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Background COVID-19 pandemic was responsible for disrupting routine immunization activities all over the world. Aim of the study was to investigate the reduced adherence to the national children vaccination schedule during the lockdown period in Italy. Materials and methods Through social channels, the Italian Pediatric Society conducted a survey among Italian families on children vaccination during lockdown period. Results In the study period, 1474 responders were collected. More than one third (34%) of them skipped the vaccine appointment as they were afraid of SARS-CoV-2-virus (44%), vaccination services postponed the appointment (42%) or was closed to public (13%). Discussion Reduction in routine immunization coverage may represent a serious life-threating problem for unvaccinated or under-vaccinated children. Conclusions Information on national and local preventive measures including physical distancing, handwashing, and proper coughing/sneezing hygiene should be spread among families in order to contrast vaccine hesitancy and maintain adequate coverage levels during COVID19 pandemic period.

Limited data exist regarding sex bias and viral decay in children with HIV. We investigated the sex differences in viral decay in 25 perinatally HIV-infected children. Females presented faster phase I viral decay regardless of their age at antiretroviral therapy (ART) initiation, baseline CD4 percentages, or baseline RNA levels. Also, for each month elapsed under ART, females had faster viral decay than males.

BACKGROUND Recent evidence suggests that neutralizing antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 may persist over time; however, knowledge regarding pediatric subjects is limited. METHODS A single-center, prospective observational study was conducted on 57 family clusters of coronavirus disease 2019, including children of neonatal and pediatric age attending the University Hospital of Padua (Italy). For each patient, blood samples were collected for both the quantification of nAbs through a plaque reduction neutralizing test and the detection of antinucleocapsid-spike protein immunoglobulin G and/or immunoglobulin M. RESULTS We analyzed 283 blood samples collected from 152 confirmed coronavirus disease 2019 cases (82 parents and 70 children or older siblings of median age of 8 years, interquartile range: 4–13), presenting asymptomatic or with mildly symptomatic disease. Despite the decrease of immunoglobulin G over time, nAbs were found to persist up to 7 to 8 months in children, whereas adults recorded a modest declining trend. Interestingly, children aged CONCLUSIONS Mild and asymptomatic severe acute respiratory syndrome coronavirus 2 infections in family clusters elicited higher nAbs among children.

Purpose We described clinical, immunological, and molecular characterization within a cohort of 22 RAG patients focused on the possible correlation between clinical and genetic data. Methods Immunological and genetic features were investigated by multiparametric flow cytometry and by Sanger or next generation sequencing (NGS) as appropriate. Results Patients represented a broad spectrum of RAG deficiencies: SCID, OS, LS/AS, and CID. Three novel mutations in RAG1 gene and one in RAG2 were reported. The primary symptom at presentation was infections (81.8%). Infections and autoimmunity occurred together in the majority of cases (63.6%). Fifteen out of 22 (68.2%) patients presented autoimmune or inflammatory manifestations. Five patients experienced severe autoimmune cytopenia refractory to different lines of therapy. Total lymphocytes count was reduced or almost lacking in SCID group and higher in OS patients. B lymphocytes were variably detected in LS/AS and CID groups. Eighteen patients underwent HSCT permitting definitive control of autoimmune/hyperinflammatory manifestations in twelve of them (80%). Conclusion We reinforce the notion that different clinical phenotype can be found in patients with identical mutations even within the same family. Infections may influence genotype–phenotype correlation and function as trigger for immune dysregulation or autoimmune manifestations. Severe and early autoimmune refractory cytopenia is frequent and could be the first symptom of onset. Prompt recognition of RAG deficiency in patients with early onset of autoimmune/hyperinflammatory manifestations could contribute to the choice of a timely and specific treatment preventing the onset of other complications.

Background Congenital malaria is usually defined as the detection of asexual forms of Plasmodium spp. in a blood sample of a neonate during perinatal age if there is no possibility of postpartum infection by a mosquito bite. The incidence of congenital malaria is highly variable and seems related to several factors, such as different diagnostic methods for Plasmodium spp. detection, and area in which the epidemiologic analyses are performed. In non-endemic countries, cases of congenital malaria are rare. Hereby, a case of a congenital malaria in an HIV exposed child is reported. Case presentation A 2-month-old male child was admitted to Bambino Gesù Children’s Hospital due to anaemia and exposure to HIV. He was born prematurely in Italy by cesarean section at 34 weeks’ gestation after a bicorial, biamniotic pregnancy by a migrant woman from Nigeria. He was the first of non-identical twins. Combined with anaemia, spleen and liver enlargement was noted, malaria was hypothesized. Malaria laboratory panel was performed on the newborn, mother and other twin blood samples, as follows: (i) malaria rapid diagnostic test (RDT); (ii) Giemsa-stained thick and thin blood smears for Plasmodium spp. identification and parasitaemia titration; (iii) molecular screening and typing of Plasmodium spp. by multiplex qualitative PCR assay based on 18S rRNA gene. Genotyping of Plasmodium falciparum isolates from mother and child was performed by neutral microsatellite and highly polymorphic marker amplification. Conclusions The maternal RDT sample was negative, while the infant RDT was positive; in both cases microscopy of blood smears and PCR showed infection with P. falciparum. Two of the genotypic molecular markers displayed different allelic variants between the two samples. This difference could imply infection multiplicity of the mother during the pregnancy, possibly harbouring more than one isolate, only one of them being transmitted to the newborn while the other persisting in the mother’s blood. Because of the increasing number of pregnant women coming from endemic areas for malaria, an accurate anamnesis of infant’s mother, and the inclusion of Plasmodium spp. research into TORCH screenings for mother-infant pair at birth, aiming at reducing morbidity and mortality associated to the disease might be suitable.

Hypoalbuminemia is considered a predictor of adverse outcomes in critically ill children1 and in adults affected by COVID-192, 3 . This article is protected by copyright. All rights reserved.

Aim of these revised recommendations for the general management of Kawasaki disease is to encourage its prompter recognition and warrant the most appropriate therapy, based on ascertained scientific data, raising awareness of the complications related to misdiagnosis or delayed treatment. A set of 20 synthetic operative statements is herein provided, including the definition of Kawasaki disease, its protean presentations, clinical course and seminal treatment modalities of all disease phases. The application of these recommendations should improve prognosis of Kawasaki disease and prevent the progression to permanent vascular abnormalities, thereby diminishing morbidity and mortality.

