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Artificial Intelligence (AI) is the notion of machines mimicking complex cognitive functions usually associated with humans, such as reasoning, predicting, planning, and problem-solving. With constantly growing repositories of data, improving algorithmic sophistication and faster computing resources, AI is becoming increasingly integrated into everyday use. In healthcare, AI represents an opportunity to increase safety, improve quality, and reduce the burden on increasingly overstretched systems. As applications expand, the need for responsible oversight and governance becomes even more important. Artificial intelligence in the delivery of healthcare carries new opportunities and challenges, including the need for greater transparency, the impact AI tools may have on a larger number of patients and families, and potential biases that may be introduced by the way an AI platform was developed and built. This study provides practical guidance in the development and implementation of AI applications in healthcare, with a focus on risk identification, management, and mitigation.

Infantile myofibromatosis is a rare and nonmalignant pediatric tumor of myofibroblastic origin that may occur in solitary or multifocal forms. Soft tissue of the head and neck, trunk, and extremities, skeleton, and viscera are usually involved. Intracranial involvement is reported to be extremely rare, and its clinical picture has been poorly characterized. We present two cases of giant infantile myofibromatosis of the skull base with intracranial involvement. The first case with prenatal diagnosis involved extensively the extradural space of the occipital region and was previously treated by chemotherapy for a previous diagnosis of hemangioperycitoma. Tumor was removed at the age of 5 months and no recurrence was observed during the 3-year follow-up. The second case in a 2-year-old baby involved the anterior cranial base, the nasal cavity, the right orbit, and presented massive involvement of the anterior cranial fossa. Surgery allowed complete removal and a recurrence-free period of 7 years after surgery. Treatment options for these unusual cases are presented and details of histological diagnosis are discussed.

Cancer predisposition syndromes (CPS) result from germline pathogenic variants, and they are increasingly recognized in the etiology of many pediatric cancers. Herein, we report the genetic/genomic analysis of 40 pediatric patients enrolled from 2016 to 2018. Our diagnostic workflow was successful in 50% of screened cases. Overall, the proportion of CPS in our case series is 10.9% (20/184) of enrolled patients. Interestingly, 12.5% of patients achieved a conclusive diagnosis through the analysis of chromosomal imbalance. Indeed, we observed germline microdeletions/duplications of regions encompassing cancer-related genes in 50% of patients undergoing array-CGH: EIF3H duplication in a patient with infantile desmoplastic astrocytoma and low-grade Glioma; SLFN11 deletion, SOX4 duplication, and PARK2 partial deletion in three neuroblastoma patients; a PTPRD partial deletion in a child diagnosed with glioblastoma multiforme. Finally, we identified two cases due to DICER1 germline mutations.

Objectives We evaluated how the Severe Acute Respiratory disease from Coronavirus 2 (SARS‐CoV‐2) epidemic impacted transfusion services, transfusion support required by Covid‐19 patients and their clinical outcome. Background In Italy, the first confirmed case of SARS‐CoV‐2 infection was registered on 21 February 2020. As of 20 April, about 250 000 cases were registered, 1143 of which were in the province of Pescara. Methods We compared transfusion services provided by the blood centre of Pescara between 1 March and 20 April 2019 and between 1 March and 20 April 2020. We assessed the number and type of blood components donated, those transfused in the various hospital departments and those transfused to Covid‐19 patients. Results Compared to 2019, we documented a decrease of 32% in the number of donations. The number of transfusions increased by 139% in the infectious diseases department (IDD), dedicated to Covid‐19 patients, and by 76% in the intensive care unit (ICU), whereas it markedly decreased in the other departments. Of 299 patients with Covid‐19, 60 were transfused (20.1%). Transfused patients in the ICU were significantly younger than those in IDD and had a lower number of lymphocytes, lower post‐transfusion increment of haemoglobin levels and higher D‐dimer and C reactive protein values. Mortality rate was 60.7% among transfused patients in the ICU and 39.0% among those in the IDD (p = 0.02). Conclusion The Covid‐19 epidemic had a profound impact on transfusion activities. The important blood demand for Covid‐19 patients was satisfied because of the reduction in activities in other hospital wards. Covid‐19‐positive transfused patients showed a very poor prognosis.

Background A prospective 2002–2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients’ molecular features. Methods Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68. Results Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66–126 mo), surviving after relapse no longer than those relapsing earlier (0–5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007). Conclusions Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.

Objectives To evaluate the utility of ultrasound markers in the management of pregnancies complicated by preterm prelabor rupture of membranes (PPROM) between 23 + 0 and 33 + 6 weeks' gestation, and to assess the ability of ultrasound markers to predict adverse neonatal outcomes. Methods This was a retrospective cohort study of all patients with PPROM between 23 + 0 and 33 + 6 weeks' gestation and latency period (PPROM to delivery) > 48 h, who delivered before 34 weeks' gestation at a tertiary referral center between 2005 and 2017. All patients underwent a non-stress test daily and an ultrasound scan twice a week for assessment of amniotic fluid volume, biophysical profile (BPP) and umbilical artery (UA) pulsatility index (PI). In patients with suspected fetal growth restriction, fetal middle cerebral artery (MCA)-PI was also assessed and the cerebroplacental ratio (CPR) calculated. The last ultrasound examination performed prior to delivery was analyzed. We compared the characteristics and outcomes between women who were delivered owing to clinical suspicion of chorioamnionitis and those who were not delivered for this indication. The primary objective was to evaluate the utility of ultrasound in the management of patients with PPROM. The secondary objective was to assess the diagnostic performance of ultrasound markers (BPP score 95th percentile, MCA-PI Results A total of 504 women were included in the study, comprising 120 with suspected chorioamnionitis and 384 without. Women with suspected chorioamnionitis, compared with those without, were less likely to be nulliparous (34.2% vs 45.3%; P = 0.03) and more likely to have fever (50.8% vs 2.6%; P 95th percentile was similar between the two groups. There was a higher incidence of composite adverse neonatal outcome in the group with suspected chorioamnionitis than in the group without (78.3% vs 64.3%, respectively; P = 0.004). However, on logistic regression analysis, none of the ultrasound markers evaluated was found to be associated with chorioamnionitis or composite adverse neonatal outcome, and they all had a poor diagnostic performance for the prediction of chorioamnionitis and composite adverse neonatal outcome. Conclusions Commonly used ultrasound markers in pregnancies complicated by PPROM were similar between women delivered for suspected chorioamnionitis and those delivered for other indications, and performed poorly in predicting composite adverse neonatal outcome. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Background More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol. Methods We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. Results The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Conclusions Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients.

Purpose of review Despite its recognized efficacy and tolerability profile, during the last decade a rise of adverse events following ibuprofen administration in children has been reported, including a possible role in worsening the clinical course of infections. Our aim was to critically evaluate the safety of ibuprofen during the course of pediatric infectious disease in order to promote its appropriate use in children. Recent findings Ibuprofen is associated with severe necrotizing soft tissue infections (NSTI) during chickenpox course. Pre-hospital use of ibuprofen seems to increase the risk of complicated pneumonia in children. Conflicting data have been published in septic children, while ibuprofen in the setting of Cystic Fibrosis (CF) exacerbations is safe and efficacious. No data is yet available for ibuprofen use during COVID-19 course. Summary Ibuprofen should not be recommended for chickenpox management. Due to possible higher risks of complicated pneumonia, we suggest caution on its use in children with respiratory symptoms. While it remains unclear whether ibuprofen may have harmful effects during systemic bacterial infection, its administration is recommended in CF course. Despite the lack of data, it is seems cautious to prefer the use of paracetamol during COVID-19 acute respiratory distress syndrome in children.

