Background and Aims
Prothrombin induced by vitamin K absence‐II (PIVKA‐II) is a serum biomarker linked to hepatocellular carcinoma (HCC), showing superiority to alpha‐fetoprotein (AFP) for early ...disease detection. We aimed to assess the clinical and analytical performance of the Elecsys® PIVKA‐II immunoassay in diagnosing HCC and evaluate PIVKA‐II's technical performance.
Methods
Serum samples from adult cases (i.e. patients with a first‐time HCC diagnosis; n = 168) and disease controls (i.e. patients without HCC with an at‐risk condition; n = 208) were assessed. An AFP cut‐off of 20 ng/mL was used to differentiate between HCC cases and disease controls. Clinical performance of the Elecsys PIVKA‐II assay was compared with that of comparator assays (Lumipulse G PIVKA‐II, μTASWako DCP, ARCHITECT PIVKA‐II) using receiver operating characteristic curve analysis to determine the area under the curve (AUC) values.
Results
The Elecsys PIVKA‐II assay compared favorably with comparator assays. Using a 28.4 ng/mL cut‐off, the Elecsys PIVKA‐II assay detected HCC with 86.9% sensitivity and 83.7% specificity. Clinical performance of the Elecsys PIVKA‐II assay (AUC: 90.8%) was equivalent to that of comparator assays (AUC: 88.3–89.6%). Relatively high PIVKA‐II concentrations were observed for cholangiocarcinoma and pancreatic cancer with the Elecsys assay in specificity panel analyses, indicating that high PIVKA‐II concentrations should not be used alone in the absence of other clinical data.
Conclusions
The Elecsys PIVKA‐II assay showed good analytical performance under routine laboratory conditions, comparing favorably with comparator assays. These findings support the suitability of the Elecsys PIVKA‐II assay as an aid in HCC diagnosis.
This multicenter study assessed the clinical and analytical performance of the Elecsys® PIVKA‐II immunoassay (Roche Diagnostics International Ltd) in diagnosing hepatocellular carcinoma (HCC), versus commercially available comparators. Under routine laboratory conditions, the Elecsys PIVKA‐II immunoassay detected HCC with 86.9% sensitivity and 83.7% specificity and the clinical performance (area under the curve AUC, 90.8%) was equivalent to comparator assays (AUC, 88.3–89.6%). These findings support the suitability of the Elecsys PIVKA‐II immunoassay as an aid in HCC diagnosis.
Cell-free DNA-based noninvasive prenatal testing (cfDNA) is a relatively new screening tool that analyzes cfDNA circulating in maternal plasma to screen for aneuploidies. Since its introduction, ...cfDNA has been rapidly adopted by health care providers (HCPs). This rapid adoption, as well as progressive developments in the technology, requires professional societies to continuously update their guidelines to indicate the broadening scope both in terms of test indications and patient populations for whom it has become the appropriate primary test. CfDNA testing, initially applied to high-risk patients, is now largely considered an option for all patients. For HCPs, the rapid introduction of cfDNA into clinical practice has come with the requirement to stay up-to-date and accurately informed. We performed a survey to understand the current practices and views of European HCPs on the use of cfDNA. European HCPs were surveyed on several topics such as familiarity with cfDNA-based noninvasive prenatal testing (NIPT), current usage, patient counseling, test menu expansion, and future perspectives. The results of this survey demonstrate increasing usage and awareness of cfDNA-based NIPT in five European countries (UK, France, Germany, Spain and Italy). Major barriers to implementation include cost and a lack of physician education on NIPT.
Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to ...genetic generalized epilepsy (GGE), which all harbor novel
mutations. In one family, we found a weak association of a novel nonsense mutation with epilepsy, suggesting reduced penetrance, and which shows, in agreement with previous findings, that gain-of-function effects rather than haploinsufficiency are important for the pathogenicity of mutations. De novo missense variants in the pore region of the channel result in severe phenotypes presenting usually with DEE with various malformations. The potential pathogenicity of a novel
germline mutation located outside of the critical pore domain observed in a GGE patient with a milder phenotype is supported by the fact that the very same amino acid exchange was detected as a somatic mutation in the resected brain tissue of a patient suffering from a focal cortical dysplasia type IIb. Thus, our case series broadens the phenotypic spectrum of
-associated diseases.
The programme of the German Congress for Laboratory Medicine 2022 was essentially designed by the divisions of the German Society for Clinical Chemistry and Laboratory Medicine (DGKL). Almost all ...chairpersons of the divisions organised a 90-min symposium on current topics, i.e. conceptualised the symposia and invited speakers. For this article all chairpersons summarised the lectures that were given within the symposia. The DGKL’s work is structured into 5 areas of expertise: Molecular Diagnostics, Learning & Teaching, Quality & Management, Laboratory & Diagnostics and Biobanks & Informatics. The areas of expertise are in turn subdivided into divisions. About the history of the establishment of this new structure within the DGKL you can find information in the editorial of this issue.
