Correction to: [89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

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[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Clinicopathological characteristics and outcome of 31 patients with ETV6-NTRK3 fusion gene confirmed (mammary analogue) secretory carcinoma of salivary glands.

OBJECTIVES: In 2010, a new subtype of salivary gland cancer (SGC), (mammary analogue) secretory carcinoma (SC), was defined, characterized by the ETV6-NTRK3 fusion gene. As clinical behavior and outcome data of this histological subtype tumor are still sparse, we aimed to describe the clinicopathological course and outcome of a series of translocation positive SC patients. PATIENT AND METHODS: We re-evaluated the pathological diagnosis of a subset of SGCs, diagnosed in 4 of 8 Dutch head and neck centers. Subsequently, tumors with a morphological resemblance to SC were tested for the ETV6-NTRK3 fusion gene using RT-PCR. Furthermore, patients prospectively diagnosed with SC were included. The clinical characteristics and outcomes were retrieved from the patient files. RESULTS: Thirty-one patients with ETV6-NTRK3 fusion gene positive SC were included. The median age was 49 years, 17 patients (55%) were male. Eighteen tumors (58%) arose in the parotid gland. One patient presented with lymph node metastasis. All patients underwent tumor resection and 4 patients had a neck dissection. Four patients had re-resection and 15 patients (48%) received postoperative radiotherapy. One patient developed a local recurrence, no regional recurrences or distant metastases were observed. After a median follow-up of 49 months the 5- and 10-year overall survival were 95%, the 5- and 10-year disease free survival were 89%. CONCLUSION: The clinical course of SC is favorable with a low rate of locoregional recurrence and excellent survival. Given the low incidence of nodal metastases, elective neck treatment, i.e. surgery and/or radiotherapy, does not seem to be indicated.

Predictive factors of speech understanding in adults with cochlear implants.

OBJECTIVE: The aim of this study was to analyse the factors that influenced speech recognition scores in quiet conditions and speech reception threshold levels (SRT) in fixed noise conditions, after cochlear implant (CI) surgery in adults with postlinguistic deafness. STUDY DESIGN: Combined retrospective and prospective study in a tertiary referral centre. METHODS: We included 66 patients that received implants between 2002 and 2013. We retrospectively collected speech recognition scores and 14 demographic, audiological, and technical factors, including gender, age at implantation, aetiology, hearing loss progression, preoperative Pure Tone Average (PTA), hearing loss onset age and duration, duration and use of hearing aids (HAs); implantation in the best or worst ear; implantation on the right or left side; use of HA after implantation; and the duration and type of CI. We prospectively tested a subgroup of 21 patients for SRT in fixed noise. RESULTS: The hearing loss duration significantly affected speech recognition scores in quiet conditions (H (4) = 10.567, p =0.032) and SRTs in fixed noise conditions (rs = 0.466, p = 0.033). The PTA of the better ear significantly affected only the SRT in fixed noise conditions (rs = 0.57 1, p = 0.007). CONCLUSION: The duration of hearing loss and the PTA of the best ear had significant effects on the outcomes of speech recognition and SRT in quiet and fixed noise conditions, respectively. These findings are important for counselling CI candidates. Further studies in larger study populations are warranted.

[Movement disorders due to modern antidepressants and mood stabilizers]. / Bewegingsstoornissen door anti-depressiva en stemmingsstabilisatoren.

BACKGROUND: Personal experience and recent literature indicate that clinicians often underestimate the severity and the range of movement disorders that can result from treatment with antidepressants and mood stabilisers. AIM: To describe the prevalence, nature, symptoms and treatment of the movement disorders arising from the use of antidepressants and mood stabilisers. METHOD: We searched Medline for relevant case-reports (patients > 18 years) and review articles for the period 1966 - January 2014). Our search was based on the search-terms '(drug-induced) movement disorders' and 'extrapyramidal symptoms', 'antidepressants', 'mood stabilisers', 'antiepileptics' and 'lithium'. The results were supplemented by movement disorders reported in the database of The Netherlands Pharmacovigilance Centre Lareb. RESULTS: The most prevalent side-effects were found to be tremor, acathisia, dystonia and (tardive) dyskinesia. CONCLUSION: The clinician needs to be aware of the movement disorders that can result from treatment with antidepressants and mood stabilisers. Symptoms can generally be alleviated by adjusting the prescribed medication or sometimes by stopping the principal causal agent completely.

Diagnostic accuracy of noninvasive detection of fetal trisomy 21 in maternal blood: a systematic review.

