Risk for cancer development in familial Mediterranean fever and associated predisposing factors: an ambidirectional cohort study from the international AIDA Network registries.

Objective: Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF. Methods: The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression. Results: 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (ß1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (ß1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (ß1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (ß1 = 0.011, 95% CI. 0.001- 0.019, p=0.008), the use of biotechnological agents (ß1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (ß1 = 2.089, 95% CI. 0.7-3.5, p=0.002). Conclusions: The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease.

Histologic and Clinical Factors Associated with Kidney Outcomes in IgA Vasculitis Nephritis.

BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

Effectiveness and Safety of Biosimilars in Pediatric Non-infectious Uveitis: Real-Life Data from the International AIDA Network Uveitis Registry.

INTRODUCTION: Since many biological drug patents have expired, biosimilar agents (BIOs) have been developed; however, there are still some reservations in their use, especially in childhood. The aim of the current study is to evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibitors BIOs as treatment for pediatric non-infectious uveitis (NIU). METHODS: Data from pediatric patients with NIU treated with TNF inhibitors BIOs were drawn from the international AutoInflammatory Disease Alliance (AIDA) registries dedicated to uveitis and Behçet's disease. The effectiveness and safety of BIOs were assessed in terms of frequency of relapses, risk for developing ocular flares, best-corrected visual acuity (BCVA), glucocorticoids (GCs)-sparing effect, drug survival, frequency of ocular complications, and adverse drug event (AE). RESULTS: Forty-seven patients (77 affected eyes) were enrolled. The BIOs employed were adalimumab (ADA) (89.4%), etanercept (ETA) (5.3%), and infliximab (IFX) (5.3%). The number of relapses 12 months prior to BIOs and at last follow-up was 282.14 and 52.43 per 100 patients/year. The relative risk of developing ocular flares before BIOs introduction compared to the period following the start of BIOs was 4.49 (95% confidence interval [CI] 3.38-5.98, p = 0.004). The number needed to treat (NNT) for ocular flares was 3.53. Median BCVA was maintained during the whole BIOs treatment (p = 0.92). A significant GCs-sparing effect was observed throughout the treatment period (p = 0.002). The estimated drug retention rate (DRR) at 12-, 24-, and 36-month follow-up were 92.7, 83.3, and 70.8%, respectively. The risk rate for developing structural ocular complications was 89.9/100 patients/year before starting BIOs and 12.7/100 patients/year during BIOs treatment, with a risk ratio of new ocular complications without BIOs of 7.1 (CI 3.4-14.9, p = 0.0003). Three minor AEs were reported. CONCLUSIONS: TNF inhibitors BIOs are effective in reducing the number of ocular uveitis relapses, preserving visual acuity, allowing a significant GCs-sparing effect, and preventing structural ocular complications. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05200715.

Therapeutic Management of Children with Vesicoureteral Reflux.

Contrasting data refer to therapies for vesicoureteral reflux (VUR), such as surgical treatments and continuous antibiotic prophylaxis (CAP). This study evaluated the effectiveness of these approaches in children with VUR, analyzing the recurrence of febrile urinary tract infections (UTIs) and the resolution of VUR after the treatment. A total of 350 pediatric patients underwent contrast-enhanced voiding urosonography (ceVUS) to diagnose a VUR, whereas renal scintigraphy evaluated potential scars. After 12 months from the treatment, the VUR, the relapse of febrile UTIs, and reflux-related nephropathy were analyzed. Twenty-seven children had recurrent febrile UTIs after surgical therapy, with a greater rate of relapses observed in III and V VUR grades. Thirteen patients who underwent surgery had scars, independently of VUR grades and gender, with evidence of chronic renal failure at the end of the follow-up period. A total of 140 subjects were treated with CAP, and 30% of them continued to suffer from febrile UTIs. Ninety-five patients with VUR underwent ceVUS after 12 months, with persistent reflux in fifty-two patients. All of them had severe VUR, correlating with the age at diagnosis and gender. CAP therapy prevented scarring better than surgery, especially in children with III and V grades of VUR. A late onset of VUR or VUR involving neonatal patients is rarely a reversible process. This study identified predictors of success or failure of surgical or CAP therapies, evaluating the relapse of UTIs or persistent reflux after the treatment and giving prognostic information in children with VUR.