To evaluate the correlation between sacral/vertebral anomalies and spinal cord anomalies (SCA) on MRI, in patients with anorectal malformation (ARM).Patients with ARM consecutively treated between January 1999 and August 2019 were included. Radiological imaging of sacrum and spine were retrospectively analyzed and correlated to the presence of SCA at MRI. Fisher's exact test and X348 patients with ARM were enrolled in the study, 147 presented SCA at MRI. 144 patients showed spinal bone anomalies, isolated vertebral and sacral anomalies were found in 17,6% and 35% respectively. Higher level of ARM was associated with a significant higher prevalence of sacral and vertebral anomalies. A significant correlation was found between the "level" of ARM and the presence of SCA (p0.05). Sacral anomalies were significantly correlated with the presence of SCA at MRI (p0.05). SCA were found in 70% of patients with vertebral anomalies (VA) and in 76% of patients with sacral anomalies. The presence of multiple malformations (vertebral and sacral anomalies) are strictly related to the presence of SCA. However, the absence of spinal bone anomalies does not exclude the presence of SCA. SD was the most represented type of SCA (n=94/147), of those 96% had fatty filum. Neurological or neurourological symptoms were detected in 11,5% patients (n=17) with SCA and required neurosurgical intervention.Our data confirm the strong relation between sacral or vertebral anomalies and SCA. However, in our series also patients without sacral/vertebral anomalies had SCA at MRI. Our results suggest that, despite the presence or absence of spinal anomalies, spinal cord MRI should be performed in all children with ARM, to allow a correct multidisciplinary follow-up and treatment. In fact, most patients with spinal bone and SCA are asymptomatic, but could develop clinical manifestations during their growth.

Purpose To evaluate ocular manifestations and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) prevalence in the tears of children with coronavirus disease 2019 (COVID-19). Methods A total of 27 pediatric patients with confirmed COVID-19 infection hospitalized from March 16 to April 15, 2020, at the Bambino Gesu Children's Hospital were enrolled in the study. At admission, all patients showed ocular manifestations. Reverse transcriptase–polymerase chain reaction from nasopharyngeal and conjunctival swabs were performed every 2-3 days before discharge. Results Of the 27 patients, 4 (15%) were asymptomatic, 15 (56%) showed respiratory symptoms, and 8 (30%) had gastrointestinal symptoms. At admission, nasopharyngeal swabs were positive for COVID-19 in all patients; on the second swabs, 7 children (26%) tested negative, and 20 remained positive for COVID-19. Ocular manifestations consistent with mild viral conjunctivitis were observed in 4 patients (15%). At first conjunctival swab, 3 patients (11%), 1 symptomatic and 2 asymptomatic for ocular infection, had positive findings for COVID-19; 2 became negative on the second test and 1 on the third. Conclusions In our study cohort, ocular manifestations of COVID-19 seem to have had a milder clinical course in pediatric patients than in adults. Despite the low prevalence and rapid regression of viral presence in the conjunctiva, SARS-CoV-2 transmission through tears may be possible, even in patients without apparent ocular involvement.

Background Strategies aimed at antiretroviral therapy (ART)–free remission will target individuals with a limited viral reservoir. We investigated factors associated with low reservoir measured as total human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood mononuclear cells (PBMCs) in perinatal infection (PaHIV). Methods Children from 7 European centers in the Early Treated Perinatally HIV Infected Individuals: Improving Children’s Actual Life (EPIICAL) consortium who commenced ART aged 5 years were included. Total HIV-1 DNA was measured by quantitative polymerase chain reaction per million PBMCs. Factors associated with total HIV-1 DNA were analyzed using generalized additive models. Age, VL at ART initiation, and baseline CD4% effects were tested including smoothing splines to test nonlinear association. Results Forty PaHIV, 27 (67.5%) female 21 (52.5%) Black/Black African, had total HIV-1 DNA measured; median 12 (IQR, 7.3–15.4) years after ART initiation. Eleven had total HIV-1 DNA 6 logs. The effect of CD4% (coefficient = 0.03 ± 0.01, P = .049) was not maintained >40%. Conclusions In this PaHIV cohort, reduced total HIV-1 DNA levels were associated with younger age and lower VL at ART initiation. The impact of early-infant treatment on reservoir size persists after a decade of suppressive therapy., Initiation of antiretroviral therapy at a younger age and lower plasma viral load were associated with a lower HIV-1 viral reservoir in peripheral blood mononuclear cells after more than a decade of sustained virological suppression.

Background Current national immunisation schedules differ between countries in terms of vaccine formulation, timing of vaccinations and immunisation programme funding and co-ordination. As a result, some HIV infected paediatric population may be left susceptible to vaccine preventable infections. Vaccines used in healthy population should be subjected to high quality ethical research and be explicitly validated for use in children with special vaccination needs such as those infected with HIV. This survey was completed to assess current vaccination practices and attitudes toward vaccination among pediatricians who care for vertically HIV infected children. Methods An online questionnaire was completed by 46 experts in paediatric HIV-infection from the Paediatric European Network for Treatment of AIDS (PENTA). Data were collected between November 2013 and March 2014. Results 46 units looking after 2465 patients completed the questionnaire. The majority of units (67%) reported that common childhood immunisation were administered by the family doctor or local health services rather than in the HIV specialist centre. Vaccination histories were mostly incomplete and difficult to obtain for 40% of the studied population. Concerns were reported regarding the use of live attenuated vaccines, such as varicella and rotavirus, and these were less frequently recommended (61% and 28% of the units respectively). Monitoring of vaccine responses was employed in a minority of centres (41%). A range of different assays were used resulting in diverse units of measurement and proposed correlates of protection. Conclusion Vaccination practices for perinatally HIV-infected children vary a great deal between countries. Efforts should be made to improve communication and documentation of vaccinations in healthcare settings and to harmonise recommendations relating to additional vaccines for HIV infected children and the use of laboratory assays to guide immunisation. This will ultimately improve coverage and vaccine induced immunity in this vulnerable patient group.

