose of this study was to evaluate the effect of two different inspiratory maneuvers on the spirogram in 15 patients with cystic fibrosis, aged 13 to 35 years, who had mild to moderate airway obstruction. Patients performed a forced expiratory maneuver either after a rapid inspiration without an end-inspiratory pause or after a slow inspiration with a 4-s end-inspiratory pause. Flow-time and volume-time curves were measured by a pneumotachograph. The mean values of FVC, FEV1, and peak expiratory flow were significantly larger by 11%, 13%, and 26%, respectively, after the rapid inspiration without an end-inspiratory pause compared to the slow inspiration with the end-inspiratory pause. This discrepancy probably reflects differences in effective elastic recoil pressure between the two maneuvers. Although the nature of this phenomenon is not fully understood, our results show that for spirometry in patients with cystic fibrosis, the preceding inspiratory maneuver influences the results. An important corollary is that this inspiratory maneuver should be standardized.

Short-term effects of three chest physiotherapy regimens in patients hospitalized for pulmonary exacerbations of cystic fibrosis: a cross-over randomized study.

The aim of our study was to compare the short-term efficacy of three different chest physiotherapy (CPT) regimens (PD, postural drainage; PEP, positive expiratory pressure physiotherapy; HFCC, high-frequency chest compression physiotherapy) on patients with cystic fibrosis (CF) hospitalized for an acute pulmonary exacerbation. Sixteen patients with CF, 8 males, 8 females, aged 15-27 years (mean, 20.3 +/- 4), met the inclusion criteria: 1) age over 14 years; 2) mild or moderate airway obstruction; 3) sputum volume > 30 mL/day; 4) being proficient in PD and PEP CPT. Patients at admission had (mean +/- SD) forced volume in 1 second (FEV1) 52.2 +/- 21.9 percent predicted; Shwachman-Kulczycki clinical score 65.1 +/- 11 points; Chrispin-Norman chest radiography score 18.6 +/- 4.3 points. The three CPT regimens and a control-treatment (CONT) were administered in a random sequence, each patient receiving each treatment twice a day (in 50 minute sessions) for 2 consecutive days. During CONT and for 30 minutes after each session only spontaneous coughing was allowed. Wet and dry weight of sputum were recorded during the 50-minute sessions and 30 minutes afterward. Lung function was measured before and 30 minutes after each session. For each treatment a score was given by the patient for efficacy, and by both the patient and the physiotherapist for tolerance. Wet and dry weights of sputum collected during the sessions were greater for all CPT regimens than for CONT (P < 0.001, P < 0.0001). No significant differences between the three CPT regimens for both wet and dry weights were found when the number of coughs was taken into account.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of maximal transdiaphragmatic pressure in adults with cystic fibrosis.

To investigate whether diaphragmatic strength could be reduced in cystic fibrosis (CF), and to examine possible mechanisms leading to diaphragmatic weakness, we measured transdiaphragmatic pressure (Pdi), together with lung mechanics, including dynamic "intrinsic" positive end-expiratory pressure (PEEPi,dyn), ventilation, lung volumes, and nutritional status in 15 adult patients with CF in stable clinical condition. Diaphragmatic strength was assessed as the maximum Pdi (Pdimax). Nutritional assessment included the calculation of weight as a percentage of ideal weight for height (Wt/Ht). On average, our 15 CF patients had airway obstruction (FEV1 = 59 +/- 28% predicted) and a small PEEPi,dyn (1 +/- 0.7 cm H2O). Functional residual capacity average 52 +/- 9% of the predicted total lung capacity. The Wt/Ht was normal on average (95%), but with a large range from malnutrition to a good nutritional status (76 to 109%). We found that Pdimax decreased with increasing FRC/TLC percent predicted (r = 0.55, p < 0.05), but more significantly with decreasing Wt/Ht (r = 0.76, p < 0.001). The multiple linear regression analysis for these factors was significant (R2 = 0.70, p < 0.05); however, the partial regression coefficient was significant only for Wt/Ht (p < 0.01). These results suggest that in CF patients, diaphragmatic strength decreases with the progression of the disease, increasing lung volume and worsening nutritional status, and that malnutrition is the strongest determinant of diaphragmatic weakness.

Hemoglobin desaturation during sleep and daytime in patients with cystic fibrosis and severe airway obstruction.

Transcutaneous hemoglobin saturation by pulse oximetry was evaluated during sleep and for 2-3 h during the day in 31 patients with cystic fibrosis (median age 15.2 years; range 7.6-33.6 years) and severe airway obstruction. Pulse oximetry readings were analyzed as a cumulative percentage of time in which oxygen saturation was < 90% during both sleep and daytime. Each patient was also examined using clinical and radiological scores, spirometry and arterial blood-gas analysis. The agreement between arterial and transcutaneous saturation was evaluated in 29 patients. The difference between transcutaneous and arterial saturation was 2.4 +/- 2.0% and it increased as arterial saturation decreased. Clinical and radiological scores and spirometry parameters showed a poor correlation with both overnight and daytime desaturation. An arterial saturation < 94% may indicate a risk of consistent desaturation. This occurred for more than 50% of the time in 11 of 20 patients during sleep and in 5 of 20 patients during daytime hours.