Background Despite ibuprofen widely recognized safety profile, an increase of suspected adverse events has been reported in the last decade in parallel with its growing over-the-counter use. The aims of this study were to assess the therapeutic approach to the feverish child and to evaluate the main indications and the most frequent adverse events related to ibuprofen administration in children. Methods A specific questionnaire-form regarding the management of ibuprofen therapy in children was distributed among a sample of pediatricians all over the Italian territory between September and October 2020. An electronic data collection through a specifically designed web-based platform was performed among the participating pediatricians. Results One-hundred-eighty-one pediatricians completed the survey. In case of fever, 177 (98%) participants prescribe paracetamol, while only 4 (2%) preferred ibuprofen as first choice. One-hundred-twenty-eight pediatricians (71%) administer paracetamol alone, while 53 (29.2%) use the combined/alternating treatment with ibuprofen. Ibuprofen is mostly administered for musculoskeletal pain (30%), upper respiratory tract infection (20%), headache (15%) and post-surgical pain (9%). Sixty-three (35%) out of 181 participating pediatricians reported 191 adverse events during ibuprofen administration. The most common were gastrointestinal (GI), with GI bleeding being reported in 30/191 cases (15.7%), epigastric pain in 29/191 (15.1%), non-specified abdominal pain in 22/191 (11.1%) and nausea/vomiting in 21/191 (11%). Severe adverse events including kidney damage (3.1%), complicated infections (0.5%), pneumonia associated empyema (0.5%), soft tissue infection (0.5%) and disseminated intravascular coagulation (0.5%) were also reported. The adverse events led to a hospitalization in 12% of children. In 53/191 cases (28%) the adverse events were related to a wrong dosage or prolonged therapy or errors in frequency of administration. Conclusions This survey demonstrate a sufficient awareness of Italian pediatricians regarding ibuprofen-prescribing patterns with the only possible concern related to the relatively high percentage of pediatricians performing a combining/alternating use of paracetamol and ibuprofen. The reported adverse events were mild in most of the cases and often related to errors in dosage, frequency and treatment duration, emphasizing the need for a major caution of both practitioners and patients in their use.

A significant growth of the railway transportation demand is forecasted in the next decades which needs an increase of network capacity. Where possible, infrastructure upgrading can provide extra capacity; although in some cases, this is not enough to satisfy the entire transportation demand even if optimised timetabling is performed. We propose a heuristic model to develop a stable timetable which maximises the satisfaction of transportation demand in situations where network capacity is limited. In case the demand cannot be fully satisfied, the model relaxes the given line plan and timetable design parameters. The aim is to keep as many train services as possible and reduce the level of service minimally. We develop a mixed integer linear programming (MILP) model for minimising the cycle time to find an optimised stable timetable for the given line plan. The heuristic iteratively solves the MILP model and applies relaxation measures. We tested the model on the Dutch network. The results showed that the model can generate stable timetables by removing train services from the critical circuit, and also, higher transportation demand can be satisfied by additionally relaxing timetable design parameters.

This study evaluated the influence of storage method on the physical and chemical properties of laricio pine wood chips for energy generation in the region of Basilicata, Italy. The storage of wood chips is a key factor in the wood fuel supply chain because it allows to compensate temporal differences between production and consumption stages. Experimental trials were performed analyzing three storage methods of wood chips: uncovered pile, under vapour-permeable and waterproof cover (PP sheet), and under waterproof PVC cover (PVC sheet). During six months of storage (from August 2016 to January 2017), only the wood chips pile covered under PP sheet registered a decrease in moisture content (about -19%). Use of cover made of vapour-permeable material was also found to improve the heating value of biomass (about +15%). However, the ash content was observed to increase throughout the storage period, reaching the maximum value for the uncovered wood chips pile (about +74%). No statistically significant differences between PP and PVC sheets were detected for dry matter losses, while significant energy losses were found in every kind of storage system. As a result of the analyzed weather conditions, open-air uncovered storage is suitable for short-term storage periods (less than 2 months), while for long-term period the use of permeable covers is more profitable.

Context Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway gliomas (OPGs) that can result in endocrine dysfunction. Data on prevalence and type of endocrine disorders in NF1-related OPGs are scarce. Objectives The aim of the study was to determine the prevalence of endocrine dysfunctions in patients with NF1 and OPGs and to investigate predictive factors before oncological treatment. Design Multicenter retrospective study. Settings and patients Records were reviewed for 116 children (64 females, 52 males) with NF1 and OPGs followed at 4 Italian centers. Main outcome measures We evaluated endocrine function and reviewed brain imaging at the time of OPG diagnosis before radio- and chemotherapy and/or surgery. OPGs were classified according to the modified Dodge classification. Results Thirty-two children (27.6%) with a median age of 7.8 years had endocrine dysfunctions including central precocious puberty in 23 (71.9%), growth hormone deficiency in 3 (9.4%), diencephalic syndrome in 4 (12.5%), and growth hormone hypersecretion in 2 (6.2%). In a multivariate cox regression analysis, hypothalamic involvement was the only independent predictor of endocrine dysfunctions (hazard ratio 5.02 [1.802-13.983]; P = .002). Conclusions Endocrine disorders were found in approximately one-third of patients with Neurofibromatosis type 1 and OPGs before any oncological treatment, central precocious puberty being the most prevalent. Sign of diencephalic syndrome and growth hormone hypersecretion, although rare, could be predictive of optic pathway gliomas in NF1. Tumor location was the most important predictor of endocrine disorders, particularly hypothalamic involvement.

s: The natural history of non-optic central nervous system (CNS) tumors in neurofibromatosis type 1 (NF1) is largely unknown. Here, we describe prevalence, clinical presentation, treatment, and outcome of 49 non-optic CNS tumors observed in 35 pediatric patients (0&ndash, 18 years). Patient- and tumor-related data were recorded. Overall survival (OS) and progression-free survival (PFS) were evaluated. Eighteen patients (51%) harbored an optic pathway glioma (OPG) and eight (23%) had multiple non-optic CNS lesions. The majority of lesions (37/49) were managed with a wait-and-see strategy, with one regression and five reductions observed. Twenty-one lesions (42.9%) required surgical treatment. Five-year OS was 85.3%. Twenty-four patients progressed with a 5-year PFS of 41.4%. Patients with multiple low-grade gliomas progressed earlier and had a lower 5-year PFS than those with one lesion only (14.3% vs. 57.9%), irrespective of OPG co-presence. Non-optic CNS tumors are common in young patients with NF1. Neither age and symptoms at diagnosis nor tumor location influenced time to progression in our series. Patients with multiple lesions tended to have a lower age at onset and to progress earlier, but with a good OS.