Anti-CD20 therapy is effective in idiopathic nephrotic syndrome (INS). However, transient or sustained hypogammaglobulinemia predisposing to an increased risk of infectious diseases can follow treatment in some patients. We analyzed the long-term effects of anti-CD20 therapy on immunological memory in 27 frequently-relapsing/steroid-dependent INS pediatric patients after more than 4 years from the first and at least 2 years from the last anti-CD20 infusion. Twenty-one INS children, never treated with anti-CD20 and under an intense oral immunosuppression with prednisone, mycophenolate mofetil, and calcineurin inhibitors were also included as control group. Levels of circulating B-cell subpopulations, total serum immunoglobulins and IgG and memory B cells directed against hepatitis B virus (HBV) and tetanus were determined and correlated with clinical characteristics. Nine patients never relapsed after more than 2 years from the last anti-CD20 administration (5 after the first, 3 after the second, and 1 after the fifth infusion). At last follow-up, most patients showed a complete recovery and normalization of total (27/27), transitional (27/27), and mature-naïve B cells (25/27). However, a sustained and significant reduction of total memory (20/27) and switched memory (21/27) B cells was found in most patients. 11/27 patients showed hypogammaglobulinemia at last follow-up and, among these, four presented with a severe hypogammaglobulinemia (IgG < 160 mg/dl). In contrast, no patient in the control group developed a severe hypogammaglobulinemia. Age at the time of first anti-CD20 administration was positively associated with IgG levels at last follow-up (p = 0.008); accordingly, younger patients had an increased risk of hypogammaglobulinemia (p = 0.006). Furthermore, severe hypogammaglobulinemia and delayed switched memory B-cell reconstitution were more frequent in non-relapsing patients. Reduced IgG levels against HBV and tetanus were observed at baseline and further declined at last follow-up. Antigen-specific memory B-cells were induced by re-immunization, but specific IgG titers remained low. In conclusion, anti-CD20 therapy can be disease-modifying in some INS patients. However, a prolonged impairment of immunological memory occurs frequently, independently from the number of anti-CD20 infusions, particularly in younger patients. Re-immunization may be necessary in these patients.

There are limited data on infants with HIV starting antiretroviral therapy (ART) in the neonatal period. We investigated the association between the timing of ART initiation and time-to-suppression among infants who tested HIV-positive and initiated ART within the first 28 days of life. The effect was estimated using cumulative probability flexible parametric spline models and a multivariable generalized additive mixed model was performed to test non-linear associations. Forty-four neonates were included. Nineteen (43.2%) initiated ART within 7 days of life and 25 (56.8%) from 8 to 28 days. Infants treated within 7 days were 4-fold more likely to suppress earlier than those treated after 7 days (HR 4.01 [1.7;9.5]). For each week the ART initiation was delayed, the probability of suppression decreased by 35% (HR 0.65 [0.46;0.92]). Age at ART start was linearly associated with time-to-suppression. However, a linear association with normally distributed residuals was not found between baseline VL and time-to-suppression, with no association found when baseline viral loads were ≤ 5 log(10) copies/ml, but with exponential increase in time-to-suppression with > 5 log(10) copies/ml at baseline. Starting ART within 7 days of life led to 4-fold faster time to viral suppression, in comparison to initiation in 8 to 28 days. Proyecto EPIICAL, Fundación PENTA-ID. 3.475 JCR (2019) Q2, 79/159 Inmunology 2.165 SJR (2019) Q1, 24/303 Infectious Diseases No data IDR 2019 UEM

Routine vaccination is among the most effective clinical interventions to prevent diseases as it is estimated to save over 3 million lives every year. However, the full potential of global immunization programs is not realised because population coverage is still suboptimal. This is also due to the inadequate immune response and paucity of informative correlates of protection upon immunization of vulnerable individuals such as newborns, preterm infants, pregnant women, and elderly individuals as well as those patients affected by chronic and immune compromising medical conditions. In addition, these groups are undervaccinated for a number of reasons, including lack of awareness of vaccine-preventable diseases and uncertainty or misconceptions about the safety and efficacy of vaccination by parents and healthcare providers. The presence of these nonresponders/undervaccinated individuals represents a major health and economic burden to society, which will become particularly difficult to address in settings with limited public resources. This review describes innovative and experimental approaches that can help identify specific genomic profiles defining nonresponder individuals for whom specific interventions might be needed. We will provide examples that show how such information can be useful to identify novel biomarkers of safety and immunogenicity for future vaccine trials. Finally, we will discuss how system biology “OMICs” data can be used to design bioinformatic tools to predict the vaccination outcome providing genetic and molecular “signatures” of protective immune response. This strategy may soon enable identification of signatures highly predictive of vaccine safety, immunogenicity, and efficacy/protection thereby informing personalized vaccine interventions in vulnerable populations. This work was supported by Associazione Volontari Bambino Gesù and Ricerca Corrente Ospedale Pediatrico Bambino Gesù 2017/2018. The Precision Vaccines Program is supported in part by NIH/NIAID Human Immunology Project Consortium U19 AI118608 and an internal award from the Boston Children’s Hospital Department of Pediatrics SI

To analyze the outcome after untethering surgery in patients with spinal dysraphism (SD), with or without associated anorectal malformation (ARM). Patients operated on for SD, with (Group A) or without (Group B) associated ARM (1999–2015), were included. The post-operative outcome was analyzed in the two groups in terms of improving of clinical symptoms (neuro-motor deficits, bladder dysfunction, bowel dysfunction) and of instrumental examinations (urodynamics, bladder ultrasound, neurophysiology). Fisher’s exact test and χ2 test were used as appropriate; p

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition. Variants in different genes have been associated with the familial forms of the syndrome (FHL), usually presenting within the first 2 years of life. Due to increasing awareness of the signs and symptoms of HLH and a better understanding of the genetic basis of the disease, FHL has been increasingly diagnosed in patients presenting beyond infancy. Here, we report on two brothers with atypical, late-onset HLH in which whole exome sequencing revealed a homozygous pathogenic UNC13D variant. In the first brother, the clinical phenotype was dominated by a massive lung involvement. In the second brother a progressive neurological deterioration was observed. In both cases, the clinical manifestations at symptom onset were misleading, making the diagnosis difficult to achieve. This report expands the spectrum of clinical presentations of FLH3. Moreover, it highlights the importance to warn clinicians to keep a high level of suspicion in patients presenting with fever, cytopenia, splenomegaly of unknown origin, and unresponsiveness to conventional treatment even beyond early childhood. Moreover, this report emphasizes that insidious neurologic symptoms may represent the initial or sole presenting sign of FHL, even in the absence of peripheral signs of activation.

