Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases.

BACKGROUND: Limited information is available on the use of natalizumab (NA) in pediatric multiple sclerosis (ped-MS) patients. OBJECTIVE: The purpose of this study was to describe the long-term effects of NA in a large cohort of active ped-MS patients. METHODS: Patients with definite ped-MS were treated with NA if in the previous year they had experienced at least two relapses or a severe relapse with incomplete recovery while on immunomodulating treatment, or at least two relapses and new magnetic resonance imaging (MRI) lesions regardless of any prior treatment. RESULTS: The study included 55 patients (mean age: 14.4 years, mean number of relapses: 4.4, pre-treatment mean disease duration: 25.5 months). They received a median number of 26 infusions. Three relapses occurred during the follow-up, one female patient continued to deteriorate in cognitive functioning. Mean Expanded Disability Status Scale (EDSS) scores decreased from 2.7 to 1.9 at the last visit (p<0.001). During the follow-up the majority of patients remained free from MRI activity. Transient and mild clinical adverse events occurred in 20 patients. Mild hematological abnormalities occurred in seven patients. Anti-JCV antibodies were detected in 20/51 tested patients. CONCLUSIONS: NA was well tolerated in all patients. A strong suppression of disease activity was observed in the majority of patients during the follow-up.

Nitrogen dioxide pollution increases vulnerability to COVID-19 through altered immune function.

Previous ecological studies suggest the existence of possible interplays between the exposure to air pollutants and SARS-CoV-2 infection. Confirmations at individual level, however, are lacking. To explore the relationships between previous exposure to particulate matter < 10 µm (PM10) and nitrogen dioxide (NO2), the clinical outcome following hospital admittance, and lymphocyte subsets in COVID-19 patients with pneumonia. In 147 geocoded patients, we assessed the individual exposure to PM10 and NO2 in the 2 weeks before hospital admittance. We divided subjects according to the clinical outcome (i.e., discharge at home vs in-hospital death), and explored the lymphocyte-related immune function as an index possibly affecting individual vulnerability to the infection. As compared with discharged subjects, patients who underwent in-hospital death presented neutrophilia, lymphopenia, lower number of T CD45, CD3, CD4, CD16/56 + CD3 + , and B CD19 + cells, and higher previous exposure to NO2, but not PM10. Age and previous NO2 exposure were independent predictors for mortality. NO2 concentrations were also negatively related with the number of CD45, CD3, and CD4 cells. Previous NO2 exposure is a co-factor independently affecting the mortality risk in infected individuals, through negative immune effects. Lymphopenia and altered lymphocyte subsets might precede viral infection due to nonmodifiable (i.e., age) and external (i.e., air pollution) factors. Thus, decreasing the burden of air pollutants should be a valuable primary prevention measure to reduce individual susceptibility to SARS-CoV-2 infection and mortality.

Efficacy and tolerability of natalizumab in relapsing-remitting multiple sclerosis patients: a post-marketing observational study.

To evaluate the efficacy and safety of natalizumab in patients with active relapsing-remitting multiple sclerosis (MS). We included 285 MS patients receiving natalizumab. Clinical, neuroradiological and safety data were registered every 6 months. Neutralizing antibodies (NABs) were tested after 6 months of treatment. After 1 year, the annualized relapse rate decreased to 0.26, with a significant reduction compared to the previous year (2.13). At 24 months the proportion of "relapse free" patients was 78% while that of "MRI free" patients was 69%. Considering clinical and MRI cumulative activity, "disease free" patients were 63% at 24 months. A total of 18 patients showed NABs positivity. We reported 34 cases of treatment interruptions. In conclusion, our data confirm the remarkable efficacy of natalizumab in a group of patients with higher disease activity than that of pivotal studies.

Natalizumab therapy of multiple sclerosis: recommendations of the Multiple Sclerosis Study Group--Italian Neurological Society.

Three years after the introduction of natalizumab (NA) therapy for the second line treatment of relapsing-remitting multiple sclerosis (MS), Italian MS centers critically reviewed the scientific literature and their own clinical experience. Natalizumab was shown to be highly efficacious in the treatment of MS. However, the risk of progressive multifocal leukoencephalopathy was confirmed and defined better. This article summarizes the MS-SIN Study Group recommendations on the use of NA in MS, with particular reference to the appropriate selection and monitoring of patients as well as to the management of adverse events.

Three years of experience: the Italian registry and safety data update.

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.

Management of gynecomastia: an outcome analysis in a multicentric study.