Amyloidosis and Glomerular Diseases in Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease with autosomal recessive transmission, characterized by periodic fever attacks with self-limited serositis. Secondary amyloidosis due to amyloid A renal deposition represents the most fearsome complication in up to 8.6% of patients. Amyloidosis A typically reveals a nephrotic syndrome with a rapid progression to end-stage kidney disease still. It may also involve the cardiovascular system, the gastrointestinal tract and the central nervous system. Other glomerulonephritis may equally affect FMF patients, including vasculitis such as IgA vasculitis and polyarteritis nodosa. A differential diagnosis among different primary and secondary causes of nephrotic syndrome is mandatory to determine the right therapeutic choice for the patients. Early detection of microalbuminuria is the first signal of kidney impairment in FMF, but new markers such as Neutrophil Gelatinase-Associated Lipocalin (NGAL) may radically change renal outcomes. Serum amyloid A protein (SAA) is currently considered a reliable indicator of subclinical inflammation and compliance to therapy. According to new evidence, SAA may also have an active pathogenic role in the regulation of NALP3 inflammasome activity as well as being a predictor of the clinical course of AA amyloidosis. Beyond colchicine, new monoclonal antibodies such as IL-1 inhibitors anakinra and canakinumab, and anti-IL-6 tocilizumab may represent a key in optimizing FMF treatment and prevention or control of AA amyloidosis.

Vitamin D and Glomerulonephritis.

Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the Renin-Angiotensin-Aldosterone System (RAAS) and erythropoiesis, exerts immunomodulatory effects, reduces the cardiovascular events and all-cause mortality. In Chronic Kidney Disease (CKD) patients, Vitamin D function is impaired; the renal hydrolyzation of its inactive form by the action of 1α-hydroxylase declines at the same pace of reduced nephron mass. Moreover, Vitamin D major carrier, the D-binding protein (DBP), is less represented due to Nephrotic Syndrome (NS), proteinuria, and the alteration of the cubilin-megalin-amnionless receptor complex in the renal proximal tubule. In Glomerulonephritis (GN), Vitamin D supplementation demonstrated to significantly reduce proteinuria and to slow kidney disease progression. It also has potent antiproliferative and immunomodulating functions, contributing to the inhibitions of kidney inflammation. Vitamin D preserves the structural integrity of the slit diaphragm guaranteeing protective effects on podocytes. Activated Vitamin D has been demonstrated to potentiate the antiproteinuric effect of RAAS inhibitors in IgA nephropathy and Lupus Nephritis, enforcing its role in the treatment of glomerulonephritis: calcitriol treatment, through Vitamin D receptor (VDR) action, can regulate the heparanase promoter activity and modulate the urokinase receptor (uPAR), guaranteeing podocyte preservation. It also controls the podocyte distribution by modulating mRNA synthesis and protein expression of nephrin and podocin. Maxalcalcitol is another promising alternative: it has about 1/600 affinity to vitamin D binding protein (DBP), compared to Calcitriol, overcoming the risk of hypercalcemia, hyperphosphatemia and calcifications, and it circulates principally in unbound form with easier availability for target tissues. Doxercalciferol, as well as paricalcitol, showed a lower incidence of hypercalcemia and hypercalciuria than Calcitriol. Paricalcitol demonstrated a significant role in suppressing RAAS genes expression: it significantly decreases angiotensinogen, renin, renin receptors, and vascular endothelial growth factor (VEGF) mRNA levels, thus reducing proteinuria and renal damage. The purpose of this article is to establish the Vitamin D role on immunomodulation, inflammatory and autoimmune processes in GN.

Maternal peripheral blood CD34+ cells for prediction of fetal kidney malformations: results from a case-control analysis.

PURPOSE: To evaluate the relation between CD34+ cells count in maternal blood and potential development of fetal congenital renal abnormalities. MATERIALS AND METHODS: We enrolled 16 women that gave birth to newborns carrying congenital renal malformations over a 3-year period and 48 women with uncomplicated pregnancies (controls) in a 1:3 ratio (three controls per case). RESULTS: CD34+ cells in the maternal peripheral blood were significantly lower in the group of women who gave birth to newborns carrying congenital renal malformations compared to the controls (p < .0001). CONCLUSIONS: CD34+ cells in maternal blood could be validated as a potential marker to predict the development of possible kidney malformations.

Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis.

OBJECTIVE: To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity. METHODS: The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant. RESULTS: A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease. CONCLUSION: The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively.