Short summary: The EPIICAL (Early-treated Perinatally HIV-infected Individuals: Improving Children's Actual Life with Novel Immunotherapeutic Strategies) project arises from the firm belief that perinatally infected children treated with suppressive antiretroviral therapy (ART) from early infancy represent the optimal population model in which to study novel immunotherapeutic strategies aimed at achieving ART-free remission. This is because HIV-infected infants treated within 2–3 months of life have a much reduced viral reservoir size, and rarely show HIV-specific immunity but preserve normal immune development. The goal of EPIICAL is the establishment of an international collaboration to develop a predictive platform using this model to select promising HIV therapeutic vaccine candidates, leading to prioritisation or deprioritisation of novel immunotherapeutic strategies.To establish this platform, the EPIICAL Consortium aims to: develop predictive models of virological and immunological dynamics associated with response to early ART and to treatment interruption using available data from existing cohorts/studies of early-treated perinatally HIV-infected children; optimise methodologies to better characterise immunological, virological and genomic correlates/profiles associated with viral control; test novel immunotherapeutic strategies using in vivo proof-of-concept (PoC) studies with the aim of inducing virological, immunological and transcriptomic correlates/profiles equivalent to those defined by the predictive model. This approach will strengthen the capacity for discovery, development and initial testing of new therapeutic vaccine strategies through the integrated efforts of leading international scientific groups, with the aim of improving the health of HIV-infected individuals.

Background Chronic Granulomatous Disease (CGD) is a primary immunodeficiency of phagocytes, characterized by life-threatening infections and hyperinflammation. Due to survival improvement, Inflammatory Bowel Disease (IBD) is becoming increasingly relevant. Here we report our 20-year experience. Methods We retrospectively analyzed clinical, endoscopic and histologic features, as well as the management of CGD-IBD patients referred to the Bambino Gesu Children's Hospital in Rome, Italy. Results Out of 20 CGD patients, 9 presented with CGD-IBD at diagnosis and/or during follow-up. Symptoms occurred at a median age of 16 years (range 3.2-42), with a median delay of 6 months for endoscopic confirmation. Patients mainly complained of nonspecific diarrhea (55%), with discrepancy between symptom paucity and severe endoscopic appearance, mainly represented by extensive colonic involvement (44%). Histology revealed at least 2 characteristic features (epithelioid granulomas, pigmented macrophages, and increased eosinophils) in 78% of patients. Eight out of 9 patients received oral mesalamine and 5 required systemic steroids. One patient received azathioprine due to steroid dependence. No patient required biological therapy, or surgery. Clinical remission was obtained in all patients, but the majority complained of mild relapses. Two episodes of severe infection occurred early after steroid therapy. Conclusions Penetrance of CGD-IBD increases with age. Clinical manifestations may be subtle, and clinicians should have a low threshold to recommend endoscopy. Treatment with NSAIDs and/or steroids achieves a good response, but relapses usually occur. Infection surveillance is mandatory during treatment, in order to prevent opportunistic infections. A close collaboration between Immunologists and Gastroenterologists is pivotal, including combined follow-up. This article is protected by copyright. All rights reserved.

To describe the association of anorectal malformation (ARM) and spinal dysraphism (SD) in terms of impact on the management of SD and embryogenetic implications. Patients with SD associated with (A) or without (B) ARM were included. The two groups were further divided into operated on (A1/B1) or not (A2/B2) for SD. Groups A and B were compared for type of SD (embryogenetic classification) and prevalence of neurosurgery; Groups A1 vs. A2 for type of ARM (Wingspread classification); Groups A1 vs. B1 for age at neurosurgery, neurophysiology, and clinical symptoms. One hundred twenty-one patients with SD, 83 with and 38 without ARM were consecutively treated (1999–2015). Group A was associated only with SDs developing after primary neurulation, corresponding to the period of cloacal septation and organogenesis (p = 0.0007). Untethering surgery was significantly less frequent in Group A (p

This study aimed to compare the interobserver Cohen κ on HE staining and on HE plus p16(INK4a) staining of all cervical biopsy specimens in a population-based screening program.All the colposcopy-guided biopsies generated by the routine screening of 23,258 women aged 25 to 64 years were stained with HE and HE plus p16. Biopsy specimens were reviewed by six external experts.The four diagnoses were available in 441 cases. The interobserver κ values were 0.52 (95% confidence interval [CI], 0.45-0.58) and 0.48 (95% CI, 0.42-0.56) with HE and HE + p16, respectively, when using a five-group classification (normal, CIN 1, CIN 2, CIN 3, and cancer); adopting a two-group classification (≤CIN 1 and ≥CIN 2), the values were 0.75 (95% CI, 0.66-0.82) and 0.70 (95% CI, 0.61-0.79), respectively.The use of p16 on all cervical biopsy specimens in a screening program showed virtually no effect on reproducibility of the histologic diagnosis.

P16-INK4A overexpression has been proposed as a prognostic marker to manage the follow up of women with positive cytology and/or HPV test but without high-grade cervical intraepithelial neoplasia (CIN2+). This study measures the relative risk (RR) of CIN2+ of p16 positive versus negative in these women. All the women referred to colposcopy from October 2008 to September 2010 with negative or CIN1 colposcopy-guided biopsy were included in the study; women surgically treated or having a CIN2-3 were excluded. All baseline biopsies were dyed with hematoxylin and eosin and p16. Women were followed up according to screening protocols, with cytology or colposcopy at 6 or 12 months. CIN2/3 RRs and 95% confidence intervals (95%CI) were computed. Of 442 eligible women, 369 (83.5%) had at least one follow-up episode. At baseline, 113 (30.6%) were CIN1, 248 (67.2%) negative, and 8 (2.2%) inadequate histology; 293 (79.4%) were p16-negative, 64 (17.3%) p16 positive and 12 (3.2%) not valid. During follow up, we found ten CIN2 and three CIN3; of these, six were p16 positive (sensitivity 46%, 95% CI 19-75). The absolute risk among p16 positives was 9.4/100 compared to 1.7/100 of the p16 negatives (RR 5.5; 95% CI 1.7-17.4). The risk was also higher for CIN1 than for histologically negative women (RR 4.4; 95% CI 1.3-14.3). The RR for p16 in CIN1 did not change (RR 5.2; 95% CI 0.6-47.5). P16 overexpression is a good candidate for modulating follow-up intensity after a negative colposcopy but is limited by its low prospective sensitivity.

