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Imported allergens are involved in many allergic reactions, with unexpected and unusual implications. They can be involved in developing asthma, allergic rhinoconjunctivitis, Hymenoptera venom allergies and food allergies. Imported allergens can be implied in respiratory allergies attributable to commercial practices and accidental diffusion through air currents that have introduced non-native species in new geographical contexts. Ambrosia artemisiifolia L., a plant native to North America and currently in the western part of Lombardy, represents an example. Moreover, a variation in the pollen concentration in the Northwest Tuscany area and Trentino Alto-Adige was observed. Cannabis sativa is another imported allergen used frequently by adolescents. Regarding potential imported food allergens, there is no validated list. Imported food allergens derive from ethnic foods, referring to Mexican/Latin American, Chinese/Japanese, Southeast Asian, Arab/Middle Eastern and African cuisine. Four insect flours were recently introduced to the European and Italian markets (Acheta domesticus, Alphitobius diaperinus, Tenebrio molitor and Locusta migratoria). The association between the accidental introduction through commercial traffic, climate change, and the absence of natural enemies in the destination ecosystem is related to the introduction of a specific Hymenoptera, Vespa velutina, in Italy and Europe. External events attributable to human activities, such as climate change and the introduction of non-native plants, foods and Hymenoptera through trade, have contributed to the issue of imported allergens. Making the correct diagnosis and guiding the diagnostic and therapeutic path in this particular context represent the concerns of the pediatric allergist., (© 2024. The Author(s).)

Background and Aims: Definitive chemoradiotherapy (CRT) is increasingly used as a nonsurgical treatment for esophageal cancer. In Japanese studies, salvage endoscopic resection (ER) has emerged as a promising strategy for local failure after definitive CRT. We aimed to evaluate the safety and efficacy of salvage ER in a Western setting., Methods: Gastroenterologists from Europe and the United States were invited to submit their experience with salvage endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) after definitive CRT. Participating gastroenterologists completed an anonymized database, including patient demographics, clinicopathologic variables, and follow-up on survival and recurrence., Results: Gastroenterologists from 10 endoscopic units in 6 European countries submitted information on 25 patients. A total of 35 salvage ER procedures were performed, of which 69% were ESD and 31% EMR. Most patients had squamous cell carcinoma (64%) of the middle or lower esophagus (68%) staged as cT2-3 (68%) and cN+ (52%) before definitive CRT. The median time from end of definitive CRT to ER was 22 months (interquartile range, 6-47). The en-bloc resection rate was 92% for ESD and 46% for EMR. During a median of 24 months (interquartile range, 12-59) of follow-up after salvage ER, 52% developed a recurrence (11 locoregional, 2 distant). The 5-year recurrence-free survival, overall survival, and disease-specific survival were 36%, 52%, and 79%, respectively. No major intra- or postprocedural adverse events, such as bleeding or perforation, were reported., Conclusions: In carefully selected esophageal cancer patients, salvage ER is technically feasible after definitive CRT. Further prospective research is recommended to validate the safety and effectivity of salvage ER for the management of local failure., (Copyright © 2021 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