A novel UMOD gene mutation associated with chronic kidney failure at a young age.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) belongs to a group of renal hereditary disorders linked by common findings of tubulointerstitial disease and dominant inheritance. The renal clinical phenotype is characterized by chronic kidney disease, hyperuricemia, gout, and, inconstantly, renal cysts. Uromodulin (UMOD) gene mutations are related to the clinical phenotype of ADTKD-UMOD. We describe here a novel heterozygous mutation of UMOD (c.249C>G; p.Cys83Trp) in an affected 9-year-old boy with progressive renal impairment and hyperuricemia. His mother is also affected and received renal transplantation at the age of 31 years. We assume that this variant is likely to be the causative mutation in this family as it segregates with the disease, it is not present in the genomic databases, and it is predicted to be damaging by the principal software tools. Considering the progressive renal impairment of our proband at an early age (serum creatinine elevation at the age of 6, hyperuricemia at the age of 9) and the early age at end-stage renal disease of his mother, we hypothesize that this variant is associated with a severe clinical phenotype.

C3 glomerulopathy in cystic fibrosis: a case report.

BACKGROUND: C3 glomerulonephritis is a rare glomerulopathy characterized at renal biopsy by C3 deposition, alone or with scanty immunoglobulins, as well as by an electron-dense material in mesangium, subendothelial and subepithelial space. An abnormal systemic activation of the alternative pathway of the complement cascade is responsible for the development of the disease if triggered by several possible environmental conditions. We report the first case in literature of a patient affected by cystic fibrosis and C3GN. CASE PRESENTATION: Our case involves a young woman with cystic fibrosis, who had persistent microscopic hematuria, proteinuria and hypocomplementemia C3 for over three months. Renal biopsy confirmed the diagnosis of C3 glomerulopathy. Complement system dysregulation was tested and resulted in a strong terminal pathway activation proved by high levels of sC5b-9 complex, amounting to 1588 ng/ml (normal value < 400 ng/ml). Next generation sequencing (NGS) showed polymorphism in CFH (p.V62I in SCR1) and THBD (p.A473V), already known as pathogenic for C3GN, as well as a mutation in C3 (p.R102G) associated only with age-related macular degeneration (AMD) so far. Treatment was based on ACE inhibitors and kidney function is currently stable (GFR 50 ml/min, serum creatinine 1.7). CONCLUSIONS: The co-existence of C3 glomerulopathy in a patient with CF, which is characterized by chronic infection/inflammation, makes this case an interesting model of chronic altered systemic activation of the alternative pathway of the complement cascade.

Cystic Fibrosis: A Risk Condition for Renal Disease.

OBJECTIVE: Cystic fibrosis (CF) is the most common autosomal recessive disease affecting the Caucasian population, with a birth incidence ranging between 1:2,500 and 1:1,800. It is caused by mutations in the CF transmembrane regulator gene which is localized on 7 chromosomes. Renal disease is reported as a relatively rare complication in adult patient with CF. We evaluated proteinuria and chronic renal failure (CRF) in a population of patients with CF. METHODS: A retrospective study was carried out in a referral center for CF at University of Messina in Italy. We identified all patients with renal disease, characterized by proteinuria and/or CRF, during the period 2007 to 2012 and reviewed their medical records to assess influence on renal disease of genotype, number of pulmonary exacerbation, pancreatic insufficiency, pulmonary function, CF-related diabetes, and antibiotics courses. RESULTS: From a population of 77 adult patients with CF, we identified 9 patients with proteinuria (11.7%), and 11 patients (14.28%) with CRF. Mean age was 35.6 (+5.1 standard deviation) years, 55% were female and 33% had diabetes mellitus. Renal biopsy was performed in 3 patients because of nephrotic syndrome in 1 patient and proteinuria with renal failure in the other 2 patients. Renal amyloidosis was disclosed in 2, whereas IgA nephropathy in 1 patient. The ΔF508 mutation in homozygosis was present in 44% of patients with proteinuria (vs. 27% of our CF population, relative risk 2.07), whereas genotype ΔF508/N1303K in 22%. ΔF508 allele mutation was present in 77.7% of proteinuric patients. CONCLUSIONS: Our study shows a higher prevalence of renal disease in patients with CF, than was previously described. The main reason may be related to increased life expectancy because of better management. Moreover, patients with ΔF508 homozygosis had higher risk of proteinuria.

Dense deposit disease in a child with febrile sore throat.