The present study aims to identify clinical and pathological factors that can predict the risk of spinal cord anomalies (SCA) in patients with anorectal malformations (ARM), the need for neurosurgery, and to define the impact of SCA on the outcome of patients with ARM. A 16-year retrospective analysis of all patients treated at a single tertiary children’s Hospital with diagnosis of ARM. Data were collected to assess the impact of defined clinical characteristics on prevalence of SCA (detected at MRI). Children surgically treated or not for SCA were compared for age, clinical symptoms and type of anomalies at surgery or at last follow-up, respectively. Moreover, patients with intermediate/high ARMs, with or without SCA were compared for neurogenic bladder (NB), constipation, soiling and need for bowel management (BM). Two hundred and seventy-five children were treated for ARM in the study period, 142 had spinal MRI that showed SCA in 85. Patients with SCA had significantly higher prevalence of preterm birth (p

Background This Phase IV study evaluated the safety and immunogenicity of a two-dose, MF59 ® -adjuvanted (Novartis Vaccines, Marburg, Germany), monovalent, A/H1N1 pandemic influenza vaccination schedule in Human Immunodeficiency Virus (HIV) positive children and young adults. Methods A total of 83 children infected with HIV-1, and 37 non-immunocompromised, age-matched controls were enrolled. All participants received two vaccine doses administered three weeks apart. Antibody responses were assessed by haemagglutination assay at baseline, three weeks after each vaccine dose, and six months after immunization. Vaccines were evaluated according to European influenza vaccine licensure criteria. Results The investigational vaccine was well tolerated. After the first vaccine dose, seroconversion rates were significantly lower in HIV-positive patients (60%) than controls (82%), with GMTs of 419 and 600, respectively. No significant differences in seroconversion rates were observed between the two study groups in response to the second vaccine dose. Persisting antibody titers were similar for both HIV-positive and non-infected controls, six months after immunization. Conclusion One dose of MF59-adjuvanted vaccine was sufficient to provide adequate levels of seroprotection against A/H1N1 influenza disease in HIV-positive children. However, a two-dose vaccination schedule may be optimal for this population.

Large cell carcinomas (LCCs) of the lung are heterogeneous and may be of different cell lineages. We analyzed 56 surgically resected lung tumors classified as LCC on the basis of pure morphologic grounds, using a panel of immunophenotypic markers (adenocarcinoma [ADC]-specific, thyroid transcription factor-1, cytokeratin 7, and napsin A; squamous cell carcinoma [SQCC]-specific, p63, cytokeratin 5, desmocollin 3, and Δnp63) and the quantitative analysis of microRNA-205 (microRNA sample score [mRSS]). Based on immunoprofiles 19 (34%) of the cases were reclassified as ADC and 14 (25%) as SQCC; 23 (41%) of the cases were unclassifiable. Of these 23 cases, 18 were classified as ADC and 5 as SQCC according to the mRSS. Our data show that an extended panel of immunohistochemical markers can reclassify around 60% of LCCs as ADC or SQCC. However, a relevant percentage of LCCs may escape convincing immunohistochemical classification, and mRSS could be used for further typing, but its clinical relevance needs further confirmation.

Background Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. Methods In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. Findings Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. Interpretation Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. Funding Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).

BACKGROUND: Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. SETTING: We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting antiretroviral therapy (ART)

The reproducibility of cervical histology diagnoses is critical for efficient screening and to evaluate the effectiveness of new technologies. The vast majority of cervical intraepithelial neoplasia (CIN) diagnoses reported in the New Technologies for Cervical Cancer study were blindly reviewed by 2 independent pathologists. Only H&E-stained slides were used for the review. The reviewers were asked to reclassify cases using the following categories: normal CIN 1, CIN 2, CIN 3, and squamous and glandular invasive cancer. We reviewed 1,003 cases. The interobserver agreement was 0.36 (95% confidence interval [CI], 0.32–0.40) with an unweighted κ and 0.54 with a weighted κ (95% CI, 0.50–0.58). The κ values from dichotomous classifications with the threshold at CIN 2 were 0.69 (95% CI, 0.64–0.73) and 0.57 (95% CI, 0.51–0.63) with the threshold at CIN 3. The CIN 2 diagnosis had the lowest class-specific agreement, with fewer than 50% of cases confirmed by the panel members, which supports the fact that CIN 2 is not a well-defined stage in the pathogenesis of cervical neoplasia.

Aims and background The presence of nodal metastases in patients with primary cutaneous melanoma adversely affects the biological behavior and is related to a poor prognosis. The role of sentinel lymph node biopsy is still debated. The aim of this study was to evaluate the prognostic role of sentinel lymph node biopsy with respect to disease-free period and overall survival. Patients and methods Patients with invasive cutaneous melanoma who underwent sentinel lymph node biopsy in the Santa Chiara Hospital of Trento between October 1997 and December 2002 were evaluated. The lymph nodes were examined with conventional histology, S100 and tyrosinase in immunohistochemistry, and tyrosinase in molecular biology. Results There were 144 patients with 198 sentinel lymph nodes. A significant association was found in conventional histology with Clark level and Breslow thickness. The prognostic role of sentinel lymph node status was independent of the other considered variables. However, no significant association was found with the molecular biology test. A significant excess of positive results at molecular biology was found. Conclusions Sentinel lymph node biopsy is an important independent prognostic factor for invasive cutaneous melanoma, but only when evaluated with conventional histology. As a result of this study, we stopped performing the tyrosinase test in molecular biology.

All cervical intraepithelial neoplasia (CIN) diagnoses identified during the New Technologies for Cervical Cancer trial (ISRCTN81678807) were blindly reviewed by 2 pathologists. Original diagnoses based on colposcopy-guided biopsies were compared with those made by the reviewers who had access to all clinical histologic samples (including postsurgical). Cases downgraded from CIN 2+ by the reviewers were considered indicative of unnecessary treatments. The analyses are presented according to the molecular (high-risk human papillomavirus [HPV]) and/or cytologic diagnosis used to refer the women for colposcopy. We reviewed 812 CIN 1 and 364 CIN 2 + diagnoses. The specificity of colposcopy-guided biopsy was 98% and the sensitivity, 84%. The probability of unnecessary treatment was 27% for women with atypical squamous cells of undetermined significance cytologic findings and 8% for women with low-grade squamous intraepithelial lesion or worse, 10% for HPV+ and positive cytologic findings, and 16% for HPV+ alone. The positive predictive value of the first-level screening test was inversely associated with probability of a histologic false-positive result (P = .015). In screening, a low positive predictive value of the colposcopy-referring test may result in unnecessary treatments.