AIM: Male gynecomastia (MG), the most frequent mammary anomaly in human males, is a clinical disease occurring mainly in adolescence and old age. The aim of this study was therefore to analyze 126 consecutive cases of mixed gynecomastia, in order to assess the incidence of early and late postoperative complications and to evaluate the aesthetic results and the quality of life after surgery. METHODS: From January 1st, 2000, to December 31st, 2006 a total of 126 cases of MG were performed by the Plastic Surgery Units of Siena and Pisa. Patients' average age was 28 years, 111 patients (88%) presented bilateral MG, and 15 (11.9%) had monolateral MG. The prevalent surgical approach was adenomammectomy with periareolar inferior or inverted "Omega" incision, other technique included circumareolar or vertical scar incision and liposuction. Before and one year after surgery, all patients were given a questionnaires to evaluate the motivations leading to the request of a treatment ,the degree of satisfaction related to the result and the improvement of the quality of life. RESULTS: Overall complication rate was 17.72% All patients reported an improvement in their quality of life with an average score of satisfaction of 8.2/10. CONCLUSION: Patients' degree of satisfaction was high, surgery, in fact, has contributed in all cases to improve their quality of life. On the basis of the short operating time and of the few sequele, we suggest to the patients affected by gynecomastia to undergo surgery always and as soon as possible. A separated analysis of the data obtained by the two University Centres show that they overlap in respect to the sample, the employed technique and results.

[Giant atypical lipoma of the thigh. Case report and literature review]. / Lipoma atipico gigante della coscia. Caso clinico e revisione della letteratura.

Lipomas are benign tumors of mesenchymal origin which may localize in various sites, both superficial or deep. Among the benign tumors they have an incidence of around 10%; most of them have small size and low weight (about 30 g); huge masses (giants lipomas) are uncommon. The Authors report the case of a 73 years old woman, with a large swelling localized at the anterior-medial region of the left thigh, of about three years, completely asymptomatic, surgically excised, and by histological examination, proved to be a giant atypical lipoma.

Analytical identification of additional impurities in urinary-derived gonadotrophins.

Advances in proteomic technology have enabled contaminant proteins to be identified from complex protein mixtures. The purity of two purified urinary gonadotrophin products, human menopausal gonadotrophin (u-HMG) and human FSH (u-hFSH), was compared with a preparation of recombinant human FSH (r-hFSH). After separation by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), western blot analysis showed that the recombinant preparation contained only FSH, whereas the urine-derived preparations exhibited several non-FSH or LH-related bands. These urinary components were further investigated by a proteomic approach using two-dimensional SDS-PAGE followed by mass spectrometric identification. The proteomic approach detected a total of 23 non-gonadotrophin-related proteins, at variable levels in different batches of the urine-derived preparations. Of these, 16 co-purified proteins have not been previously reported to be present in urine-derived gonadotrophins. These results indicate that the process used to purify urinary gonadotrophins may not remove all non-gonadotrophin proteins. By using a comprehensive proteomic approach, it has been shown that the recombinant FSH preparation has greater purity than either of the urine-derived preparations.

HLA-A*01 is associated with late onset of Alzheimer's disease in Italian patients.

In this study, the distribution of HLA-A alleles was analyzed in Italian Alzheimer's Disease (AD)patients. Interaction between HLA alleles, APOE genotypes, age of onset, and gender were also analyzed. The results were compared to those obtained in healthy controls (HC). One hundred-seventy-three AD patients and 258 age-and-sex-matched healthy controls were enrolled in the study. AD patients were classified according to age at the onset of disease using quartiles of the distribution. HLA-A genotyping was performed by PCR-SSP; APOE genotyping was performed by RFLP. A correlation between late disease onset and HLA-A*01 was observed. Thus, HLA-A*01, calculated as number of alleles, was significantly more present in patients with age of onset > 74.0 years than in HC (20% vs 10.5%; p=0.014); the distribution of this allele was skewed also in patients 68.1-74 years of age (16.3%), even if the difference did not reach statistical significance. The relative risk ratio (RRR) of AD onset calculated by a multinomial logistic regression adjusted for sex and presence of APOE-4 confirmed a significant association of HLA-A*01 with AD onset > 74.0 years of age (RRR=2.2; 95%CI: 1.1-4.6; p=0.033). A high RRR (2.04) was also present in patients 68.1-74 years (p=0.064). Lower age of disease onset did not correlate with HLA-A*01. Data herein suggest that the presence of HLA-A*01 results in delayed AD development, even in patients carrying APOE-4. These results could offer new insights into the etiopathogenesis of Alzheimer's disease.