Background In the modern era evidence-based medicine, guidelines and recommendations represent a key-point of daily activity. The Spinal Section of the Italian Society of Neurosurgery introduced some recommendations regarding Degenerative Lumbar Spine Stenosis based on those of the Spine Committee of World Federation of Neurosurgical Societies, revising them on the basis of Italian common practice. Methods In June 2019, a Committee of 21 spine surgeons met in Rome to validate the recommendations of the WFNS. Furthermore, they decided to review the ones that did not reach a consensus to create Italian Recommendations on Degenerative Lumbar Spine Stenosis. A literature review of the last ten years was performed and the statements were voted using the Delphi method. Results 41 statements were discussed and 7 statements were voted again to reach a consensus with respect to those of the WFNS. A total of 40 statements reached a consensus, of which 36 reached a positive consensus and 4 a negative consensus, while no consensus was reached in 1 case. Conclusions Conservative multimodal therapy, tailored on the patient, is a reasonable and effective first option choice for the treatment of LSS patients with tolerable moderate symptoms. Surgical treatment is reserved for symptomatic patients non-responding to conservative treatment or with neurological deficits. The best surgical technique to use depends on personal experience; modern MISS techniques are equivalent to open decompressive surgery with some advantages and higher cost-effectiveness. Fusion surgery and mobility preserving surgery only have a marginal role in the treatment of DLSS without instability.

Background Estimation of fetal weight (EFW) by ultrasound is useful in clinical decision-making. Numerous formulas for EFW have been published but have not been validated in pregnancies complicated by preterm premature rupture of membranes (PPROM). The purpose of this study is to compare the accuracy of EFW formulas in patients with PPROM, and to further evaluate the performance of the most commonly used formula - Hadlock IV. Methods A retrospective cohort study of women with singleton gestations and PPROM, admitted to a single tertiary center between 2005 and 2017 from 220/7–330/7 (n = 565). All women had an EFW within 14 days of delivery by standard biometry (biparietal diameter, head circumference, abdominal circumference and femur length). The accuracy of previously published 21 estimated EFW formulas was assessed by comparing the Pearson correlation with actual birth weight, and calculating the random error, systematic error, proportion of estimates within 10% of birth weight, and Euclidean distance. Results The mean gestational was 26.8 ± 2.4 weeks at admission, and 28.2 ± 2.6 weeks at delivery. Most formulas were strongly correlated with actual birth weight (r > 0.9 for 19/21 formulas). Mean systematic error was − 4.30% and mean random error was 14.5%. The highest performing formula, by the highest proportion of estimates and lowest Euclidean distance was Ott (1986), which uses abdominal and head circumferences, and femur length. However, there were minimal difference with all of the first 10 ranking formulas. The Pearson correlation coefficient for the Hadlock IV formula was strong at r = 0.935 (p p p Conclusions In women with singleton gestation and PPROM, the Ott (1986) formula for EFW was the most accurate, yet all of the top ten ranking formulas performed quite well. The commonly used Hadlock IV performed quite similarly to Ott’s formula, and is acceptable to use in this specific setting.

Desmoplastic infantile astrocytomas and gangliogliomas (DIA/DIG) usually present with a large size, large cystic component, large dural implant, encasement of big vessels, clinical presentation within 18 months of life, high incidence of seizures and overall good prognosis, even if tumour surgery can be very challenging at first procedure. We retrospectively reviewed clinical and radiological data of patients diagnosed with desmoplastic infantile tumours who were surgically treated between 2008 and 2019. The series included 12 patients. The median age at surgery was 91 days. The average tumour volume was 212 cm3. Cystic components were predominant ranging from 0 to 295 cm3. Active hydrocephalus was pre-operatively evident in 5 cases. Eight patients (66.6%) received total or subtotal removal, three of them (25%) underwent partial removal, and one patient (8.3%) received a biopsy. One patient died within 24 h after surgery due to severe hypotension, as a consequence of significant intraoperative blood loss. Overall, seven (58.3%) patients were reoperated on the tumour after the first procedure: 4 patients were operated twice; 3 patients were operated 3 times. Two patients presented remote localizations and underwent chemotherapy. At last follow-up, 7 patients were tumour-free, 2 are alive with stable disease, and 2 are alive with progressive disease (leptomeningeal seeding). Desmoplastic infantile tumours are rare giant neonatal tumours. Total removal is the goal of treatment, but prognosis remains good even if total removal is not achieved. In case of tumour progression or epilepsy from residual tumour, reoperation is the first option, with chemotherapy reserved to unresectable or disseminated cases with mixed results, while, to date, radiotherapy still plays no role.

Background The prognosis for patients with relapsed rhabdomyosarcoma (RMS) depends on a number of variables, including tumor characteristics, type of relapse, and treatment received. All published studies have considered tumor characteristics at initial diagnosis, but not at the time of recurrence. In this study, we compared tumor characteristics at diagnosis and at the moment of local relapse to better define the chance of cure in this group of patients. Methods We first analyzed 92 children with localized RMS treated according to the RMS96 and RMS2005 protocols who developed relapse after achieving complete remission at the end of treatment. Then we restricted our analysis to 51 patients with local recurrence to compare their initial tumor characteristics with those at relapse. All characteristics were studied using univariate and multivariate analyses. Results The 10-year progression-free survival (PFS) and overall survival (OS) rates for the whole group were 23.5% (15.4-32.6) and 34.4% (24.8-44.1), respectively. On multivariate analysis, only primary tumor site appeared to have a strong impact on prognosis (P = .0010). The 10-year PFS and OS rates of patients with locoregional recurrences were 22.7% (12.3-35.0) and 34.9% (22.1-47.9), respectively. Multivariate analysis showed that tumors at unfavorable sites (P = .0044), and tumor size > 5 cm at recurrence (P = .0088) were associated with the poorest prognosis. Conclusion Our study demonstrates that to estimate the chance of cure in patients with relapsed RMS, we should also consider tumor characteristics at the time of relapse, and tumor size in particular.

Purpose To evaluate clinical features at diagnosis, prognostic factors, and outcomes of malignant sacrococcygeal germ cell tumors (SC-GCTs) in patients enrolled in the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) TCG 2004 protocol. Patients and methods A prospective analysis was conducted on all consecutive patients diagnosed with malignant SC-GCTs between January 2004 and May 2017. Patients with stage I underwent surgery and subsequent surveillance, the others received pediatric cisplatinum-etoposide-bleomycin (pPEB) regimen and eventual deferred surgery. Results Of 45 patients, 35 were females. Age at diagnosis ranged from 1 day to 3.6 years (median 1.6 years); 26 were stage IV. Of 38 patients who underwent surgery, pathology revealed yolk sac tumor (YST) in 27 and teratoma + YST/embryonal carcinoma in 11, while seven patients were diagnosed based on imaging and elevated levels of alpha-fetoprotein (AFP). Of six patients approached with surgery, only one relapsed and was rescued with first-line chemotherapy. Overall, 38 out of 45 achieved complete remission, three a partial remission, and four were resistant. Ten out of 41 patients who entered remission later relapsed and nine were rescued with a second-line treatment. We observed a global failure percentage of 31% and a 5-year overall survival (OS) and event-free survival (EFS) of 95% and 69%, respectively. Conclusions Chemotherapyis generally effective in malignant SC-GCTs, even though almost one-third of our patients experienced events salvageable with second-line treatment. Most of the relapses occurred within 1 year from diagnosis. A close follow up with serial AFP level monitoring should be done for at least 2 years after diagnosis.

