Fabio Vittadello

P16INK4a expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri

The aim of the study was to evaluate the immunohistochemical expression of p16INK4a as a marker of progression risk in low-grade dysplastic lesions of the cervix uteri. p16INK4a immunohistochemistry was performed on 32 CIN1 with proven spontaneous regression of the lesion in the follow-up (group A), 31 (group B) with progression to CIN3 and 33 (group C) that were randomly chosen irrespective of the natural history of the lesion. p16INK4a staining pattern was scored as negative (less than 5% cells in the lower third of dysplastic epithelium stained), as focally positive (≤25%) and as diffuse positive (>25%). A diffuse staining pattern was detected in 43.8% of CIN1 of group A, 74.2% of group B and 56.3% of group C. No p16INK4a staining was detected in 31.3% and 12.9% CIN1 lesions of groups A and B, respectively. Overall, 71.4% and 37.8% of p16INK4a-negative and diffusely positive CIN1 had regressed at follow-up, whereas 28.6% and 62.2% negative and diffusely positive CIN1 were progressed to CIN3, respectively (P<0.05). All CIN3 lesions analyzed during follow-up of group B were diffusely stained for p16INK4a. Although p16INK4a may be expressed in low-grade squamous lesions that undergo spontaneous regression, in this study, CIN1 cases with diffuse p16INK4a staining had a significantly higher tendency to progress to a high-grade lesion than p16INK4a-negative cases. p16INK4a may have the potential to support the interpretation of low-grade dysplastic lesions of the cervix uteri.

Safety and efficacy of infliximab and adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1-year followup data from the Italian Registry.

Objective. To evaluate safety and efficacy of adalimumab (ADA) and infliximab (IFX) for the treatment of juvenile idiopathic arthritis-related anterior uveitis (JIA-AU). Methods. Starting January 2007, patients with JIA-AU treated with IFX and ADA were managed by a standard protocol and data were entered into the National Italian Registry (NIR). At baseline, all patients were refractory to standard immunosuppressive treatment and/or were corticosteroid-dependent. Data recorded every 3 months included uveitis course, number/type of ocular complications, drug-related adverse events (AE), treatment change or withdrawal, and laboratory measures. Data of patients treated for at least 1 year were retrieved from the NIR and analyzed using descriptive statistics. Treatment efficacy was based on change in uveitis course and in number of ocular complications. Results. Up to December 2009, data for 108 patients with JIA-AU treated with anti-tumor necrosis factor-α agents were recorded in the NIR and data from 91, with at least 12 months’ followup, were included in the study. Forty-eight patients were treated with IFX, 43 with ADA. Forty-seven patients (55.3%) achieved remission of AU, 28 (32.9%) had recurrent AU, and 10 (11.8%) maintained a chronic course. A higher remission rate was observed with ADA (67.4% vs 42.8% with IFX; p = 0.025). Ocular complications decreased from 0.47 to 0.32 per subject. Five patients experienced resolution of structural complications. No patient reported serious AE; 8 (8.8%) experienced 11 minor AE (9 with IFX, 2 with ADA). Conclusion. IFX and ADA appear to be effective and safe for treatment of refractory JIA-related uveitis, with a better performance of ADA in the medium-term period.