Discontinuation of teriflunomide and dimethyl fumarate in a large Italian multicentre population: a 24-month real-world experience.

BACKGROUND: Teriflunomide (TRF) and Dimethyl fumarate (DMF) are licensed drugs for relapsing-remitting Multiple Sclerosis (RRMS). OBJECTIVES: We aimed to compare the rate and the time to discontinuation among persons with RRMS (pwRRMS), newly treated with TRF and DMF. MATERIALS AND METHODS: A retrospective study on prospectively collected data was performed in nine tertiary MS centers, in Italy. The 24-month discontinuation rate in the two cohorts was the primary study outcome. We also assessed the time to discontinuation and reasons of therapy withdrawn. Discontinuation of TRF and DMF was defined as a gap of treatment ≥ 60 days. RESULTS: A cohort of 903 pwRRMS (316 on TRF and 587 on DMF) was analyzed. During 24 months of follow-up, pwRRMS on TRF and DMF showed similar discontinuation rates. The analysis of predictors with Cox regression model showed differences between the two groups (p for log-rank test = 0.007); male gender [HR 2.21 (1.00-4.90); p = 0.01] and the number of previous switches [HR 1.47 (1.16-1.86); p = 0.01] were associated with higher hazard of discontinuation in the DMF group. CONCLUSIONS: In a real-world setting, pwRRMS on TRF and DMF had similar discontinuation rates over 24 months. Male pwRRMS on DMF with a previous history of therapeutic failure are at more risk of discontinuation therapy.

[Solid pseudo papillary tumor of the pancreas: case report and literature review]. / Tumore solido pseudopapillare del pancreas. Caso clinico e revisione della letteratura.

Solid pseudopapillary neoplasm (SPT) of the pancreas is a rare exocrine tumor, for the first time described from Frantz et al. in 1959. Despite the increasing recognition of the tumor in this last year, its pathogenesis remain unclear. It occurs predominantly in young woman and behave in an indolent fashion, even when distant metastasis are present. The Authors report the case of a 24 years-old woman with an abdominal mass localized in retro-peritoneum, removed with body-tail of the pancreas and spleen, diagnosed as pancreatic SPT after histological examination.

Mayer-Rokitansky-Küster-Hauser syndrome presenting as vaginal atresia: report of two cases.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome) is characterized by Müllerian duct structures agenesis: the vagina atresia is the commonest variant. There can be some anomalies associated, such as renal, skeletal, spine malformations and others. Patients with MRKH can show different presentation from newborn period to adolescence. We report our experience in treatment of the vaginal atresia presenting in two young girls as a sign of MRKH syndrome.

[Post licensure safety surveillance for Prevenar]. / Suivi de pharmacovigilance du vaccin Prevenar.

OBJECTIVE: The aim was to detect as soon as possible a rare but severe or unexpected adverse effect (AE) of Prevenar vaccine. A pharmacovigilance survey was required by the French drug agency (Afssaps) to the regional pharmacovigilance centre of Tours (France). METHOD: Two approaches were used. One based upon systematic reports and the other upon spontaneous reports. Only severe and /or unexpected AEs were recorded. RESULTS: During the 19 months of intensive follow up, 24 AEs (8.7 [5-12.7]/100000 vaccinations) reported by 349 participating paediatricians have been analyzed. Prevenar was the only drug taken in 67% of children. AEs were severe (19 cases) or non severe but unexpected (5 cases). AEs were fever above 39 degrees C (10 cases), cutaneous manifestations (6 cases), neurologic manifestations (5 cases), diarrhoea-vomiting (2 cases), and purulent otitis media (1 case). During the 3.5 years of spontaneous reporting, 130 AEs (6 [5-7]/100000 vaccinations) have been reported and analyzed. AEs were severe (107 cases) or non severe but unexpected (23 cases). AEs were mainly: fever above 39 degrees C (17 cases), cutaneous (39 cases), neurologic (34 cases) and haematological (3 cases) manifestations and diarrhoea-vomiting (5 cases). In 3 children local AE limited the walk (5 cases). DISCUSSION: Our results are not far from north American data (VAERS) regarding incidence, kind of AEs and severity. Abnormal crying, members hypertonia and vascularitis not yet mentioned in Prevenar SPC need to be added. CONCLUSION: Regarding these new data, benefice-risk balance of Prevenar vaccine remains favourable for active immunisation against invasive infections due to pneumococcus in children.