Dense deposit disease or membranoproliferative glomerulonephritis type II is a rare glomerulopathy characterized on renal biopsy by deposition of abnormal electron-dense material in the glomerular basement membrane. The pathophysiologic basis is uncontrolled systemic activation of the alternate pathway of the complement cascade. C3 nephritic factor, an autoantibody directed against the C3 convertase of the alternate pathway, plays a key role. In some patients, complement gene mutations have been identified. We report the case of a child who had persistent microscopic hematuria, proteinuria, and hypocomplementemia C3 for over 2 months. Renal biopsy confirmed the diagnosis of dense deposit disease.

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study.

OBJECTIVES: To analyse the prevalence of CECR1 mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study. METHODS: Direct sequencing of CECR1 was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor. RESULTS: Biallelic homozygous or compound heterozygous CECR1 mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without CECR1 mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect. CONCLUSIONS: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.

The Italian Society for Pediatric Nephrology (SINePe) consensus document on the management of nephrotic syndrome in children: Part I - Diagnosis and treatment of the first episode and the first relapse.

This consensus document is aimed at providing an updated, multidisciplinary overview on the diagnosis and treatment of pediatric nephrotic syndrome (NS) at first presentation. It is the first consensus document of its kind to be produced by all the pediatric nephrology centres in Italy, in line with what is already present in other countries such as France, Germany and the USA. It is based on the current knowledge surrounding the symptomatic and steroid treatment of NS, with a view to providing the basis for a separate consensus document on the treatment of relapses. NS is one of the most common pediatric glomerular diseases, with an incidence of around 2-7 cases per 100000 children per year. Corticosteroids are the mainstay of treatment, but the optimal therapeutic regimen for managing childhood idiopathic NS is still under debate. In Italy, shared treatment guidelines were lacking and, consequently, the choice of steroid regimen was based on the clinical expertise of each individual unit. On the basis of the 2015 Cochrane systematic review, KDIGO Guidelines and more recent data from the literature, this working group, with the contribution of all the pediatric nephrology centres in Italy and on the behalf of the Italian Society of Pediatric Nephrology, has produced a shared steroid protocol that will be useful for National Health System hospitals and pediatricians. Investigations at initial presentation and the principal causes of NS to be screened are suggested. In the early phase of the disease, symptomatic treatment is also important as many severe complications can occur which are either directly related to the pathophysiology of the underlying NS or to the steroid treatment itself. To date, very few studies have been published on the prophylaxis and treatment of these early complications, while recommendations are either lacking or conflicting. This consensus provides indications for the prevention, early recognition and treatment of these complications (management of edema and hypovolemia, therapy and prophylaxis of infections and thromboembolic events). Finally, recommendations about the clinical definition of steroid resistance and its initial diagnostic management, as well as indications for renal biopsy are provided.

Advanced breast cancer rates in the epoch of service screening: The 400,000 women cohort study from Italy.

BACKGROUND: The objective of this study was to evaluate if mammography screening attendance is associated with a reduction in late-stage breast cancer incidence. METHODS: The cohort included over 400,000 Italian women who were first invited to participate in regional screening programmes during the 1990s and were followed for breast cancer incidence for 13 years. We obtained individual data on their exposure to screening and correlated this with total and stage-specific breast cancer incidence. Socio-economic status and pre-screening incidence data were used to assess the presence of self-selection bias. RESULTS: Overall, screening attendance was associated with a 10% excess risk of in situ and invasive breast cancer (IRR = 1.10; 95% confidence interval (CI): 1.06-1.14), which dropped to 5% for invasive cancers only (IRR = 1.05; 95% CI: 1.01-1.09). There were significant reductions among attenders for specific cancer stages; we observed a 39% reduction for T2 or larger (IRR = 0.61; 95% CI: 0.57-0.66), 19% for node positives (IRR = 0.81; 95% CI: 0.76-0.86) and 28% for stage II and higher (IRR = 0.72; 95% CI: 0.68-0.76). Our data suggest that the presence of self-selection bias is limited and, overall, invited women experienced a 17% reduction of advanced cancers compared with pre-screening rates. CONCLUSIONS: Comparing attenders' and non-attenders' stage-specific breast cancer incidence, we have estimated that screening attendance is associated with a reduction of nearly 30% for stages II+.

Mixed Botryoid and Spindle Cell Bladder Rhabdomyosarcoma: An Outstanding Pediatric Case.