Methotrexate treatment in juvenile localized scleroderma: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE Juvenile localized scleroderma is a chronic progressive fibrotic disorder of the skin that causes permanent disability and aesthetic damage. This study was undertaken to assess the safety and efficacy of methotrexate (MTX) in the treatment of juvenile localized scleroderma. METHODS In this double-blind study, patients with active juvenile localized scleroderma were randomized (2:1) to receive oral MTX (15 mg/m², maximum 20 mg) or placebo once weekly, for 12 months or until treatment failure. Both groups received oral prednisone (1 mg/kg/day, maximum 50 mg) for the first 3 months. A target lesion was evaluated clinically, with infrared thermography and using a computerized scoring system with skin score rate (SSR) evaluation. Response to treatment was defined as the absence of new lesions, SSR ≤ 1, and a decrease in lesion temperature of at least 10% compared to baseline. Treatment failure was defined as the occurrence of new lesions, SSR > 1, or increased lesion temperature. All analyses were done on the intent-to-treat population. RESULTS Of the 85 patients screened, 70 (ages 6-17 years) were randomized (46 to the MTX group, 24 to the placebo group). The mean disease duration was 2.3 years. After an initial response in all patients, disease relapsed in 15 MTX-treated patients (32.6%) and 17 placebo-treated patients (70.8%) (P < 0.005). New lesions appeared in 3 MTX-treated patients (6.5%) versus 4 placebo-treated patients (16.7%). The mean SSR decreased from 1 to 0.79 in the MTX group and increased from 1 to 1.1 in the placebo group, and the mean target lesion temperature decreased by 44.4% in the MTX group versus 12.1% in the placebo group. Twenty-six patients in the MTX group (56.5%) and 11 patients in the placebo group (45.8%) developed mild side effects related to treatment. None of the side effects were severe enough to necessitate treatment discontinuation. CONCLUSION Our findings indicate that MTX is efficacious in the treatment of juvenile localized scleroderma and is well tolerated.

Ocular involvement in children with localised scleroderma: A multi-centre study

Background: Most of the available documentation in the literature on ocular involvement in localised scleroderma (LS) are descriptions of single cases in adult patients. This article reports the frequency and specific features of ocular involvement in a large cohort of children with juvenile LS (JLS). Methods: Data from a large, multi-centre, multinational study of children with LS were used to collect and analyse specific information on ocular involvement. Results: 24 out of 750 patients (3.2%) revealed a significant ocular involvement. 16 were female and 8 male. 16 patients (66.7%) had scleroderma “en coup de sabre” (ECDS) of the face, 5 (20.8%) had the linear subtype, 2 (8.3%) had generalised morphea (GM) and one (4.2%) had plaque morphea (PM). Of the 24 patients with eye involvement, 10 patients (41.7%) reported adnexa (eyelids and eyelashes) abnormalities, 7 (29.2%) anterior segment inflammation (5 anterior uveitis, 2 episcleritis) and 3 central nervous system-related abnormalities. 4 patients presented single findings such as paralytic strabismus (1), pseudopapilloedema (1) and refractive errors (2). Other extracutaneous manifestations were detected in a significantly higher number of patients with ocular involvement and were mostly neurological. Conclusion: Ocular abnormalities are not unusual in patients with JLS, especially in the ECDS subtype. They are frequently associated with other internal organ involvement, particularly the central nervous system (CNS). Careful ophthalmic monitoring is recommended for every patient with JLS, but is mandatory in those with skin lesions on the face and/or concomitant CNS involvement.

Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes

It is estimated that around 20% of patients with systemic lupus erythematosus (SLE) have their onset in childhood but there have been conflicting data about the prevalence and severity of the clinical features in different age classes. We conducted this study to analyse the clinical features of patients with pediatric SLE (pSLE) with onset in infancy, prepubertal and postpubertal age.The charts of patients followed at the Department of Pediatrics, University of Padua, who met the criteria for SLE diagnosis, were reviewed. Patients were divided into three groups based on age at disease onset: group A, patients ≤2 years old, group B patients aged between 2 and 10 years, group C patients between 11 and 16 years of age. The clinical and laboratory characteristics of each group were compared. Forty-two patients with pSLE entered the study: 2 were diagnosed before the age of 2 years, 11 between 2 and 10 years and 29 between 10 and 16 years. Eleven more patients with infantile (onset <2 years) SLE (iSLE) were found by a systematic literature search on PubMed and EmBASE and added for analysis to the group A. The female preponderance was significant only in postpubertal patients (F:M = 6.3: 1) whereas the other two groups presented a similar F:M ratio (1.2: 1). In comparison with the other two groups, iSLE showed a significantly higher prevalence of cardiovascular and pulmonary involvement, anemia and thrombocytopenia and a shorter disease duration at time of diagnosis. The postpubertal group showed a higher frequency of musculoskeletal involvement and leukopenia. In prepubertal patients there was no female preponderance and the frequency of clinical features was intermediate between infantile and postpubertal patients. Complement fractions level, antinuclear antibodies (ANA), anti-dsDNA, anti-cardiolipin antibodies and lupus anti-coagulant autoantibodies were not significantly different in the three groups. In general, the prevalence of internal organs involvement in pSLE seems to decrease with age. In infants, SLE is more severe than in the following ages. Postpubertal patients have a strong female preponderance and more specific signs of disease at onset. Prepubertal patients have an intermediate disease severity and no gender predilection. Lupus (2007) 16, 550—555.