The measurement of the patient experience is a global movement that has caught the attention of healthcare reformers. The use of patient experience data to ameliorate healthcare practice is promising, although standardization in what, where, how and whose experience is measured does not yet exist. To truly further the patient experience agenda, there needs to be adoption at the system, regional and local level to help promote, inspire and lead to sustainable change. Caregiver insight into the patient experience should be leveraged to learn what is important to patients and extract more useful data, as they are often present during transitions in care that span across the continuum. Embracing the voice of the patient as part of the process to improve quality, outcomes and experience will no doubt lead to impactful change and better care.

Objectives Numerous formulas for estimated fetal weight (EFW) calculations have been proposed over the years but have not been validated in patients with preterm premature rupture of membranes (PPROM). The study objective was to compare the accuracy of the various sonographic EFW formulas in patients with PPROM. Methods This was a retrospective cohort study of women with PPROM and singleton gestations who were admitted between 220–330 weeks to a single, university-affiliated tertiary referral centre between 2003–2017. All women had a sonogram for EFW within 14 days of delivery by standard biometry (biparietal diameter, head circumference, abdominal circumference, and femur length). We compared the accuracy of 21 previously published EFW formulas in the setting of PPROM by comparing the correlation with actual birth weight and calculating the systematic error (SE), random error (RE), proportion of estimates (POE) within 10% of birth weight and Euclidean distance. Results Overall, 565 women were included in the study. Most formulas had strong correlation with actual birth weight (19/21 formulas with r >0.9). The mean SE was -4.30% and mean RE 14.48%. The formula that performed the best, by the highest POE and lowest Euclidean distance was that of Ott (1986), utilizing abdominal and head circumferences, and femur length, yet all of the first 10 ranking formulas (including the mostly used Hadlock IV) performed quite similarly with minimal differences between them. Conclusions Most formulas accurately calculation EFW in PPROM patients, but the Ott (1986) formula ranked highest, thus it may be the preferred formula to use in this population.

BACKGROUND This 2002–2014 Italian prospective study stratified 160 patients by surgical resection (complete=NED/incomplete=ED) and centrally-reviewed grade. Grade2/NED patients received focal radiotherapy (RT) up to 59.4Gy, Grade3/NED received 4 courses of VEC(vincristine,etoposide,cyclophosphamide) after RT.ED patients received 1–4 VEC courses, second-look surgery, 59.4 Gy+8Gy boost on measurable residue. METHODS We re-analyzed data at 115 months follow-up including methylation profile on available samples. RESULTS Global PFS/OS at 5/10 years were 66/59% and 80/74%, respectively. Of the 64 relapsers at median 20 months, 53 died at median 37/18 months after diagnosis/relapse, respectively.10/64 relapsed after 5 years (66–126 months); 4 died, relapse was local in 8/10, metastatic 1, combined 1;5/10 patients were below age 3, 5 females, 8 PF tumors. Their survival post-relapse was not longer than earlier relapsers’. At univariable analysis, age over 3 years, female sex, complete surgery, grade 2, no shunt confirmed better PFS/OS. 66/95 analyzed tumors received a score >0.80 through the DNA methylation-based central nervous system tumor classifier: 41/8 as PFA/PFB, respectively,14/17 ST as RELA-positive (3 scored for other molecular entities i.e. anaplastic PXA, LGG MYB, HGNET). Prognostic factors were equally distributed among PFA/PFB groups,1 only group B patient relapsed locally at 96 months. CONCLUSIONS Already published prognostic factors remained at long-term follow-up;6.2% patients had late relapses. OS after relapse was not better in late relapsers. Group B confirmed better prognosis but all patients had received «at least» adjuvant RT. Modern ependymoma trials need long follow-up to draw firm conclusions.

In conservation, there is a high demand for methods to predict how animals respond to human infrastructure, such as estimating the location of road mortalities and evaluating the effectiveness of mitigation measures. Computer-based simulation models have emerged as an important tool in understanding wildlife-infrastructure interactions. Such models, however, often assume animal omniscience of the landscape yielding unrealistic movements, focus more on genetic connectivity than actual movement paths, or are case-specific and mathematically/computationally challenging to apply. Here, we illustrate the potential of SiMRiv, a novel R package for simulating spatially explicit, individual multistate (Markovian) movements incorporating landscape heterogeneity, in the subject of road ecology. In particular, we used SiMRiv to reproduce wildlife movement patterns and predict high-risk areas for road-kill, using Eurasian otters (Lutra lutra) as a model species. We compared the number of road crossings in real otter movements and null models (simulated, multistate Markovian movements) incorporating the effect of the landscape structure (here, water dependence). The number of road crossings in real and simulated movements was remarkably similar, and available limited real road-kill data supported SiMRiv’s road-kill risk predictions. Further, other emergent movement properties were also very similar in real and simulated movements. Overall, results show that SiMRiv has potential for reconstructing real wildlife movement patterns, as well as for predicting road-kill risk areas. SiMRiv constitutes a flexible, powerful, and intuitive tool to help biologists and managers to test mechanistic hypotheses on wildlife movement ecology, including those related to wildlife-vehicle interactions.

Background Malignant spinal cord compression (MSCC) is associated withpoor prognosis and may lead to permanent paralysis, sensory loss, and sphincter dysfunction. Very limited data are available on incidence and etiology of MSCC in pediatric population. We aimed to examine etiology, clinical presentation and treatment of pediatric patient with MSCC admitted to the Santobono-Pausilipon Children’s Hospital, Naples, Italy. Methods Forty-four children under 18 yearsadmitedsince 2007 and assessed for MSCC clinical presentations, evaluation, and treatment.were retrospectively collected from our institutional pediatric oncology and neurosurgery database. Results The median age at time of MSCC diagnosis was 52 months, with a peak in young (≤3 years) patients. The leading cause of MSCC was extramedullary tumors (63.6%), in particular neuroblastoma (27.2%) followed by Ewing sarcomas (15.9%). Cord compression was the presenting feature of a new malignancy in 33 (75%) patients, and a consequence of metastatic disease progression or relapse in the remaining 11 (25%) patients. Motor deficit was the initial symptoms of spinal compression in all patients, while pain was present in about 60% of patients, followed by sphincteric deficit (43.2%). The primary tumor site was located in the neck in 3 (6.8%) patients, thorax in 16 (36.4%), cervico-thoracic region in 3 (6.8%), thoraco-lumbar region in 8 (18.2%), abdomen in 5 (11.4%), lumbar-sacral region in 7 (15.9%) and thoracic-lumbar-sacral region in 1 (2.3%). The median length of the interval between symptom onset and tumor diagnosis varied widely from 0 to 360 days in the entire population, however this interval was significantly shorter in patients with known neoplasia in comparisonto patients with new diagnosis (at relapse 7 days [interquartile range 3–10] vs at diagnosis 23 days [7–60]). Pre and post-operative spine magnetic resonance imagingwas performed in all cases, and most(95%) patients underwent neurosurgical treatment as first treatment. Severe motor deficit was associated with younger age and severe motor deficit at diagnosis was associated withworst motor outcomes at discharge from neurosurgery. Patients with progression or relapsed disease showed a worst prognosis, while the majority of patients (70.5%) were alive at 5 years after diagnosis. Conclusions The natural history of MSCC in children is associated to permanent paralysis, sensory loss, and sphincter dysfunction, thus prompt diagnosis and correct management are needed to minimize morbidity. Treatment strategies differed widely among cancer types and study groups in the absence of optimal evidence-based treatment guidelines. When the diagnosis is uncertain, surgery provides an opportunity to biopsy the lesion in addition to treating the mass.