Background Kabuki syndrome is a rare disorder characterized by the association of mental retardation and postnatal growth deficiency with distinctive facial appearance, skeletal anomalies, cardiac and renal malformation. Two causative genes have been identified in patients with Kabuki syndrome. Mutation of KMT2D (MLL2) was identified in 55–80 % of patients, while 9–14 % of KMT2D negative patients have mutation in KDM6A gene. So far, few tumors have been reported in patients with Kabuki syndrome. We describe the first case of a patient with spinal ependymoma and Kabuki syndrome. Case presentation A 23 years old girl followed at our Center for KMT2D mutated Kabuki syndrome since she was 4 years old presented with acute lumbar pain and intermittent tactile hyposthenia of the feet. Spine magnetic resonance revealed a lumbar endocanalar mass. She underwent surgical resection of the lesion and histologic examination showed a tanycytic ependymoma (WHO grade II). Conclusion Kabuki syndrome is not considered a cancer predisposition syndrome. Nonetheless, a number of tumors have been reported in patients with Kabuki syndrome. Spinal ependymoma is a rare disease in the pediatric and young adult population. Whereas NF2 mutations are frequently associated to ependymoma such an association has never been described in Kabuki syndrome. To our knowledge this is the first case of ependymoma in a KMT2D mutated Kabuki syndrome patient. Despite KMT2D role in cancer has previously been described, no genetic data are available for previously reported Kabuki syndrome patients with tumors. Nonetheless, the association of two rare diseases raises the suspicion for a common determinant.

Background: Human papillomavirus (HPV)–based screening needs triage. In most randomized controlled trials (RCTs) on HPV testing with cytological triage, cytology interpretation has been blind to HPV status. Methods: Women age 25 to 60 years enrolled in the New Technology in Cervical Cancer (NTCC) RCT comparing HPV testing with cytology were referred to colposcopy if HPV positive and, if no cervical intraepithelial neoplasia (CIN) was detected, followed up until HPV negativity. Cytological slides taken at the first colposcopy were retrieved and independently interpreted by an external laboratory, which was only aware of patients’ HPV positivity. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were computed for histologically proven CIN2+ with HPV status–informed cytology for women with a determination of atypical squamous cells of undetermined significance (ASCUS) or more severe. All statistical tests were two-sided. Results: Among HPV-positive women, informed cytology had cross-sectional sensitivity, specificity, PPV and 1-NPV for CIN2+ of 85.6% (95% confidence interval [CI] = 76.6 to 92.1), 65.9% (95% CI = 63.1 to 68.6), 16.2% (95% CI = 13.0 to 19.8), and 1.7 (95% CI = 0.9 to 2.8), respectively. Cytology was also associated with subsequent risk of newly diagnosed CIN2+ and CIN3+. The cross-sectional relative sensitivity for CIN2+ vs blind cytology obtained by referring to colposcopy and following up only HPV positive women who had HPV status–informed cytology greater than or equal to ASCUS was 1.58 (95% CI = 1.22 to 2.01), while the corresponding relative referral to colposcopy was 0.95 (95% CI = 0.86 to 1.04). Conclusions: Cytology informed of HPV positivity is more sensitive than blind cytology and could allow longer intervals before retesting HPV-positive, cytology-negative women.

Low-risk prostate cancer is found in about half of newly diagnosed men subjected to PSA screening.To define the role of active surveillance and focal therapy in low- and intermediate-risk prostate cancers, an invited international panel of practicing physicians in the field of localized prostate cancer discussed the available literature in three consecutive meetings to come to a broad interpretation of the available data.The panel ("new prostate cancer management group," npm) agreed on the following observations. In most men with a low-volume Gleason 6 tumor, initial conservative management is appropriate. In men with a larger unifocal Gleason score 6 or 3 + 4 lesion, focal therapy, although still considered an investigational approach, appears to be a suitable option in early non-randomized comparison studies. Furthermore, in patients with multifocal small satellite Gleason 6 lesions in the presence of a larger index lesion, focal therapy of the index lesion is an option. For patients with high-grade, large-volume disease, or in young men with evidence of high-volume multifocal low-grade prostate cancer, whole-gland treatment should be considered.Active surveillance is a preferred and safe option for low-risk prostate cancer. Focal therapy is still under investigation, but the available phase II data are promising. Clinical benefits must be shown in prospective trials. With improved imaging, focal therapy may be an option for patients not choosing active surveillance with low-risk disease, progression upon active surveillance or intermediate-risk cancers with a localizable lesion.

Summary From the use of antiretroviral therapy to prevent mother-to-child transmission to the possibility of HIV cure hinted at by the Mississippi baby experience, paediatric HIV infection has been pivotal to our understanding of HIV pathogenesis and management. Daily medication and indefinite antiretroviral therapy is recommended for children infected with HIV. Maintenance of life-long adherence is difficult and the incidence of triple-class virological failure after initiation of antiretroviral therapy increases with time. This challenge shows the urgent need to define novel strategies to provide long-term viral suppression that will allow safe interruption of antiretroviral therapy without viral rebound and any associated complications. HIV-infected babies treated within a few days of birth have a unique combination of a very small pool of integrated viruses, a very high proportion of relatively HIV resistant naive T cells, and an unparalleled capacity to regenerate an immune repertoire. These features make this group the optimum model population to investigate the potential efficacy of immune-based therapies. If successful, these investigations could change the way we manage HIV infection.

Within a large Italian randomized trial on new technologies for cervical cancer screening involving 7 laboratories with different levels of experience, an intralaboratory and interlaboratory quality control program for human papillomavirus (HPV) DNA testing by Hybrid Capture 2 (HC2; Digene, Gaithersburg, MD) was implemented. To monitor the hybridization and detection steps, target samples containing purified, concentration-defined, HPV DNA were introduced in each test run. Only 3 of 1,024 showed a mistake in a positive vs negative classification with a 1 relative light unit (RLU)/positive control specimen (PC) ratio cutoff. To monitor the preanalytic steps (particularly denaturation), blinded specimens (33 collected in PreservCyt [Cytyc, Boxborough, MA] and 36 in Specimen Transport Medium [STM, Digene]) were centrally prepared, divided into aliquots, and sent to each laboratory. The multiple-rater κ scores for negative (

A significant proportion of mother-to-child transmission (MTCT) of HIV still occurs during breastfeeding in settings where replacement feeding is unsafe and impractical. However, very few babies born to HIV-infected women and breastfed during the first 6 months of life become infected postnatally. The fact that the majority of babies who are breastfed by HIV-infected mothers remain uninfected even after several months of breastfeeding constitutes one of the major enigmas of HIV transmission via breast milk.