This technology review expresses the current view of the European Society of Gastrointestinal Endoscopy (ESGE) on the available techniques for intraductal biliopancreatic imaging. The three cholangioscopy techniques are described: the "dual-operator" and " single-operator" mother-baby approaches using dedicated instruments, and the "direct" technique using currently available ultrathin gastroscopes. The mother-baby method is standardized and reproducible, while direct cholangioscopy is technically demanding and its safety requires further evaluation. As well as direct visualization of the bile ducts, cholangioscopy has the further advantage of allowing targeted biopsy. Image quality is still suboptimal for single-operator cholangioscopy, while the other techniques have achieved adequately detailed imaging. The costs of mother-baby cholangioscopy are high and its application in clinical practice should be restricted to selected cases (i.e. indeterminate biliary strictures/intraluminal lesions, difficult biliary stones) and to the setting of tertiary care centers. Peroral pancreatoscopy may find an indication in situations where other imaging modalities (mainly EUS) are inconclusive (i.e. delineation of main duct intraductal papillary mucinous neoplasia extension, sampling of indeterminate main pancreatic duct strictures). Intraductal ultrasonography (IDUS) has a poorer performance than EUS in the staging of pancreatic malignancies and can increase the risk of pancreatitis. A promising indication for IDUS could be the evaluation of indeterminate biliary strictures and ampullary tumors. Probe-based confocal laser endomicroscopy (pCLE) of the bile ducts is a difficult and expensive technique. Appropriate training needs to be established, since interpretation of images is challenging. pCLE can be an important diagnostic tool in the setting of indeterminate biliary strictures., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: The proposed guideline for performing endoscopic resection of early gastric carcinoma (EGC) in Paris classification is a well-differentiated carcinoma with maximum involvement Sm1. Signet ring cell carcinomas (SRC) are excluded from this recommendation. Authors from Eastern countries have proposed extending this resection to include selected undifferentiated EGC. Via an analysis of a series of cases of signet ring carcinoma, we will discuss whether it is possible to resect EGC with signet ring cells in Europe., Methods: We retrospectively included patients with histological classification pT1 of EGC showing SRC. Data was extracted from the hospital gastrectomy register. Lymphadenomectomy D1.5 was performed on all patients. Histology results were retrospectively obtained from the electronic patient file., Results: Twelve patients (mean age = 55.4, four women, eight men) underwent surgery, without previous chemotherapy, between 2000 and 2012, for EGC with SRC. Mean size of the lesions was 20.2 mm (5-35 mm). Seven lesions were located in the antrum, five in the fundus. In the case of nine patients, histology showed no lymphovascular involvement. None of these nine patients presented lymph node metastases (LNM). Five patients had intramucosal carcinoma, four were classified as Sm1, one patient was Sm2, and one patient was Sm3. On surgery, the three patients with lymphovascular invasion showed LNM., Conclusion: Endoscopic resection of EGC with SRC does not systematically imply complementary treatment by surgery, although criteria for endoscopic resection are difficult to determine because of the lack of data in Europe.

Objective: Sapropterin dihydrochloride, the synthetic form of 6R-tetrahydrobiopterin (BH4), is an approved drug for the treatment of patients with BH4-responsive phenylketonuria (PKU). The purpose of this study was to assess genotypes and data on the long-term effects of BH4/sapropterin on metabolic control and patient-related outcomes in 6 large European countries., Methods: A questionnaire was developed to assess phenotype, genotype, blood phenylalanine (Phe) levels, Phe tolerance, quality of life, mood changes, and adherence to diet in PKU patients from 16 medical centers., Results: One hundred forty-seven patients, of whom 41.9% had mild hyperphenylalaninemia, 50.7% mild PKU, and 7.4% classic PKU, were followed up over ≤12 years. A total of 85 different genotypes were reported. With the exception of two splice variants, all of the most common mutations were reported to be associated with substantial residual Phe hydroxylase activity. Median Phe tolerance increased 3.9 times with BH4/sapropterin therapy, compared with dietary treatment, and median Phe blood concentrations were within the therapeutic range in all patients. Compared with diet alone, improvement in quality of life was reported in 49.6% of patients, improvement in adherence to diet was reported in 47% of patients, and improvement in adherence to treatment was reported in 63.3% of patients. No severe adverse events were reported., Conclusions: Our data document a long-term beneficial effect of orally administered BH4/sapropterin in responsive PKU patients by improving the metabolic control, increasing daily tolerance for dietary Phe intake, and for some, by improving dietary adherence and quality of life. Patient genotypes help in predicting BH4 responsiveness.