Purpose: The aims of patients’ radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear. Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months. Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5–104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients. Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI

BACKGROUND Despite the prophylactic use of platelet transfusion, hemorrhagic complications still represent an important cause of morbidity and mortality in patients with hematologic malignancies. Patient-related factors and characteristics of the transfused product can affect transfusion efficacy. STUDY DESIGN AND METHODS The aim of this study was to develop and validate the Platelet Efficacy Score (PEscore), based on patient and product characteristics, to predict the likelihood of a satisfactory platelet transfusion (absolute increment ≥10.5 × 109/L). This study utilized data relative to 16,265 platelet transfusions performed in 1592 oncohematologic patients. The whole sample was divided into two random samples: a training set, in which different patient-related and transfusion-related characteristics were included in a predictive model to develop the PEscore; and a validation set, in which the predictive properties of the PEscore were confirmed. In the training set, multilevel logistic regression analysis was performed in which the likelihood of attaining a satisfactory transfusion was modeled. RESULTS The predictive score ranged between 0 and 30. Predictive properties of the PEscore were confirmed by the observed rates of satisfactory transfusions in the validation sample; the probability of a satisfactory transfusion was less than 10% for a score less than 12 and exceeded 50% if the score was 22 or higher. The likelihood of a satisfactory transfusion increased by 29% for a 1-unit increase in the PEscore (odds ratio, 1.29; 95% confidence interval, 1.27-1.31). CONCLUSION The availability of a prediction score can increase transfusion efficacy, help the transfusion medicine specialist in the choice of the best product for the individual patient, and avoid waste of resources.

This article tackles the real-world planning problem of railway operations. Improving the timetable planning process will result in more reliable product plans and a higher quality of service for passengers and freight operators. We focus on the microscopic models for computing accurate track blocking times for guaranteeing feasibility and stability of railway timetables. A conflict detection and resolution model manages feasibility by identifying conflicts and computing minimum headway times that provide conflict-free services. The timetable compression method is used for computing capacity consumption and verifying the stability according to the UIC Capacity Code 406. Furthermore, the microscopic models have been incorporated in a multilevel timetabling framework for completely automated generation of timetables. The approach is demonstrated in a real-world case study from the Dutch railway network. Practitioners can use these microscopic timetabling models as an important component in the timetabling process to improve the general quality of timetables.

COVID-19 pandemic raised concern about management of patients with paediatric cancer. We present the operating system that the Hemato-Oncology Department of the Santobono-Pausilipon Hospital applied. We divided our department in three zones: surveillance and screening; quarantine and COVID free, in order to screen admitted patients and to reduce the risk of cross infection. From 3 April until 29 May 2020 (56 days), 662 patients and caregivers underwent rapid serological tests for a total of 1397 assays. No patient or parent with SARS-CoV2 infection was found, demonstrating the effectiveness of COVID-19 screening process.

Objectives Estimated fetal weight (EFW) helps inform clinical decision making in patients with preterm premature rupture of membranes (PPROM). The Hadlock IV formula is the most commonly used calculation of EFW using biparietal diameter, head circumference, abdominal circumference, and femur length. The study objective was to assess the accuracy of the Hadlock IV calculation in patients with PPROM. Methods We performed a retrospective cohort study of singleton gestations with PPROM admitted between 220–330 weeks gestational age (GA) to a single, university-affiliated, tertiary hospital between 2003–2017. All women had a sonographic EFW performed within 14 days of delivery calculated by Hadlock IV formula. The Pearson correlation was calculated to determine the association between EFW and birthweight (BW). Results Five-hundred-sixty-five women were included. Mean GA was 26.8±2.4 at admission, and 28.2±2.6 at delivery. The median EFW-to-delivery interval was three days (0–14 days, intraquartile range 5 days), mean BW 1154±418 grams, and mean EFW 1078±382 grams. Overall, 49.4% of women had maximal vertical pocket (MVP) Conclusions The study shows that Hadlock IV provides an accurate EFW in patients with PPROM, regardless of fetal sex or amniotic fluid levels.

Breast cancer (BC) is the second most common cancer worldwide and the most commonly occurring malignancy in women. There is growing evidence that lifestyle factors, including diet, body weight and physical activity, may be associated with higher BC risk. However, the effect of dietary factors on BC recurrence and mortality is not clearly understood. Here, we provide an overview of the current evidence obtained from the PubMed databases in the last decade, assessing dietary patterns, as well as the consumption of specific food-stuffs/food-nutrients, in relation to BC incidence, recurrence and survival. Data from the published literature suggest that a healthy dietary pattern characterized by high intake of unrefined cereals, vegetables, fruit, nuts and olive oil, and a moderate/low consumption of saturated fatty acids and red meat, might improve overall survival after diagnosis of BC. BC patients undergoing chemotherapy and/or radiotherapy experience a variety of symptoms that worsen patient quality of life. Studies investigating nutritional interventions during BC treatment have shown that nutritional counselling and supplementation with some dietary constituents, such as EPA and/or DHA, might be useful in limiting drug-induced side effects, as well as in enhancing therapeutic efficacy. Therefore, nutritional intervention in BC patients may be considered an integral part of the multimodal therapeutic approach. However, further research utilizing dietary interventions in large clinical trials is required to definitively establish effective interventions in these patients, to improve long-term survival and quality of life.

Background Lack of suitable analytical software and computational power constrains the comprehension of animal movement. In particular, we are aware of no tools allowing simulating spatially-explicit multistate Markovian movements constrained to linear features or conditioned by landscape heterogeneity, which hinders movement ecology research in linear/dendritic (e.g. river networks) and heterogeneous landscapes. SiMRiv is a novel, fast and intuitive R package we designed to fill such gap. It does so by allowing continuous-space mechanistic spatially-explicit simulation of multistate Markovian individual movements incorporating landscape bias on local behavior. Results We present SiMRiv and its main functionalities, illustrate its simulation capabilities and easy-of-use, and discuss its limitations and potential improvements. We further provide examples of use and a preliminary evaluation, using real and simulated data, of a parameter approximation experimental method. SiMRiv allowed us to generate increasingly complex movements of three theoretical species (aquatic, semiaquatic and terrestrial), showing the effects of input parameters and water-dependence on emerging movement patterns, and to parameterize a high-frequency simulation model from real, low-frequency movement (telemetry) data. Typical running times for conducting 1000 simulations with 10,000 steps each, of two-state movement trajectories in a river network, were of ca. 3 min in an Intel Core i7 CPU X990 @ 3.47 GHz. Conclusions SiMRiv allows simulation of movements constrained to linear habitats or conditioned by landscape heterogeneity, therefore enhancing the application of movement ecology to linear/dendritic and heterogeneous landscapes. Importantly, the software is flexible enough to be used in linear, heterogeneous, as well as homogeneous landscapes. Using the same software, algorithm and approach, one can therefore use SiMRiv to study the movement of different organisms in a variety of landscapes, facilitating comparative research. SiMRiv balances ease and speed with high realism of the movement models obtainable, constituting a fast, powerful, yet intuitive tool, which should contribute exploring several movement-related questions. Its applications depart from the generation of mechanistic null movement models, up to population level (e.g. landscape connectivity) analyses, holding potential for all fields requiring the simulation of random trajectories. Electronic supplementary material The online version of this article (10.1186/s40462-019-0154-8) contains supplementary material, which is available to authorized users.