[DRESS syndrome, a drug reaction which remains bad known from paediatricians]. / Le DRESS syndrome, une réaction d'hypersensibilité aux médicaments, qui reste mal connue des pédiatres.

The DRESS syndrome (Rash with Eosinophilia and Systemic Symptoms) is a drug hypersensitivity reaction poorly known by paediatricians. It occurs within 1 to 8 weeks of treatment. Clinical features associate in variable patterns, fever, rash, lymphadenopathies, arthritis and potentially life-threatening damage (hepatitis, nephritis, pneumonitis), hyperleucocytosis and eosinophilia. This condition must be early recognized in order to immediately stop suspect drugs. A 6.5 year old girl had a febrile rash, hyperleucocytosis, lymph nodes and cytolitic hepatitis probably due to phenobarbital. Diagnosis of DRESS syndrome was performed only 13 days after the beginning of the eruption. Evolution was favorable but characterized by the recurrence of the febrile eruption with pleuritis. DRESS syndrome is a well described disease that occurs during treatment with a number drugs, particularly anti-epileptic drugs. Steroid therapy and immunoglobulins are proposed for treatment but have not been evaluated.

Portal dose measurements by a 2D array.

A 2D array (PTW, type 10024), equipped with 729 vented plane parallel ion-chambers, has been calibrated as a detector for the in vivo comparison between measured and predicted portal doses for head-neck tumors. The comparison of absolute portal doses measured to ones predicted by a commercial treatment planning system within the field of view of the CT scanner, can help the delivered dose verification during different treatment fractions, in particular when the patient's present weight loss. This paper reports the preliminary results of the comparison of the portal doses measured by a PTW 2D array during several radiotherapy fractions and the predicted portal doses for seven patients undergoing head-neck tumor radiotherapy. The gamma index analysis supplied an agreement of more than 95% of the dose-point P(gamma)>95% within acceptance criteria, in terms of dose difference, DeltaD(max), and distance-agreement, Deltad(max), equal to 5% and 4mm, respectively. After the third week, one patient showed a decrease of P(gamma) values due to the markedly reduced patient's thickness. Even if the spatial resolution of the 2D array was 1cm, there were two advantages in the use of this 2D array as a portal dose device for IMRT quality control. The first one was the use of a stable and efficient absolute dosimeter for in vivo verification, although its construction and behavior for other gantry angles need to be tested, and the second one was the time efficiency in verifying the correct dose delivery in several fractions of the therapy. This study presents acceptance criteria for the comparison of TPS-predicted portal dose images with in vivo 2D ion-chamber measurements for IMRT. In particular, portal dose measurements offer clues for additional studies as to which indicators can signal the need for replanning during treatment.

[Eosinophilic colitis: an unusual cause of acute abdomen. Case report and review of literature]. / Colite eosinofila: una causa rara di addome acuto. Presentazione di un caso e revisione della letteratura.

The Authors report a case of acute abdomen caused by a colic stenosis due to eosinophilic gastroenteritis. It is a not frequent disease, often clinically unclear: in the medical literature the Authors have found only 346 cases in publications concerning the period January 1990 - December 2005. The clinical presentation is very changeable, related to the involved site of alimentary tract and to the level of eosinophilic infiltration of the wall. There are no diagnosis criteria universally acknowledged and the most efficient procedure is thought being the intestinal biopsy which enables showing the infiltration of the digestive wall. The cure is above all medical with administration of corticosteroid: surgery surely has a less important role, reserved to the cases with acute onset.

[Pharmacovigilance of vaccines]. / Pharmacovigilance des vaccins.

Safety of vaccines must be excellent to make vaccine's strategy acceptable, since it usually has a deferred individual benefit but immediate adverse drug reactions (ADRs). Pharmacovigilance of vaccines after their marketing is crucial because, prior to its availability on the market, the size of clinical trials is insufficient to identify rare or deferred adverse effects. The Pharmacovigilance is based on "spontaneous reporting" of ADRs to the Pharmacovigilance Regional Centre (PVRC) which establishes a relationship between each drug taken by the patient and the ADRs occurrence (imputability). This method is crucial to generate alerts, but under-estimates the real frequency of ADRs (1 to 10% of severe ADRs are reported). Thus pharmacoepidemiology studies are necessary to confirm the alerts identified by spontaneous reporting. ADRs can be specific, related to the antigen of an attenuated alive virus vaccine (lymphocyte meningitis after anti-mumps vaccine) or non-specific, related to a component different from the antigen (aluminium hydroxide involved in the "macrophagic myofasciitis", allergic reactions to neomycin, latex, egg or gelatine). Importance of Pharmacovigilance of vaccines is illustrated. Data, especially case-control studies, about the relationship between multiple sclerosis and hepatitis B vaccine are summarised. Data about the relationship between Crohn's disease or autism and MMR vaccine are analysed. As vaccines are used in healthy people, their safety must be excellent to be accepted. To monitor them after their marketing is the unique way to detect rare ADRs. This surveillance is made through reporting of ADRs to the PVRC. However, an active and intensive surveillance of ADRs as the one set up from the marketing of Prevenar should be systematic.