P16ink4a and HPV L1 Immunohistochemistry is Helpful for Estimating the Behavior of Low-grade Dysplastic Lesions of the Cervix Uteri

As only a minority of low-grade dysplastic lesions of the cervix uteri will eventually progress to carcinoma, predicting the behavior of these lesions could be of high value in clinical practice. The aim of the study was to evaluate p16ink4a and L1 as immunohistochemical markers of the biologic potentiality of low-grade dysplasia of the uterine cervix. The study included 38 conization specimens with coexisting cervical intraepithelial neoplasia grade 1 (CIN1) and 3 (CIN3) (group A) and 28 punch biopsies from women with CIN1 and proven spontaneous regression in the follow-up (group B). In group A, all CIN3 were p16ink4a positive (p16+) and L1 negative (L1−). The CIN1 of this group were p16+L1− and p16+L1+ in 68.42% and 31.57%, respectively. No other expression pattern was found in this group. In group B, the p16+L1−, p16+L1+, p16−L1+, and p16−L1− patterns were found in 3.57%, 25%, 14.29%, and 57.14%, respectively. Overall, 96.29% p16+L1− CIN1 were found in group A, whereas all the p16−L1+ and p16−L1− CIN1 were found in group B. A significant difference between staining pattern distributions of group A and B was observed (P<0.0001). The results of the study show that p16ink4a and L1 immunohistochemistry can be helpful for estimating the biologic potentiality of low-grade squamous cervical lesions. Particularly in cases in which the grade of the lesion is morphologically difficult to assess, the p16/L1 expression pattern could be useful for planning the clinical management of these women.

uCyt+/ImmunoCyt in the detection of recurrent urothelial carcinoma: an update on 1991 analyses.

The authors provide an update on the clinical value and role of the uCyt+/ImmunoCyt™ test as a noninvasive tool for the detection of recurrent urothelial carcinoma.

A long-term follow-up study of methotrexate in juvenile localized scleroderma (morphea).

BACKGROUND Recent studies report that methotrexate (MTX) is beneficial in the treatment of juvenile localized scleroderma (JLS) but little is known about its long-term effectiveness. OBJECTIVE We assessed the therapeutic role of MTX in children with JLS who were followed up for a prolonged period. METHODS A cohort of patients with JLS, previously enrolled in a double-blind, randomized controlled trial and treated with oral MTX (15 mg/m(2)/wk) and prednisone (1 mg/kg/d, maximum 50 mg) for the first 3 months, were prospectively followed up. Lesions were evaluated clinically, with infrared thermography, and by a computerized skin score. Response to treatment was defined as: (1) no new lesions; (2) skin score rate less than 1; and (3) decrease in lesion temperature by at least 10% compared with baseline. Clinical remission (CR) on medication was defined when response was maintained, on treatment, for at least 6 months, and complete CR when response was maintained, without treatment, for at least 6 months. RESULTS Of 65 patients treated with MTX, 48 (73.8%) were responders, 10 (15.4%) relapsed by 24 months since MTX start, and 7 (10.8%) were lost to follow-up. Among the responders, 35 (72.9%) maintained CR for a mean of 25 months and 13 (27.1%) were in CR on medication. Adverse effects seen in 28 patients (48.3%) were generally mild and never required treatment discontinuation. LIMITATIONS The use of objective measures not widely available, such as infrared thermography and computerized skin score, makes it difficult to compare data from previous studies. CONCLUSIONS Long-term MTX therapy is beneficial and well tolerated for JLS.