Background Diagnosis and treatment of primary lung adenocarcinoma in children remains challenging given its rarity. Here we highlight the clinical history, pathological evaluation, genomic findings, and management of a very young patient with metastatic lung adenocarcinoma. Case presentation A 10-year-old white girl presented with brain metastases due to primary pulmonary adenocarcinoma. Next generation sequencing analysis with “Comprehensive Cancer Panel” highlighted the presence of multiple non-targetable mutations in the FLT4, UBR5, ATM, TAF1, and GUCY1A2 genes. She was treated aggressively with chemotherapy, surgery, and radiation therapy for local and distant recurrence. Eventually, therapy with nivolumab was started compassionately, and she died 23 months after diagnosis. Conclusions Extremely rare cancers in children such as lung adenocarcinoma need accurate and specific diagnosis in order to develop an optimal plan of treatment. It is also necessary to underline that “children are not little adults,” thus implying that an adult-type cancer in the pediatric population might have a different etiopathogenesis. Diagnostic confirmation and primary treatment of such rare conditions should be centralized in reference centers, collaborative networks, or both, with multidisciplinary approaches and very specific expertise.

Automatic real-time control of traffic perturbations has recently become a central issue for many European railway infrastructure managers. The aim is to make use of mathematical algorithms to maintain the required service availability during unplanned disturbances to operations. In the literature many tools for real-time traffic control are proposed, but their effects on traffic have never been studied neither in real life nor in fully realistic simulation environments. We can mention only a few pilot tests and a unique installation in the Lötschberg Base tunnel in Switzerland, which uses a replanning framework that is generally applicable but does not consider a standard data communication format. Standardisation of railway data is instead one of the main requirements of the European Railway Traffic Management System (ERTMS) to enable traffic interoperability across different countries along the Trans-European Transport Network (TEN-T). Following this direction, this paper introduces one of the outputs of the European project ON-TIME: a framework for the automatic real-time management of railway traffic, designed for being standard and interoperable across different European railways. We make use of a web-based Service-Oriented Architecture to ensure scalability and flexibility of application. A standard railML interface is used for the input/output data of the modules, allowing immediate applicability of the framework to any network having a railML representation. A proof-of-concept is provided where the framework is tested in a closed-loop with the simulation environment HERMES for perturbed traffic scenarios on different networks in the UK, the Netherlands and Sweden. Tests are performed for two different replanning algorithms (ROMA and RECIFE) used for the automatic detection and optimised resolution of train conflicts. The two algorithms are compared on the test case in Sweden. Results show that the design of the proposed framework is effective in managing traffic perturbations and is extendible to real-life systems.Automatic real-time control of traffic perturbations has recently become a central issue for many European railway infrastructure managers. The aim is to make use of mathematical algorithms to maintain the required service availability during unplanned disturbances to operations. In the literature many tools for real-time traffic control are proposed, but their effects on traffic have never been studied neither in real life nor in fully realistic simulation environments. We can mention only a few pilot tests and a unique installation in the Lötschberg Base tunnel in Switzerland, which uses a replanning framework that is generally applicable but does not consider a standard data communication format. Standardisation of railway data is instead one of the main requirements of the European Railway Traffic Management System (ERTMS) to enable traffic interoperability across different countries along the Trans-European Transport Network (TEN-T). Following this direction, this paper introduces one of the outputs of the European project ON-TIME: a framework for the automatic real-time management of railway traffic, designed for being standard and interoperable across different European railways. We make use of a web-based Service-Oriented Architecture to ensure scalability and flexibility of application. A standard railML interface is used for the input/output data of the modules, allowing immediate applicability of the framework to any network having a railML representation. A proof-of-concept is provided where the framework is tested in a closed-loop with the simulation environment HERMES for perturbed traffic scenarios on different networks in the UK, the Netherlands and Sweden. Tests are performed for two different replanning algorithms (ROMA and RECIFE) used for the automatic detection and optimised resolution of train conflicts. The two algorithms are compared on the test case in Sweden. Results show that the design of the proposed framework is effective in managing traffic perturbations and is extendible to real-life systems.

With the increasing demand for railway transportation infrastructure managers need improved automatic timetabling tools that provide feasible timetables with enhanced performance in short computation times. This paper proposes a hierarchical framework for timetable design which combines a microscopic and a macroscopic model of the network. The framework performs an iterative adjustment of train running and minimum headway times until a feasible and stable timetable has been generated at the microscopic level. The macroscopic model optimizes a trade-off between minimal travel times and maximal robustness using an Integer Linear Programming formulation which includes a measure for delay recovery computed by an integrated delay propagation model in a Monte Carlo setting. The application to an area of the Dutch railway network shows the ability of the approach to automatically compute a feasible, stable and robust timetable. Practitioners can use this approach both for effective timetabling and post-evaluation of existing timetables.

Recently the growing demand in railway transportation has raised the need for practitioners to improve the design of railway systems. This means to identify a configuration of the infrastructure components (e.g. number of rail tracks, type and layout of the signalling system, layout of station tracks) and the operational schedule (e.g. train headways, scheduled dwell times) that improves given measures of performance such as the level of capacity, the punctuality of the service and the energy saving.Planners and designers involved in this process have the hard task of determining sound design solutions in order to achieve certain levels of network performances in a cost-effective way, especially when investment funds are limited. To this aim, a sensitivity analysis can support early decisional phases in order to better understand dependencies between performances and design variables and drive the decisional process towards effective solutions.In this paper, the Sobol variance-based method is applied to this purpose. A practical application has been carried out for a mass transit line in the city of Naples. Such study has investigated how train delays and energy consumption are affected by variations in design variables relative to the operational plan, the signalling system and factors related to the layout of station platforms. Results highlight the ability of this analysis in explaining the effects of different design solutions from a statistical point of view and finding the most influential factors for a given performance. This aspect suggests to practitioners the usefulness of this approach in addressing decisions towards cost-effective interventions. �� 2013 Elsevier Ltd.

