BACKGROUND: The aim of this study was to record the current status of newborn bloodspot screening (NBS) for CF across Europe and assess performance. METHODS: Survey of representatives of NBS for CF programmes across Europe. Performance was assessed through a framework developed in a previous exercise. RESULTS: In 2022, we identified 22 national and 34 regional programmes in Europe. Barriers to establishing NBS included cost and political inertia. Performance was assessed from 2019 data reported by 21 national and 21 regional programmes. All programmes employed different protocols, with IRT-DNA the most common strategy. Six national and 11 regional programmes did not use DNA analysis. CONCLUSIONS: Integrating DNA analysis into the NBS protocol improves PPV, but at the expense of increased carrier and CFSPID recognition. Some programmes employ strategies to mitigate these outcomes. Programmes should constantly strive to improve performance but large datasets are needed to assess outcomes reliably.

• MeSH
• Cystic Fibrosis * diagnosis   genetics   MeSH
• Genetic Testing * methods   MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Neonatal Screening methods   MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator genetics   MeSH
• Trypsinogen MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH

Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0-17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 × upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2×10-8). Moreover, rs13228878 (OR=0.61; P=7.1×10-6) and rs10273639 (OR=0.62; P=1.1×10-5) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children's Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (P=0.77), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma complications   drug therapy   genetics   MeSH
• Alleles MeSH
• Asparaginase administration & dosage   adverse effects   MeSH
• Models, Biological MeSH
• Child MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Variation * MeSH
• Genetic Association Studies MeSH
• Genotype MeSH
• Polymorphism, Single Nucleotide MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Pancreatitis etiology   MeSH
• Polyethylene Glycols administration & dosage   adverse effects   MeSH
• Child, Preschool MeSH
• Antineoplastic Agents administration & dosage   adverse effects   MeSH
• Trypsin genetics   MeSH
• Trypsinogen genetics   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous  = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous  = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10-6 ) and MORC4-rs 12837024 (ORhomozygous  = 2.07 (1.55-2.77, ptrend  = 0.7 × 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants.

• MeSH
• Adenocarcinoma genetics   pathology   MeSH
• Pancreatitis, Chronic genetics   pathology   MeSH
• Adult MeSH
• Carcinoma, Pancreatic Ductal genetics   pathology   MeSH
• Nuclear Proteins genetics   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Pancreatic Neoplasms genetics   pathology   MeSH
• Follow-Up Studies MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Trypsin genetics   MeSH
• Trypsinogen genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• alpha-Amylases blood   MeSH
• Diabetes Mellitus, Type 2 * drug therapy   complications   MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Hypoglycemic Agents administration & dosage   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipase blood   MeSH
• Liraglutide * administration & dosage   therapeutic use   MeSH
• Metformin administration & dosage   therapeutic use   MeSH
• Overweight complications   MeSH
• Pancreas * metabolism   drug effects   MeSH
• Randomized Controlled Trials as Topic MeSH
• Glucagon-Like Peptide-1 Receptor agonists   metabolism   MeSH
• Aged MeSH
• Sitagliptin Phosphate * administration & dosage   therapeutic use   MeSH
• Trypsinogen blood   urine   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH

BACKGROUND: In cystic fibrosis newborn screening (CFNBS), immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) can be used as screening parameters. We evaluated the IRT×PAP product as second-tier parameter in CFNBS in newborns with elevated IRT. METHODS: Data on 410,111 screened newborns including 78 patients with classical cystic fibrosis (CF) from two European centers were retrospectively analyzed by discrimination analysis to identify a screening protocol with optimal cutoffs. We also studied differences in PAP measurement methods and the association of IRT and PAP with age. RESULTS: PAP values differed systematically between fluorometric and photometric assays. The IRT×PAP product showed better discrimination for classical CF than PAP only as second-tier screening parameter (p<0.001). In CF patients, IRT decreased while PAP values remained high over years. In newborns without CF, IRT decreased after birth over weeks while PAP increased within days. CONCLUSIONS: The IRT×PAP product performs well as second-tier cutoff parameter for CFNBS. Screening quality parameters depend on the analytic method and on age at blood collection.