This article is the second of a two-part publication that expresses the current view of the European Society of Gastrointestinal Endoscopy (ESGE) about endoscopic ultrasound (EUS)-guided sampling, including EUS-guided fine needle aspiration (EUS-FNA) and EUS-guided Trucut biopsy. The first part (the Clinical Guideline) focused on the results obtained with EUS-guided sampling, and the role of this technique in patient management, and made recommendations on circumstances that warrant its use. The current Technical Guideline discusses issues related to learning, techniques, and complications of EUS-guided sampling, and to processing of specimens. Technical issues related to maximizing the diagnostic yield (e.g., rapid on-site cytopathological evaluation, needle diameter, microcore isolation for histopathological examination, and adequate number of needle passes) are discussed and recommendations are made for various settings, including solid and cystic pancreatic lesions, submucosal tumors, and lymph nodes. The target readership for the Clinical Guideline mostly includes gastroenterologists, oncologists, internists, and surgeons while the Technical Guideline should be most useful to endoscopists who perform EUS-guided sampling. A two-page executive summary of evidence statements and recommendations is provided., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background & Aims: By using strain assessment, real-time endoscopic ultrasound (EUS) elastography provides additional information about a lesion's characteristics in the pancreas. We assessed the accuracy of real-time EUS elastography in focal pancreatic lesions using computer-aided diagnosis by artificial neural network analysis., Methods: We performed a prospective, blinded, multicentric study at of 258 patients (774 recordings from EUS elastography) who were diagnosed with chronic pancreatitis (n = 47) or pancreatic adenocarcinoma (n = 211) from 13 tertiary academic medical centers in Europe (the European EUS Elastography Multicentric Study Group). We used postprocessing software analysis to compute individual frames of elastography movies recorded by retrieving hue histogram data from a dynamic sequence of EUS elastography into a numeric matrix. The data then were analyzed in an extended neural network analysis, to automatically differentiate benign from malignant patterns., Results: The neural computing approach had 91.14% training accuracy (95% confidence interval [CI], 89.87%-92.42%) and 84.27% testing accuracy (95% CI, 83.09%-85.44%). These results were obtained using the 10-fold cross-validation technique. The statistical analysis of the classification process showed a sensitivity of 87.59%, a specificity of 82.94%, a positive predictive value of 96.25%, and a negative predictive value of 57.22%. Moreover, the corresponding area under the receiver operating characteristic curve was 0.94 (95% CI, 0.91%-0.97%), which was significantly higher than the values obtained by simple mean hue histogram analysis, for which the area under the receiver operating characteristic was 0.85., Conclusions: Use of the artificial intelligence methodology via artificial neural networks supports the medical decision process, providing fast and accurate diagnoses., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Early introduction of solid food has been suspected to induce excessive infant energy intake and weight gain., Objective: The objective of this study was to test whether introduction of solid foods influences energy intake or growth., Design: Healthy, formula-fed infants who were recruited in 5 European countries were eligible for study participation. Anthropometric measurements were taken at recruitment and at 3, 6, 12, and 24 mo. Time of introduction of solid foods and energy intake were determined by questionnaires and 3-d weighed food records at monthly intervals. Age at introduction of solid food was categorized into 4 groups: ≤ 13 wk, 14-17 wk, 18-21 wk, and ≥ 22 wk., Results: Of 1090 recruited infants, 830 (76%) had data available for age at first introduction of solid food, and 671 (61%) completed the study until 24 mo of age. The median age at introduction of solid food was 19 wk. The time of introduction of solid foods was associated with country, sex, birth weight, parental education and marital status, and maternal smoking. Energy intake was higher in the first 8 mo of life in children with solid-food intake. Solid-food introduction did not predict anthropometric measures at 24 mo. Growth trajectories differed significantly: children with solid-food introduction in the first 12 wk experienced early catch-up growth, whereas those introduced to solid food at >22 wk of age grew more slowly and stayed on lower trajectories., Conclusions: Solid foods do not simply replace infant formula but increase energy intake. Time of introduction of solid food has little influence on infant growth. This trial was registered at clinicaltrials.gov as NCT00338689.