Railway traffic is heavily affected by disturbances and/or disruptions, which are often cause of delays and low performance of train services. The impact and the propagation of such delays can be mitigated by relying on automatic tools for rescheduling traffic in real-time. These tools predict future track conflict based on current train information and provide suitable control measures (e.g. reordering, retiming and/or rerouting) by using advanced mathematical models. A growing literature is available on these tools, but their effects on real operations are blurry and not yet well known, due to the very scarce implementation of such systems in practice. In this paper we widen the knowledge on how automatic real-time rescheduling tools can influence train performance when interfaced with railway operations. To this purpose we build up a novel traffic control framework that couples the state-of-the art automatic rescheduling tool ROMA, with the realistic railway traffic simulation environment EGTRAIN, used as a surrogate of the real field. At regular times ROMA is fed with current traffic information measured from the field (i.e. EGTRAIN) in order to predict possible conflicts and compute (sub) optimal control measures that minimize the max consecutive delay on the network. We test the impact of the traffic control framework based on different types of interaction (i.e. open loop, multiple open loop, closed loop) between the rescheduling tool and the simulation environment as well as different combinations of parameter values (such as the rescheduling interval and prediction horizon). The influence of different traffic prediction models (assuming e.g. aggressive versus conservative driving behaviour) is also investigated together with the effects on traffic due to control delays of the dispatcher in implementing the control measures computed by the rescheduling tool. Results obtained for the Dutch railway corridor Utrecht–Den Bosch show that a closed loop interaction outperforms both the multiple open loop and the open loop approaches, especially with large control delays and limited information on train entrance delays and dwell times. A slow rescheduling frequency and a large prediction horizon improve the quality of the control measure. A limited control delay and a conservative prediction of train speed help filtering out uncertain traffic dynamics thereby increasing the effectiveness of the implemented measures.

Railways wish to reduce the costs of engineering interlocking systems by simplifying the exchange of technical information between stakeholders. Exchanging interlocking data in a machine-readable and standardized format removes inefficiency due to misinterpretation and conversion of data from non-standard, often paper-based formats. This paper proposes an UML class representation of the interlocking data that maps the characteristics of the interlocking system. These data model represents both tabular and geographical interlocking. The model reflects the topology of the railway network that the interlocking controls, routes, relations between signal aspects, speed indication signals, automatic train protection (ATP) and the state of movable and non-movable track elements. The data are machine-readable RailML, an incarnation of XML that is gaining the status of standard in railway modelling. We applied our approach to model the Dutch Santpoort Noord station, starting from paper-based track and signal plans. The resulting database captures all the features of the interlocking, whilst removing data redundancy. The model has general validity and it is easily extendible to other interlocking and ATP systems. Our approach contributes to create standard, electronic interlocking databases, directly from technical documents currently used in the practical world. We propose a database of railway interlocking mapping logical and physical features.The database builds on a novel UML formalization of interlocking elements.The standard machine-readable language RailML is used to structure the database.Our formalization overcomes the limits of previous approaches proposed so far.Using a standard database eases the communication process among stakeholders.

Background Rhabdomyosarcoma (RMS) is a highly malignant tumor typically affecting children and adolescents. Central nervous system (CNS) dissemination is rare in RMS patients, but seems to have a particularly negative impact. The aim of this study was to analyze treatment and outcome of patients with RMS and evidence of CNS disease who were registered in the protocols coordinated by the Italian Soft Tissue Sarcoma Committee from March 1979 to December 2016. Methods We analyzed 39 patients with CNS disease. Depending on when their CNS disease was identified, we grouped patients as: Group A, at diagnosis; Group B, progression during treatment; Group C, at first relapse. Results Six patients were in Group A (2.7% of metastatic RMS patients at diagnosis); 24 were in Group B and 9 in Group C (6.5% of patients with tumor progression/relapse included in the protocols). Only 5 patients (4 in Group A, 1 in Group B) survived the event and are alive in complete remission with a median follow-up of 17.5 years. These 5 patients received systemic chemotherapy and craniospinal radiotherapy, and 2 of them also received intrathecal therapy with topotecan. Conclusions CNS involvement at diagnosis is a rare and prognostically negative event in RMS patients, but not always fatal when it is found at diagnosis. It is more frequent during or shortly after treatment, and the more dismal prognosis in these cases underscores the need to improve our ability to identify patients at risk of CNS dissemination in order to attempt more effective treatments that can sterilize the meninges.

OBJECTIVEIn the past, the outcome of surgical treatment for thalamic tumor was poor. These lesions were often considered inoperable. However, contemporary microsurgical techniques, together with improvements in neuroimaging that enable accurate presurgical planning, allow resection to be accomplished in a safer way.METHODSThe medical records, imaging studies, and operative and pathology reports obtained for pediatric patients who were treated for thalamic tumors at the authors’ department were reviewed. Neuronavigation and intraoperative monitoring of motor and somatosensory evoked potentials were used. Preoperative tractography, which helped to identify internal capsule fibers, was very important in selecting the surgical strategy. Postoperatively, an MRI study performed within 24 hours was used to assess the extent of tumor resection as partial (≤ 90%), subtotal (> 90%), or gross total (no residual tumor).RESULTSSince 2002, 27 children with thalamic tumors have been treated at the authors’ department. There were 9 patients with unilateral thalamic tumors, 16 with thalamopeduncular tumors, and 2 with a bilateral tumor. These last 2 patients underwent endoscopic biopsy and implantation of a ventriculoperitoneal shunt. Thirty-nine tumor debulking procedures were performed in the remaining 25 patients. Different surgical approaches were chosen according to tumor location and displacement of the posterior limb of the internal capsule (as studied on axial T2-weighted MRI) and corticospinal tract (as studied on diffusion tensor imaging with tractography, after it became available). In 12 cases, multiple procedures were performed; in 7 cases, these were done as part of a planned multistage resection. In the remaining 5 cases, the second procedure was necessary because of late recurrence or regrowth of residual tumor.At the end of the surgical phase, of 25 patients, 15 (60%) achieved a gross-total resection, 4 (16%) achieved a subtotal resection, and 6 (24%) achieved a partial resection. Eighteen patients harbored low-grade tumors in our series. In this group, the mean follow-up was 45 months (range 4–132 months). At the end of follow-up, 1 patient was dead, 12 patients were alive with no evidence of disease, 4 patients were alive with stable disease, and 1 was lost to follow-up. All patients were independent in their daily lives. The outcome of high-grade tumors in 9 patients was very poor: 2 patients died immediately after surgery, 6 died of progressive disease, and 1 was alive with residual disease at the time of this report.CONCLUSIONSThis institutional review seems to offer further evidence in favor of attempts at radical resection in pediatric patients harboring unilateral thalamic or thalamopeduncular tumors. In low-grade gliomas, radical resection in a single or staged procedure can be curative without complementary treatment. Recurrences or residual regrowth can be safely managed surgically. In high-grade tumors, the role of and opportunity for radical or partial resection remains a matter of debate.