We report a case of a 3-year-old North African child, initially assessed for nonspecific urinary symptoms such as haematuria and burning urination. The ultrasound evaluation showed a vegetating mass occupying the lumen with weak vascular signs at the Colour-Doppler evaluation. An explorative cystoscopy was performed and it revealed a nonbleeding lesion, white in colour, pedunculated, projecting into the lumen, and associated with a brown satellite formation. Histological examination showed a mixed Botryoid and Spindle Cell Rhabdomyosarcoma. This mixed histology has not been described before and no statistical data are reported in literature so far. Despite the Embryonal Rhabdomyosarcoma variant being the most common, the association characterized by two histological Rhabdomyosarcoma subtypes such as Botryoid and Spindle Cell is rarely observed and it is important to get an accurate histological diagnosis in order to immediately start the correct treatment protocol.

Disease status, reasons for discontinuation and adverse events in 1038 Italian children with juvenile idiopathic arthritis treated with etanercept.

BACKGROUND: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN). METHODS: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment. RESULTS: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis. CONCLUSIONS: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity.

N-Acetylcysteine in hemodialysis diabetic patients resets the activation of NF-kB in lymphomonocytes to normal values.

BACKGROUND: Oxidative stress pathways are activated in diabetes, particularly when dialysis is required (DD). NF-kB is activated in this clinical condition. Since N-Acetyl-cysteine (NAC) is an anti-oxidant, we aimed at investigating its effect in modulating NF-kB activation in lymphomonocytes (PBMC) of DD patients. METHODS: Twenty-five DD patients were enrolled in a cross-over designed study. Tests were performed at T0 and after one month (T1) of treatment with NAC and three months after NAC withdrawal. We assessed NF-kB activation by EMSA, levels of advanced oxidation protein products (AOPP) by spectral analysis, total antioxidant capacity (TAC) by colorimetry, and apoptosis by FACS. RESULTS: At T0 a statistically significant increased activation of the subunits of NF-kB, p50/p65, was detected in PBMC of DD patients in comparison to controls (both P<.0001). After one month of NAC both p50-p50/p50-p65 dimers were significantly reduced (P<.004 and .006). Three months after drug withdrawal NF-kB increased again to basal levels (P<.002 and P<.001 vs. end of treatment with NAC). AOPP and TAC levels and the percentage of apoptotic PBMC revealed modifications in accordance with NFkB activation. In a multivariate linear regression model using delta AOPP as the dependent variable and delta p50-p50, delta TAC, and delta APO as independent variables, we found that all three dependent parameters all retained an independent correlation with delta AOPP. CONCLUSIONS: Our data indicate in vivo a modulation by NAC of parameters indicating a redox imbalance in DD patients on hemodialysis. The use of NAC might suggest a potential clinical benefit.

Human epidermal growth factor receptor 2 status and interval breast cancer in a population-based cancer registry study.

PURPOSE: To determine whether human epidermal growth factor receptor 2 (HER2) -positive status is associated with risk of breast cancer diagnosis in the interval between mammographic screening, we estimated the distribution of features of aggressive tumor behavior in a general population with newly diagnosed breast cancer and known screening status. PATIENTS AND METHODS: We evaluated all invasive breast cancers (N = 641) that were systematically collected by the Parma Province Cancer Registry and diagnosed in women age 50 to 69 years from 2004 to 2007. From this population, 292 screen-detected cancers and 48 interval cases with negative screening mammograms on expert rereading (true interval cancers) were selected for study purposes. Unconditional logistic regression adjusted for age and tumor size was used to determine whether interval cancers were associated with selected clinicobiologic characteristics. RESULTS: Tumors with a high histologic grade (odds ratio [OR], 1.8; 95% CI, 1.2 to 3.8), high proliferative rate (OR, 2.4; 95% CI, 1.2 to 4.5), negative estrogen receptor status (OR, 1.6; 95% CI, 1.1 to 3.1), or HER2-positive status (OR, 3.4; 95% CI, 1.7 to 7.1) were more likely to be diagnosed in the interval between screening. Women age less than 60 years with HER2-positive breast cancer were four times more likely to be diagnosed in the interval between screening compared with only a two-fold increased risk for older women. CONCLUSION: This population-based cancer registry study demonstrated that HER2-positive tumors account for a substantial proportion of mammographic screening failure. The distribution of biologic characteristics in screen-detected cancers differs from that observed in interval cancers and may account in part for the more aggressive behavior of interval-detected cases.