[Prescriptions and children]. / L'enfant et les médicaments: application à la prescription en pédiatrie.

Because of a lack in drug evaluation in children, they receive many off license drugs prescription, which means drugs prescribed in an indication, dosage, formulation or age different from the license terms. However, drug evaluation is crucial in paediatrics population because of pharmacokinetics and pharmacodynamics modifications throughout organism development, which make usually wrong any extrapolation to children of data obtained in adults. Drug safety is generally better in infants except in newborns who are at a particularly high drug-related risk because of high frequency of off license drug use, many drugs association and drugs metabolism immaturity. The lack of evaluation in children, the fact that children are the unique target population of some drugs or the maturation phenomena explain some adverse effects more specific in children. The more the children are young, the more they are exposed to medication or drug utilization errors. Physician must take what the SPC, as found in the Vidal dictionary, mentions about children into account while prescribing. Drugs with a paediatric license must be preferred overall, however it should be kept in mind that a paediatric license means only that the drug is active in the indication of the license but it doesn't position it regarding other therapeutic alternatives. Off labeling prescription should be based on a supposed benefit, which had to be justified if a severe side effect occurred.

Nipple-areola complex reconstruction techniques: A literature review.

Many techniques for nipple-areola complex (NAC) reconstruction are described. Clarity is required on the currently available options. Since a complete list of all the techniques described until now is not available, a possibly comprehensive literature overview was carried out from 75 papers (years 1946-2015). The local flap was the most frequently described technique for the nipple reconstruction with no significant difference in complications' rate among the various types of techniques. Complications in nipple reconstruction were 46.9% after graft, 7.9% after local flap, and 5.3% in case of flaps with autologous graft/alloplastic/allograft augmentation, while complications in areola reconstruction were 10.1% after graft, and 1.6% after areola tattoo. Flaps appear to be more reliable than grafts in nipple reconstruction, while tattoo is thought to be safer than graft in areola reconstruction. The loss of projection, although considerable (45%-75%), had not significant impact on patients' satisfaction. Due to contraction, overcorrection of 25-50% of the desired result is advisory when adopting local flaps, in order to prevent loss of projection. The use of flaps with autologous graft/alloplastic/allograft augmentation (cartilage, fat, calcium hydroxylapatite, acellular dermal matrix, polymethylmethacrylate, biologic collagen) showed a minor loss of nipple projection but may expose to a relative increased number of postoperative flap necrosis.

Comparative characterisation of a commercial human chorionic gonadotrophin extracted from human urine with a commercial recombinant human chorionic gonadotrophin.

BACKGROUND: A commercial preparation of recombinant human chorionic gonadotrophin (r-hCG, Ovitrelle) was launched in 2001. Generally, hCG is available in two formats: human chorionic gonadotrophin (u-hCG), derived from the urine of pregnant females, and r-hCG produced by DNA based biotechnology. METHOD: The analytical characteristics of a highly purified u-hCG (Gonasi HP) were assessed and compared, for the first time, with the recombinant derived r-hCG (Ovitrelle). Gonasi HP is produced by extracting and purifying hCG from urine to obtain a specific bioactivity of 5000 IU/mg protein. Ovitrelle is produced via a recombinant derived mammalian cell line and purified to obtain a specific activity of 26 000 IU/mg. RESULTS AND CONCLUSION: It has been documented that commercially available u-hCG preparations can contain a number of urine derived protein contaminants as well as hCG related metabolites. This is also the case for Gonasi HP, where hCG related molecules and other proteins were found to be present, including epidermal growth factor (EGF) and eosinophil derived neurotoxin (EDN). It was also demonstrated that this preparation contained high levels of oxidised hCG. r-hCG was confirmed to be essentially intact hCG, free from contaminant proteins and with very low levels of oxidised hCG.