Background Data on the short-term risk of disease progression in HIV-1-infected children are needed to address the question of when to begin combination antiretroviral therapy. We estimated 12-month risks of progression to AIDS and death, by age and most recent measurement of CD4 T-cell percentage (CD4%) or viral load, in children receiving no antiretroviral therapy or zidovudine monotherapy only. Methods We undertook a meta-analysis of individual longitudinal data for 3941 children from eight cohort studies and nine randomised trials in Europe and the USA. Estimates of risk were derived from parametric survival models. Findings 997 AIDS-defining events were recorded over 7297 person-years of follow-up in the analysis of CD4%, and 284 events over 2282 person-years in the viral load analysis, corresponding to 568 deaths (9087 person-years) and 129 deaths (2816 person-years), respectively. In children older than 2 years, risk of death increased sharply when CD4% was less than about 10%, or 15% for risk of AIDS, with a low and fairly stable risk at greater CD4%. Children younger than 2 years had worse outlook than older children with the same CD4%. Risk of progression increased when viral load exceeded about 10(5) copies per mL, although this association was more gradual compared with CD4%. Both markers had independent predictive value for disease progression; CD4% was the stronger predictor. Interpretation This information is important for paediatricians making decisions, and for researchers designing trials, about when to initiate or restart antiretroviral therapy.

OBJECTIVEDuring the last 3 decades, robotic technology has rapidly spread across several surgical fields due to the continuous evolution of its versatility, stability, dexterity, and haptic properties. Neurosurgery pioneered the development of robotics, with the aim of improving the quality of several procedures requiring a high degree of accuracy and safety. Moreover, robot-guided approaches are of special interest in pediatric patients, who often have altered anatomy and challenging relationships between the diseased and eloquent structures. Nevertheless, the use of robots has been rarely reported in children. In this work, the authors describe their experience using the ROSA device (Robotized Stereotactic Assistant) in the neurosurgical management of a pediatric population.METHODSBetween 2011 and 2016, 116 children underwent ROSA-assisted procedures for a variety of diseases (epilepsy, brain tumors, intra- or extraventricular and tumor cysts, obstructive hydrocephalus, and movement and behavioral disorders). Each patient received accurate preoperative planning of optimal trajectories, intraoperative frameless registration, surgical treatment using specific instruments held by the robotic arm, and postoperative CT or MR imaging.RESULTSThe authors performed 128 consecutive surgeries, including implantation of 386 electrodes for stereo-electroencephalography (36 procedures), neuroendoscopy (42 procedures), stereotactic biopsy (26 procedures), pallidotomy (12 procedures), shunt placement (6 procedures), deep brain stimulation procedures (3 procedures), and stereotactic cyst aspiration (3 procedures). For each procedure, the authors analyzed and discussed accuracy, timing, and complications.CONCLUSIONSTo the best their knowledge, the authors present the largest reported series of pediatric neurosurgical cases assisted by robotic support. The ROSA system provided improved safety and feasibility of minimally invasive approaches, thus optimizing the surgical result, while minimizing postoperative morbidity.

Background Chronic granulomatous disease (CGD) is a primary immune deficiency characterized by a defect in reactive oxygen species production. Although the effect of CGD mainly reflects on the phagocytic compartment, B-cell responses are also impaired in patients with CGD. Objective We sought to investigate how defective gp91 phox expression in patients with CGD and CGD carriers might affect the B-cell compartment and maintenance of long-term memory. Methods We studied the B-cell compartment of patients with CGD in terms of phenotype and ability to produce reactive oxygen species and proliferate on stimuli differently directed to the B-cell receptor and Toll-like receptor 9. We further studied their capacity to maintain long-term memory by measuring cellular and serologic responses to measles. Results We show that the memory B-cell compartment is impaired among patients with CGD, as indicated by reduced total (CD19 + CD27 + ) and resting (CD19 + CD27 + CD21 + ) memory B cells in parallel to increased naive (CD19 + CD27 − IgD + ) B-cell frequencies. Data on CGD carriers reveal that such alterations are related to gp91 phox expression. Moreover, proliferative capabilities of B cells on selective in vitro stimulation of B-cell receptor or Toll-like receptor 9 pathways were reduced in patients with CGD compared with those seen in age-matched healthy control subjects. Significantly lower measles-specific antibody levels and antibody-secreting cell numbers were also observed, indicating a poor ability to maintain long-term memory in these patients. Conclusion Altogether, our data suggest that patients with CGD present a defective B-cell compartment in terms of frequencies of memory B cells, response to in vitro stimulation, and maintenance of long-term antigen-specific memory.

We have previously reported that an early initiation of highly active antiretroviral therapy (HAART) in HIV-1 vertically infected children enhanced the function of memory B-cells gained during childhood routine vaccinations. On the other hand, a significant waning of immunity was observed for patients with a late treatment. In this follow-up study, we report data from a sample of patients in our cohort including late-treated patients being revaccinated with routine childhood vaccines.The levels of serum antibodies and cellular immunity were measured by antigen-specific enzyme-linked immunosorbent assay and B-cell ELISpot. Moreover, flow cytometry on the frequencies of mature-activated (CD10-CD21-) and double-negative (CD27-IgD-) B-cells as hallmarks of immune activation and immune senescence, respectively, was performed for all patients.Reduced protective humoral immunity and cellular immunity to routine childhood vaccines was observed in late-treated patients. Moreover, we found that timing of HAART related with the frequencies of mature activated and double negative.Altogether the data presented in this follow-up study reenforce the importance for an early start of HAART in HIV-1 vertically infected individuals and suggest that timing of HAART is a fundamental factor to take into account for vaccination design in this population.

Background: Neutropenia is not uncommon in childhood. The aim of our study was to analyze the underlying causes of neutropenia and to evaluate its clinical significance in a series of children referred to our center. Methods: One hundred and four consecutive children with neutropenia were enrolled in this study. Clinical and laboratory features were analyzed. Results: The majority of patients (63.5%) showed chronic neutropenia. Among all chronic forms, the most frequent was chronic idiopathic neutropenia (CIN), followed by autoimmune neutropenia (AIN). Congenital neutropenia was identified in 6 patients. Acute neutropenia was mainly due to infections.Overall, at the time of first detection, neutropenia was more frequently severe or moderate. One-third of our patients who presented with severe neutropenia were ultimately diagnosed with a postinfectious acute form. Conversely, nearly half patients with CIN, AIN, or congenital neutropenia showed moderate/mild neutropenia at onset.Among patients with AIN and CIN, nearly half recovered between 7 months and 46 months and approximately one-fourth experienced infectious episodes during follow-up. No significant difference was noticed in terms of mean ANC between patients with and without remission, neither between patients with and without infections. Conclusions: Our study confirms the great etiological heterogeneity of neutropenia in children. We could not demonstrate a correlation between ANC level at onset and the underlying disorder, nor a correlation between mean ANC and duration of neutropenia or infectious episodes during follow-up. Neutropenia remains a disease of concern to pediatricians, requiring several laboratory investigations, prolonged follow-up, and, in few cases, advanced molecular methods.