• MeSH
• Chemistry Techniques, Analytical MeSH
• Cystic Fibrosis * blood   diagnosis   MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Neonatal Screening methods   MeSH
• Pancreatitis-Associated Proteins analysis   MeSH
• Retrospective Studies MeSH
• Sensitivity and Specificity MeSH
• Trypsinogen * analysis   immunology   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Zatiaľčo u dospelých sa ako hlavný etiologický faktor chronickej pankreatitídy uvádza nadmerná konzumácia alkoholu, u detí sa okrem anatomických anomálií pankreasu a žlčových ciest uplatňujú predovšetkým genetické faktory. Cieľ: Charakterizovať frekvenciu výskytu mutácií jednotlivých génov asociovaných so vznikom rekurentnej akútnej pankreatitídy alebo chronickej pankreatitídy u detí a následne sledovať genotypovo-fenotypové korelácie u týchto pa­cientov. Materiál a metodika: Do štúdie bolo zaradených 21 detí s dia­gnózou rekurentnej akútnej pankreatitídy/chronickej pankreatitídy nejasnej etiológie, ktoré boli v období 2008–2013 vyšetrené na II. detskej klinike LF UK a DFNsP v Bratislave. Molekulovo-genetická analýza génov PRSS1, SPINK1 a CTRC sa uskutočnila v spolupráci s Oddelením lekárskej genetiky Onkologického ústavu sv. Alžbety. Výsledky: Rodin­ná anamnéza bola pozitívna v piatich prípadoch. U dvoch pa­cientov bola dokázaná prítomnosť mutácie p.R122H génu PRSS1; jeden pa­cient je zmiešaný heterozygot pre mutácie p.G208A (PRS­S1) a p.G60G (CTRC). Mutácia p.N34S génu SPINK1 sa potvrdila u šiestich pa­cientov (dvaja homozygotní a štyria heterozygotní), z nich u štyroch bola potvrdená aj mutácia p.G60G (CTRC) v heterozygotnom stave. Jeden pa­cient je homozygot pre mutáciu p.G60G; jeden heterozygot pre p.R254W a jeden heterozygot pre mutáciu p.G214R génu CTRC. Záver: V súbore 21 detských pa­cientov s rekurentnou akútnou pankreatitídou/chronickou pankreatitídou neznámej etiológie sme zaznamenali vysoký výskyt kauzálnych mutácií asociovaných so vznikom ochorenia. Uvedené výsledky potvrdzujú dôležitosť genetického vyšetrenia u detí s idiopatickou rekurentnou akútnou pankreatitídou /chronickou pankreatitídou.

While in adults the major etiological factor of chronic pancreatitis is excessive alcohol consumption, in children, together with anatomical anomalies of the pancreas and biliary tract, genetic factors seem to be crucial. Aim: Our aim was to investigate the frequency of mutations in genes associated with the development of recurrent acute pancreatitis or chronic pancreatitis in children and then monitor the genotype-phenotype correlations in the patients. Material and methods: Twenty-one children with recurrent acute pancreatitis or chronic pancreatitis of unknown etiology diagnosed between 2008 and 2013 at the 2nd Department of Pediatrics, University Children’s Hospital, Bratislava, were enrolled in the study. Molecular genetic analysis of PRSS1, SPINK1 and CTRC genes was performed in cooperation with the Department of Medical Genetics at St. Elisabeth’s Institute of Oncology. Results: Family history was positive in five cases. In 2 out of 21 patients, the p.R122H mutation of PRSS1 gene was found; one patient was a trans-heterozygous carrier of the p.G208A (PRSS1) and p.G60G (CTRC) variants. The p.N34S mutation of SPINK1 gene was seen in six patients (two homozygous and four heterozygous), out of which four were trans-heterozygotes with the p.G60G (CTRC) variant. One patient was homozygous for p.G60G, one was heterozygous for p.R254W and one was heterozygous for p.G214R variant of the CTRC gene. Conclusion: In a group of 21 pediatric patients with recurrent acute pancreatitis/chronic pancreatitis of unknown etiology, a high prevalence of causal mutations associated with the development of the disease was found. These results confirm the importance of genetic testing in children with idiopathic recurrent acute pancreatitis/chronic pancreatitis. Key words: chronic pancreatitis – hereditary pancreatitis – genetic predisposition to disease – genetic analysis – pancreatitis in children The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for bio­­­­medical papers. Submitted: 5. 11. 2015 Accepted: 29. 11. 2015