About 30% of children with nephrotic syndrome (NS) have inherited forms. Among them, mutations in Wilms tumor suppressor gene 1 (WT1) are a well characterized cause associated with steroid-resistant ...NS, Wilms tumor, and urogenital malformation in males. However, the role of WT1 mutations in adult-onset focal segmental glomerulosclerosis (FSGS) is unclear. We report the case of a 38-year-old female with FSGS. She had been diagnosed with streak ovaries during diagnostic workup for infertility. Mutational analysis identified the heterozygous mutation c.1372C>T (p.Arg458*) in WT1 and the heterozygous non-neutral polymorphism c.868G>A (p.Arg229Gln) in NPHS2. Chromosomal analysis revealed a normal 46,XX female karyotype. Our case highlights that WT1 mutations should be considered in XX females with adult-onset FSGS, especially if urogenital abnormalities are present.
Fraser syndrome (FS) is a rare autosomal recessive inherited disorder characterized by cryptophthalmos, laryngeal defects and oral clefting, mental retardation, syndactyly, and urogenital defects. To ...date, 250 patients have been described in the literature. Mutations in the FRAS1 gene on chromosome 4 have been identified in patients with Fraser syndrome. So far, 26 mutations have been identified, most of them are truncating mutations. The mutational spectrum includes nucleotide substitutions, splicing defects, a large insertion, and small deletions/insertions. Moreover, single heterozygous missense mutations in FRAS1 seem to be responsible for non-syndromic unilateral renal agenesis.
Here we report the first case of a family with two patients affected by Fraser syndrome due to a deletion of 64kb (deletion 4q21.21) and an additional novel frameshift mutation in exon 66 of the FRAS1 gene. To date, large deletions of the FRAS1 gene have not yet been described. Large deletions seem to be a rare cause for Fraser syndrome, but should be considered in patients with a single heterozygous mutation.
•A large deletion of FRAS1 should be considered in patients with one FRAS1 mutation.•Array-CGH represents an important and valuable addition in the diagnostics of FS.•Patients with deletions have a similar phenotype as with known types of mutations.
Cancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs ...such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity.
We performed a whole gene approach covering the entire coding region and compared DPYD genotype frequencies between cancer patients with good (n = 89) and with poor (n = 39) tolerance of a fluoropyrimidine-based chemotherapy regimen. Applying logistic regression analysis and sliding window approaches we identified the strongest association with fluoropyrimidine-related grade III and IV toxicity for the non-synonymous polymorphism c.496A>G (p.Met166Val). We then confirmed our initial results using an independent sample of 53 individuals suffering from drug-adverse-effects. The combined odds ratio calculated for 92 toxicity cases was 4.42 95% CI 2.12-9.23; p (trend)<0.001; p (corrected) = 0.001; the attributable risk was 56.9%. Comparing tumor-type matched sets of samples, correlation of c.496A>G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies.
Our results show compelling evidence that, at least in distinct tumor types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.
Background
In 2010,
INF2
mutations were associated with autosomal-dominant focal segmental glomerulosclerosis (FSGS), clinically presenting with moderate proteinuria in adolescence. However, in the ...meantime, cases with more severe clinical courses have been described, including progression to end-stage renal disease (ESRD) during childhood.
INF2
mutations in patients with isolated FSGS are clustered in exons 2 to 4, encoding the diaphanous inhibitory domain, involved in the regulation of the podocyte actin cytoskeleton.
Methods
We report a family with 14 affected individuals (autosomal-dominant mode of inheritance), most of whom presented with nephrotic-range proteinuria, hypertension, and progressive renal failure. Four members received a kidney transplant without disease recurrence. Two patients underwent renal biopsy with the result of minimal-change glomerulopathy and IgA nephropathy respectively. We performed mutational analysis of
ACTN4
,
CD2AP
,
COQ6
,
INF2
,
LAMB2
,
NPHS1
,
NPHS2
,
PLCE1
,
TRPC6
, and
WT1
in the index patient by next-generation sequencing. Additionally, in 6 affected and 2 unaffected family members target diagnostics were performed.
Results
We identified a novel heterozygous mutation c.490G>C (p.(Ala164Pro) in exon 3 of the
INF2
gene in the index patient and 6 additionally examined affected family members. In silico analysis predicted it as “probably damaging”. Additionally, three patients and 2 unaffected relatives harbored a novel heterozygous variant in
ACTN4
(c.1149C>G, p.(Ile383Met)) with uncertain pathogenicity.
Conclusion
Mutations in
INF2
are associated with familial proteinuric diseases - irrespective of the presence of FSGS and in the case of rapid disease progression. Therefore, mutational analysis should be considered in patients with renal histology other than FSGS and severe renal phenotype.
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