Clinical Features and Outcome of Cogan Syndrome

OBJECTIVE To review the clinical features of Cogan syndrome, a rare vasculitis characterized by systemic, ocular, and audiovestibular symptoms. STUDY DESIGN Clinical records of patients with Cogan syndrome followed at 2 pediatric rheumatology institutions and those from a database search were reviewed. Data included clinical features at onset and during the disease course, treatments, and outcomes. RESULTS Twenty-three children with Cogan syndrome (15 males; mean age, 11.4 years [range, 4-18 years]) were included in the analysis. Eleven patients (47.8%) exhibited systemic features at disease onset, including fever, arthralgias-arthritis or myalgias, headache, and weight loss. Twenty-one patients (91.3%) had ocular symptoms, due mainly to interstitial keratitis, uveitis, or conjunctivitis/episcleritis. Vestibular symptoms (39.1%) included vertigo, vomiting, and dizziness. Auditory involvement (65.2%) consisted of sensorineural hearing loss, tinnitus, and deafness. Four patients had cardiac valve involvement, and 3 had skin manifestations. After a median 2 years of follow-up, 30.4% of the patients were in clinical remission, but all others had irreversible complications (deafness, 21.7%; sensorineural hearing loss, 13.0%; vestibular dysfunction, 4.3%; ocular complications, 13.0%; cardiac valve damage, 17.4%). CONCLUSION Audiovestibular and ocular involvement have a major impact on prognosis in children with Cogan syndrome.

Usefulness of p16ink4a, ProEX C, and Ki-67 for the diagnosis of glandular dysplasia and adenocarcinoma of the cervix uteri.

Although the diagnostic criteria of in-situ and invasive adenocarcinomas of the cervix uteri are well established, the differentiation from benign mimics may be difficult and the morphologic features of the precursors of endocervical adenocarcinoma are still debated. In this study, we evaluated the usefulness of p16ink4a (p16), ProEX C, and Ki-67 for the diagnosis of endocervical adenocarcinoma and its precursors. Immunohistochemistry with p16, ProEX C, and Ki-67 was performed in 82 glandular lesions including 15 invasive adenocarcinomas, 29 adenocarcinomas in situ (AIS), 22 non-neoplastic samples, and 16 cases of glandular dysplasia (GD), which showed significant nuclear abnormalities but did not meet the diagnostic criteria for AIS. The immunohistochemical expression pattern was scored according to the percentage of the stained cells (0, 1+, 2+, and 3+ when 0% to 5%, 6% to 25%, 26% to 50%, and more than 50% of the cells were stained, respectively) and was evaluated for each antibody. p16 was at least focally expressed (1+ or more) in 14 of 15 invasive adenocarcinomas, in all AIS and in 7 negative samples. ProEX C and Ki-67 both scored 1+ or more in all adenocarcinomas and AIS and in 8 and 6 negative samples, respectively. Of the GD 15, 14, and 15 expressed p16, ProEX C, and Ki-67, respectively. The score differences between neoplastic and non-neoplastic samples were highly significant for each marker (P<0.001); however, the score distribution by marker differed significantly only in GD (P=0.006) in which, compared with the other markers, p16 showed more often a 3+ pattern. Our study shows that p16, Ki-67, and ProEX C may be helpful for the diagnosis of glandular lesions of the cervix uteri and may also improve the diagnostic accuracy of endocervical GD. In particularly problematic cases, the combination of p16 and a proliferation marker can provide additional help for the interpretation of these lesions.