Entrapment of the brachial plexus (BP) can be primary or secondary to either trauma or surgery. Most frequently, the BP is entrapped at the “thoracic outlet” resulting in thoracic outlet syndrome (TOS). Hyperabduction syndrome, scalenus anterior (or anticus) syndrome, costoclavicular syndrome, cervical rib syndrome, and long-C7 transverse process syndrome are all entrapment syndromes of the BP. These last terms are used either independently or as part of TOS, although “true TOS” is due to an alteration of the soft tissues at the thoracic outlet and not to bone causes. In 1956, Peet et al. [4] introduced the term TOS to describe a clinical picture with signs and symptoms due to compression of the BP and subclavian vessels at the thoracic outlet. The etiology and clinical presentation of BP entrapment syndromes, including TOS, are variable; diagnosis may be difficult, and treatment is controversial. Knowledge of the anatomy, clinical presentation, diagnostic tools and therapeutic options is very important for correct diagnosis and therapy.

In this review, the first four papers deal with an important chapter in peripheral nerve surgery: cranial nerve reconstruction after injury occurring during skull base surgery. The last paper discusses the problem of peripheral nerves affected by a ganglion cyst. Damage to a cranial nerve is no longer considered to be an absolutely irreparable event. The first two studies are related to facial nerve management during the surgical treatment of vestibular schwannomas. The most common mechanisms responsible for facial nerve injury during tumor removal and the technical means to avoid them are cited. The importance of intraoperative neurophysiologic monitoring to save the facial nerve is stressed. A comparison between microsurgery and radiosurgery results in the conclusion that for vestibular schwannomas, the first choice of treatment is microsurgery. These two large and exceptional series show that by using a refined technique it is possible to obtain both total tumor removal and preservation of the facial nerve in most of the vestibular schwannomas. In the minority of patients in whom the facial nerve is severed, there are several therapeutic options to re-establish facial nerve function. After facial nerve reconstruction, performed immediately during the same tumor operation, a satisfactory reinnervation was obtained in 74% of the cases. After facial nerve reanimation, using as donor nerve the hypoglossus and performed 1 week after the tumor operation, a satisfactory reinnervation was obtained in 96% of the cases. The other two papers deal with the intraoperative transection of the trochlear and abducens nerve during surgery for skull base tumors. These two cranial nerves, owing to their simply organized motor nerve system (they are purely motor nerves and supply one muscle each), show quite a good expectation of functional recovery. The behavior of ganglion cysts involving peripheral nerves is the topic of the last paper reviewed. These cysts are benign lesions that can cause permanent neurologic deficits of the involved nerve. The etiology, clinical presentation, surgical techniques, and recurrence rate are reported. In the present series, the outcomes after ganglion cyst excision are not as favorable as those reported in other series. Before surgery, patients must be informed about the possibility of residual motor deficits and recurrences.

PI3K/AKT/mTOR pathway alterations are frequent in patients with infiltrating breast cancer (IBC). Their clinical and pathological relevance has been insufficiently documented. We evaluated PI3KCA for mutations and the expression of PTEN, AKT, mTOR and p70S6K by immunohistochemistry in 246 IBC patients treated with hormone therapy (median follow-up, 97 months). A PI3KCA mutation was observed in 50 out of 229 informative cases (21.8 %), PTEN loss in 107 out of 210 (51 %), moderate/high level of expression of AKT in 133 out of 188 (71 %), moderate/high level of expression of mTOR in 173 out of 218 (79 %) and moderate/high level of expression of p70S6K in 111 out of 192 cases (58 %). PI3KCA mutation was associated with the absence of Her2/neu amplification/overexpression and a low level of MIB1/Ki-67 labelling. The expression of p70S6K was associated with a high level of mTOR immunoreactivity, and high PTEN expression was associated with high AKT expression level. Univariate analysis showed that PI3KCA mutation status was not associated with clinical outcome in the series as a whole or in the node-negative subgroup. However, in the node-positive subgroup, exon 9 PI3KCA mutation was associated with unfavourable overall survival (OS), although its impact on the final model in multivariate analysis seemed to be limited. Of the other markers, only high p70S6K expression was associated with a significantly prolonged OS. PI3KCA mutation status is of limited prognostic relevance in oestrogen receptor-positive breast cancer patients treated with hormone therapy.

Background Although among women a decreasing prevalence of human papillomavirus (HPV) infection with increasing age has been consistently observed in high-resource countries, different age profiles have been reported elsewhere. Methods We compared the age profile of high-risk (HR)-HPV prevalence in nine different areas of Northern and Central Italy by studying the women recruited in the intervention arm of the New Technologies in Cervical Cancer study and tested by Hybrid Capture 2. Differences in the age-distribution of HPV infection were investigated in each centre by the joinpoint approach in a logistic model. 46,900 women aged 25 to 60 years were included in the analysis. Results The HR-HPV age-standardised (on Italian population) prevalence ranged from 5.7% (Trento) to 10.3% (Ravenna). HR-HPV prevalence decreased as a logistic function of increasing age in 6 of 9 centres (Trento, Verona, Florence, Bologna, Imola, and Viterbo). The effect of age on HR-HPV prevalence slopes did not differ significantly among these 6 centres, whereas significant heterogeneity in intercepts (p

Human immunodeficiency virus (HIV) chronically infected patients are at increased risk of developing non-Hodgkin lymphoma compared with the general population. Highly active antiretroviral therapy has had a dramatic effect on the natural history of HIV infection, reducing the incidence of acquired immunodeficiency syndrome-related non-Hodgkin lymphoma and improving overall survival. However, problems related to adherence to treatment, frequently experienced during adolescence, may increase the risk of acquired immunodeficiency syndrome-related cancers. Optimizing highly active antiretroviral therapy and monitoring noncompliant patients with persisting HIV replication should be considered by physicians who take care of these patients. We herein report 2 cases of relapsed/progressive Burkitt lymphoma in HIV vertically infected adolescents.