To gain better insight in the most current diagnosis and treatment practices for phenylketonuria (PKU) from a broad group of experts, a European PKU survey was performed. The questionnaire, consisting of 33 questions, was sent to 243 PKU professionals in 165 PKU centers in 23 European countries. The responses were compiled and descriptive analyses were performed. One hundred and one questionnaires were returned by 93/165 centers (56%) from 19/23 European countries (83%). The majority of respondents (77%) managed patients of all age groups and more than 90% of PKU teams included physicians or dieticians/nutritionists. The greatest variability existed especially in the definition of PKU phenotypes, therapeutic blood phenylalanine (Phe) target concentrations, and follow-up practices for PKU patients. The tetrahydrobiopterin (BH4; sapropterin) loading test was performed by 54% of respondents, of which 61% applied a single dose test (20mg/kg over 24h). BH4 was reported as a treatment option by 34%. This survey documents differences in diagnostic and treatment practices for PKU patients in European centers. In particular, recommendations for the treatment decision varied greatly between different European countries. There is an urgent need to pool long-term data in PKU registries in order to generate an evidence-based international guideline., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Background and Objective: Untreated phenylketonuria is characterized by neurocognitive and neuromotor impairment, which result from elevated blood phenylalanine concentrations. To date, the recommended management of phenylketonuria has been the use of a protein-restricted diet and the inclusion of phenylalanine-free protein supplements; however, this approach is often associated with poor compliance and a suboptimal clinical outcome. Sapropterin dihydrochloride, herein referred to as sapropterin, a synthetic formulation of 6R-tetrahydrobiopterin (6R-BH4), has been shown to be effective in reducing blood phenylalanine concentrations in patients with phenylketonuria. The objective of the current study was to characterize the pharmacokinetics and pharmacokinetic variability of sapropterin and to identify the characteristics that influence this variability., Patients and Methods: This was a 12-week, fixed-dose phase of an open-label extension study. The study was conducted at 26 centres in North America and Europe.Patients with phenylketonuria were eligible to participate if they were > or =8 years of age and had received > or =80% of the scheduled doses in a previous 6-week, randomized, placebo-controlled study or had been withdrawn from that study after exceeding a plasma phenylalanine concentration of > or =1500 micromol/L to > or =1800 micromol/L, depending on the subject's age and baseline plasma phenylalanine concentration. A total of 78 patients participated. Patients received oral once-daily doses of sapropterin (Kuvan) 5, 10 or 20 mg/kg/day. Blood samples for the pharmacokinetic analysis were obtained during weeks 6, 10 and 12. A D-optimal sparse sampling strategy was used, and data were analysed by population-based, nonlinear, mixed-effects modelling methods., Main Outcome Measure: In a prospectively planned analysis, the apparent clearance, apparent volume of distribution, absorption rate constant and associated interindividual variabilities of each parameter were estimated by modelling observed BH4 plasma concentration-time data., Results: The best structural model to describe the pharmacokinetics of sapropterin was a two-compartment model with first-order input, first-order elimination and a baseline endogenous BH4 concentration term. Total bodyweight was the only significant covariate identified, the inclusion of which on both the apparent clearance (mean = 2100 L/h/70 kg) and central volume of distribution (mean = 8350 L/70 kg) substantially improved the model's ability to describe the data. The mean (SD) terminal half-life of sapropterin was 6.69 (2.29) hours and there was little evidence of accumulation, even at the highest dose., Conclusion: These findings, taken together with the observed therapeutic effect, support bodyweight-based, once-daily dosing of sapropterin 5-20 mg/kg/day.

The current burden of allergic diseases, estimated by both direct and indirect costs, is very relevant. In fact the cost estimation for rhinitis amount globally to 4-10 billion dollars/year in the U.S. and to an average annual cost of 1089 euros per child/adolescent and 1543 euros per adult in Europe. The estimated annual costs in Northern America for asthma amounted to 14 billion dollars. Consequently, preventive strategies aimed at reducing the clinical severity of allergy are potentially able to reduce its costs. Among them, specific immunotherapy (SIT) joins to the preventive capacity the carryover effect once treatment is discontinued. A number of studies, mainly conducted in the US and Germany demonstrated a favourable cost-benefit balance. In the nineties, most surveys on patients with allergic rhinitis and asthma reported significant reductions of the direct and indirect costs in subjects treated with SIT compared to those treated with symptomatic drugs. This is fully confirmed in recent studies conducted in European countries: in Denmark the direct cost per patient/year of the standard care was more than halved following SIT; in Italy a study on Parietaria allergic patients demonstrated a significant difference in favor of SIT plus drug treatment for three years versus drug treatment alone, with a cost reduction starting from the 2nd year and increasing to 48% at the 3rd year, with a highly statistical significance which was maintained up to the 6th year, i.e. 3 years after stopping immunotherapy, corresponding to a net saving for each patient at the final evaluation of 623 euros per year; in France a cost/efficacy analysis comparing SIT and current symptomatic treatment in adults and children with dust mite and pollen allergy showed remarkable savings with SIT for both allergies in adults and children.

Hyperphenylalaninemia due to a deficiency of hepatic phenylalanine hydroxylase (PAH) is the most common inborn error of amino acid metabolism. Clinically, the disorder is highly heterogeneous, spanning from nonphenylketonuria hyperphenylalaninemia to classical phenylketonuria. Only little is known about the molecular defects underlying hyperphenylalaninemia in Southern Europe. In this study, we conducted a systematic analysis of 53 patients from the Sicilian population. Each patient included in the study had persistently elevated blood levels of phenylalanine and met the differential criteria for PAH deficiency. Genomic DNA was analysed by scanning all PAH-coding exons for mutations by PCR in combination with denaturing gradient gel electrophoresis (DGGE). 52 patients were completely genotyped. A spectrum of 40 different mutations was established including 17 novel PAH mutations. Our results explain the clinical heterogeneity of hyperphenylalaninemia in Southern Europe, and form the basis for the establishment of phenotype-genotype correlations in Sicily and surrounding countries.