To meet the growing demand in railway transportation, practitioners are more and more required to upgrade or substitute the signalling system in order to increase the capacity of the network. Existing approaches for the design of the signalling layout, usually tend to maximize the technological efficiency of the system by shortening the length of block sections, thus reducing the minimum line headway and the energy consumption but increasing investment costs. This paper presents a design approach addressed to identify the signalling layout which minimizes the investment and management costs, while respecting the required level of capacity. To solve this problem an innovative design framework is introduced which integrates a stochastic multi-train simulation model within a “black-box” optimization loop. Results obtained from an application to a real metro line confirm the effectiveness of such method in finding the solution which minimizes total costs for the line manager. A comparison with the block layout which maximizes the technological efficiency highlights that the obtained solution constitutes a satisfying trade-off between total costs and network performances.

Aims of patient follow-up are: discovering relapse to apply second-line therapy for possible cure, accruing patients in phase 1/2 protocols if second-line therapy is not standardized/curative, evaluating/treating iatrogenic effects. To lessen the patient/family emotional and social economic burdens, we should ideally understand if scheduled radiological follow-up has a better rationale/outcome than the symptomatic relapse. We analyzed the Italian series of 2016 (doi:10.1093/neuonc/now108) comprehending 160 newly diagnosed pediatric/adolescent patients with intracranial ependymoma (EPD) according to relapse status (recurrence at scheduled exam [RECPT]/sign-symptomatic recurring [SYMPPT]). RECPT and SYMPPT were assessed in Cox model as time-dependent variables for overall survival (OS). Differences in characteristics between RECPT and SYMPPT subgroups were assessed by Wilcoxon-Mann-Whitney or Fisher Exact tests. Kaplan-Meier curves depicted event-free survival (EFS) and OS after recurrence according to signs/symptoms. There were 16 SYMPPT /34 RECPT, at a median follow-up of 55 months. No significant differences were found between SYMPPT/RECPT for gender, age, tumor grade/site, shunt, residual disease, radiation boost, type of relapse (local/distant/combined). Time-to-relapse (median:19 months, range 5–104) and treatment adoption did not differ between SYMPPT/RECPT while signs/symptoms depicted an unfavorable factor for OS after relapse (5-year OS: 8% vs 37%). Adjusted model in multivariate analysis confirmed that presence of signs/symptoms was prognostically unfavorable. In order to improve the OS in symptomatic patients, their early identification-in the first two/three years after diagnosis- would be desirable. Perhaps, this could be obtained paying attention to “heuristically detected” subgroup of patients, not just describing general prognostic variables but discovering possible biology differences according to signs/symptoms.

Background This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). Methods WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. Results From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. Conclusions In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

The performance of railway operations depends highly on the quality of the railway timetable. In particular for dense railway networks it can be challenging to obtain a stable robust conflict-free and energy-efficient timetable with acceptable infrastructure occupation and short journey times. This paper presents a performance-based railway timetabling framework integrating timetable construction and evaluation on three levels: microscopic, macroscopic, and a corridor fine-tuning level, where each performance indicator is optimized or evaluated at the appropriate level. A modular implementation of the three-level framework is presented and demonstrated on a case study on the Dutch railway network illustrating the feasibility of this approach to achieve the highest timetabling design level.

Background Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis. Patients and Methods Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed. Results Median age at initial SEC was 104 days (IQR 47–234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7–34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P = 0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion >66% (P = 0.039) and grade 3 motor deficit (P = 0.084). Conclusions Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted. Pediatr Blood Cancer 2014; 61:1369–1375. © 2014 Wiley Periodicals, Inc.

In the last decade simulation models and optimization environments have been developed that are able to address the complexity of real-time railway dispatching. Nevertheless, actual implementations of these systems in practice are scarce. Essential for implementation of an advanced dispatching system is the trust of traffic controllers into a stable working of the system. Nervous systems might change advice suddenly, and even switch back to a solution previously discarded, as time and knowledge of the perturbation progress. To this end, we propose several metrics and a framework to assess the stability of railway dispatching solutions under incomplete knowledge, and report on the evaluation of the state-of-the-art dispatching system ROMA, coupled with the simulation environment EGTRAIN, here considered as a surrogate of the real field. Rescheduling plans calculated at different control stages have been compared for different prediction horizons of the rescheduling tool. This setup has been applied to the Dutch Utrecht–Den Bosch corridor. Results show that the instability increases as stochastic disturbances propagate. Shorter prediction horizons give plans which are more stable over time in terms of train reordering, but tend to manage perturbations mostly by retiming. Larger horizons instead allow to manage traffic essentially by reordering trains but lead to more unstable plans. Enlarging the prediction horizon over a given threshold does not alter neither the structure of plans nor their variation over time.

Management of posterior fossa tumors in infants and neonates is challenging. The characteristics of the young babies make surgery very difficult, sometimes precluding a safe complete removal. Methods: A review of the literature was undertaken to examine the incidence, histology, surgical aspects, and prognosis of posterior fossa tumors in the first year of life. Therapeutical strategies of the most frequent tumor types are also discussed in detail. Results: Histology is dominated by tumors with aggressive behavior, such as medulloblastomas, atypical teratoid/rhabdoid tumors, and anaplastic ependymomas. The most important surgical considerations in small children are the small circulating blood volume; the poor thermoregulation; and incomplete maturation of the brain, of the skull, and of the soft tissue. Treatment toxicity is inversely related to the age of the patients. Radiation therapy is usually considered as contraindicated in young children, with few exceptions. Proton therapy is a promising tool, but access to this kind of treatment is still limited. The therapeutic limitations of irradiation render resection of this tumor and adjuvant chemotherapy often the only therapeutic strategy in many cases. Conclusions: The overall prognosis remains dismal because of the prevalent aggressive histologies, the surgical challenges, and the limitations of adjuvant treatment. Nevertheless, the impressive improvements in anesthesiology and surgical techniques allow, in the vast majority of the cases, complete removal of the lesions with minor sequelae in high-volume referral pediatric centers

Melanotic neuroectodermal tumor of infancy is a rare congenital pigmented neoplasm of neural crest origin, locally aggressive, growing rapidly and developing during the 1st year of life. It most commonly arises from the maxilla, cranial vault, and mandible. Occasionally, it exhibits malignant behavior with local lymph nodes involvement. Cases misdiagnosed and left untreated for a long time can present challenges due to the tumor mass and infiltration. In these cases, adjuvant chemotherapy can be extremely helpful before radical excision.Authors of this report describe a 4-year-old boy from a developing country who was referred to their hospital with an ulcerated bulging lesion in the midline/right parietooccipital region, extending to the right laterocervical and parotid regions, resulting in significant craniofacial deformation. Magnetic resonance imaging of the brain revealed a highly enhancing tumor with intracranial and extracranial development extending mainly at the level of the right parietooccipital region, with lytic and hypertrophic alterations of the skull. The patient was managed with neoadjuvant and adjuvant chemotherapy and radically resective surgery on metastatic lymph nodes and the primary tumor of the skull. Scheduled radiotherapy was not performed, according to the parents' wishes. The patient returned to his native country where the lesion recurred, and he ultimately died approximately 10 months after the end of the treatment.The literature indicates that tumor removal alone has been the treatment of choice in most isolated cases, but in cases of highly advanced tumor with involvement of the skull and cervical lymph nodes, it is preferable to proceed with preoperative chemotherapy with the aim of reducing the tumor volume, allowing better technical conditions for complete surgical removal, and decreasing the risk of local recurrence or metastasis.