• Keywords
• hereditární pankreatitída,
• MeSH
• Acute Disease MeSH
• Pancreatitis, Chronic * genetics   MeSH
• Chymotrypsin genetics   MeSH
• Child MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Testing MeSH
• Genotype MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation MeSH
• DNA Mutational Analysis * MeSH
• Pancreatitis genetics   MeSH
• Child, Preschool MeSH
• Recurrence MeSH
• Pedigree MeSH
• Carrier Proteins genetics   MeSH
• Trypsin genetics   MeSH
• Trypsinogen genetics   MeSH
• Age of Onset MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: In recent years different IRT/PAP protocols have been evaluated, but the individual performance remains unclear. To optimize the IRT/PAP strategy we compared protocols from three regional CF newborn screening centers (Heidelberg, Dresden, and Prague). METHODS: We evaluated the effect of elevating the IRT-cut-off from 50 to 65 μg/l (~97.5th to ~99.0th percentile), the need of a failsafe protocol (FS, IRT ≥ 99.9th percentile) and the relative performance using either two IRT-dependent PAP-cut-offs or one PAP-cut-off. FINDINGS: Elevation of the IRT cut-off to 65 μg/l (~99.0th percentile) increased the PPV significantly (Dresden: 0.065 vs. 0.080, p < 0.0001, Prague: 0.052 vs. 0.074, p < 0.0001) without reducing sensitivity. All three IRT/PAP protocols showed a trend towards a higher sensitivity with FS than without and when using one PAP-cut-off instead of two IRT-dependent PAP-cut-offs. CONCLUSIONS: For best performance we suggest an IRT/PAP protocol with an IRT-cut-off close to the 99.0th percentile, FS, and a single PAP-cut-off.

• MeSH
• Antigens, Neoplasm analysis   blood   genetics   MeSH
• Cystic Fibrosis blood   diagnosis   genetics   MeSH
• Genetic Testing methods   standards   MeSH
• Chemistry, Clinical methods   standards   MeSH
• Lectins, C-Type analysis   blood   genetics   MeSH
• Humans MeSH
• Biomarkers, Tumor analysis   blood   genetics   MeSH
• Infant, Newborn MeSH
• Neonatal Screening methods   standards   MeSH
• Prospective Studies MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator genetics   MeSH
• Retrospective Studies MeSH
• Sensitivity and Specificity MeSH
• Dried Blood Spot Testing methods   standards   MeSH
• Trypsinogen analysis   blood   genetics   MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Geographicals
• Europe MeSH

x

• MeSH
• alpha-Macroglobulins analysis   MeSH
• Amylases administration & dosage   MeSH
• Survival Analysis MeSH
• Chymotrypsinogen administration & dosage   MeSH
• Immunosuppression Therapy MeSH
• Drug Therapy, Combination methods   MeSH
• Melanoma, Experimental * drug therapy   pathology   MeSH
• Neoplasm Metastasis pathology   MeSH
• Mice, Inbred BALB C MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Lung Neoplasms epidemiology   pathology   secondary   MeSH
• Follow-Up Studies MeSH
• Enzyme Precursors * administration & dosage   MeSH
• Peptide Hydrolases * administration & dosage   MeSH
• Sarcoma 180 * drug therapy   pathology   MeSH
• Statistics as Topic MeSH
• Drug Synergism MeSH
• Transforming Growth Factor beta blood   MeSH
• Trypsinogen administration & dosage   MeSH
• Tumor Burden drug effects   MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH

Chronická pankreatitida je progresivní zánětlivé onemocnění, které vede k destrukci parenchymu pankreatu a jeho náhradě vazivem s následnou alterací exogenní a později i endogenní funkce slinivky břišní. Nejčastější příčinou chronické pankreatitidy ve vyspělých zemích je konzumace alkoholu, u většiny pacientů je však etiologie multifaktoriální a onemocnění vzniká následkem působení kombinace faktorů genetických, metabolických a vnějšího prostředí. Původní teorie vysvětlující mechanizmus vzniku chronické pankreatitidy v důsledku působení toxinů a metabolitů, oxidativního stresu, obstrukce či nekrózy jsou podložené řadou pozorování, avšak částečně rozporuplné. V posledních letech bylo dosaženo významného pokroku zejména v pochopení genetických predispozic chronické pankreatitidy. Mutace způsobující alterace v aktivaci a inaktivaci trypsinu či sekreci duktálních buněk se podílí na rozvoji chronické pankreatitidy a modifikují její průběh. Novější SAPE hypotéza zahrnuje poznatky předchozích teorií do vícestupňového modelu vzniku chronické pankreatitidy. Patogeneze je však nejspíše, podobně jako etiologie, komplexní s účastí různých patogenetických mechanizmů a jejich kombinací v závislosti na příčině. Klíčovým momentem v chápání pato­geneze onemocnění byla charakterizace pankreatických stelárních buněk jako efektorových elementů fibrogeneze. Reprezentují centrální buňky, které reagují na různé patologické inzulty svou aktivací a tvorbou vaziva. Bližší pochopení mechanizmů pato­geneze chronické pankreatitidy představuje naději na nové kauzální postupy v její léčbě.

Chronic pancreatitis is a progressive inflammatory disease, which leads to destruction of pancreatic parenchyma and its replacement with fibrotic tissue. Subsequently it is associated with exogenous and later endogenous alteration of pancreatic function. The most prevalent cause of chronic pancreatitis in western countries is alcohol overconsumption. However, etiology of the disease of most patients is multi-factorial and the disease is a result of combined actions of genetic, metabolical factors and also of the influence of external environment. Former theories explaining mechanisms of genesis of chronic pancreatitis as an effect of toxins, metabolites, oxidative stress, obstruction or necrosis, are supported by many observations, but they are also partially inconsistent. Recently, there has been a major advance in the understanding of the genetic predisposition of chronic pancreatitis. Mutations causing alteration in regulation of trypsin activity or secretion of ductal cells contributes to the origin of chronic pancreatitis and modify the course of the disease. Newer SAPE hypothesis links knowledge of previous theories into a step-wise model of chronic pancreatitis origin. Pathogenesis, similarly to etiology, is probably complex with involvement of various pathogenetic mechanisms, depending on the cause. A key moment in understanding the disease pathogenesis was the characterization of pancreatic stellate cells as effector elements of fibrogenesis. They represent central cells, which activate themselves and create fibrotic tissue as a response to different pathological events. Better understanding of pathogenetic mechanisms of chronic pancreatitis gives hope for new causal modalities for treatment. Key words: chronic pancreatitis – etiology – pathogenesis – pancreatic stellate cell – SAPE hypothesis The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers. Submitted: 26. 7. 2013 Accepted: 12. 8. 2013

• Keywords
• teorie nekrózy-fibrózy, SAPE hypotéza,
• MeSH
• Autoimmune Diseases MeSH
• Pancreatitis, Chronic * etiology   genetics   classification   pathology   MeSH
• Chymotrypsin MeSH
• Cystic Fibrosis genetics   MeSH
• Extracellular Matrix Proteins physiology   MeSH
• Fibrosis MeSH
• Genetic Predisposition to Disease MeSH
• Haplotypes MeSH
• Serine Proteinase Inhibitors genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Oxidative Stress MeSH
• Pancreas physiology   MeSH
• Pancreatic Stellate Cells metabolism   MeSH
• Receptors, Calcium-Sensing MeSH
• Risk Factors MeSH
• Severity of Illness Index MeSH
• Trypsinogen physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

• Keywords
• hereditární pankreatitida, obstruktivní pankreatitida,
• MeSH
• Pancreatitis, Chronic * etiology   classification   therapy   MeSH
• Genetic Diseases, Inborn MeSH
• Humans MeSH
• Alcohol Drinking adverse effects   MeSH
• Risk Factors * MeSH
• Trypsinogen metabolism   MeSH
• Check Tag
• Humans MeSH