BACKGROUND: Both pregnant women and providers of obstetric care are aware of the rapid advances in noninvasive prenatal diagnosis (NIPD) of fetal trisomies, and appear to look forward to its clinical introduction. OBJECTIVES: To review and critically assess the published literature on diagnostic accuracy of NIPD using cell-free fetal DNA or RNA in maternal blood to detect fetal trisomy 21. METHOD: An electronic search was performed in MEDLINE, EMBASE and the Cochrane library (1997 to April 2011). Of a total of 201 citations, 9 studies were eligible for full-text analysis by 2 independent reviewers, using the QUADAS tool. RESULTS: Two of the 9 analyzed studies complied with the criteria of the QUADAS tool. Combining the selected 2 studies, with a total of 681 pregnancies included, overall sensitivity was 125/125 (100%, 95% CI 97.5-100%) and specificity 552/556 (99.3%, 95% CI 98.7-99.3%). CONCLUSIONS: NIPD of fetal trisomy 21, using fetal nucleic acids in maternal plasma, appears to have a high diagnostic accuracy. Large-scale prospective studies are awaited before implementation in clinical practice.

Intra-isolate genome variation in arbuscular mycorrhizal fungi persists in the transcriptome.

Arbuscular mycorrhizal fungi (AMF) are heterokaryotes with an unusual genetic makeup. Substantial genetic variation occurs among nuclei within a single mycelium or isolate. AMF reproduce through spores that contain varying fractions of this heterogeneous population of nuclei. It is not clear whether this genetic variation on the genome level actually contributes to the AMF phenotype. To investigate the extent to which polymorphisms in nuclear genes are transcribed, we analysed the intra-isolate genomic and cDNA sequence variation of two genes, the large subunit ribosomal RNA (LSU rDNA) of Glomus sp. DAOM-197198 (previously known as G. intraradices) and the POL1-like sequence (PLS) of Glomus etunicatum. For both genes, we find high sequence variation at the genome and transcriptome level. Reconstruction of LSU rDNA secondary structure shows that all variants are functional. Patterns of PLS sequence polymorphism indicate that there is one functional gene copy, PLS2, which is preferentially transcribed, and one gene copy, PLS1, which is a pseudogene. This is the first study that investigates AMF intra-isolate variation at the transcriptome level. In conclusion, it is possible that, in AMF, multiple nuclear genomes contribute to a single phenotype.

TREX1 mutations are not associated with sporadic inclusion body myositis.

BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most frequent acquired myopathy above the age of fifty. The exact mechanism causing this disease is not known, but immune-mediated features are prominent and are probably to play a role in its pathogenesis. TREX1 gene mutations are associated with a large range of autoimmune diseases, such as systemic lupus erythematosus. We investigated whether mutations in the TREX1 gene were associated with sIBM. METHODS: Fifty-four patients with sIBM were tested for TREX1 mutations by direct sequencing. RESULTS: All 54 patients tested negative for pathogenic mutations in the TREX1 gene. One presumed non-pathogenic polymorphism was found in 42 out of 54 patients. CONCLUSION: TREX1 mutations do not play a role in the pathogenesis of sIBM.

Infantile nystagmus and late onset ataxia associated with a CACNA1A mutation in the intracellular loop between s4 and s5 of domain 3.

PURPOSE: Mutations in the 1A-subunit of the brain P/Q-type calcium channel gene CACNA1A are responsible for spinocerebellar ataxia type 6 (SCA6), familial haemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). Considerable clinical and genetic overlap exists between these 3 allelic disorders. Clinical findings are varied and may include nystagmus. OBJECTIVE: To study the clinical phenotype and identify a causative mutation in a family who presented when the youngest member was diagnosed with apparent isolated congenital nystagmus (age 3 months). PATIENTS AND METHODS: 8 patients from one family underwent detailed clinical phenotyping comprising; ophthalmic and neurological examination, nystagmology, electrodiagnostic tests and brain imaging. The CACNA1A gene was screened for mutations by direct sequencing in one patient. Co-segregation of the disease and an identified sequence variation was shown using direct sequencing. RESULTS: Phenotyping revealed isolated atypical nystagmus in 4 family members and nystagmus in addition to late onset ataxia in 1 family member. Direct sequencing of the CACNA1A gene identified a novel missense mutation; (c.4110T>G p.Phe1370Leu (NM_000068.3)). CONCLUSIONS: We have shown that a mutation in the intracellular domain between s4 and s5 of repeat 3 can cause atypical nystagmus/cerebellar phenotypes, including isolated nystagmus in an infant. We also illustrate the necessity for detailed examination of relatives in cases of apparent isolated congenital nystagmus.

MET signalling in primary colon epithelial cells leads to increased transformation irrespective of aberrant Wnt signalling.

It has been shown that in hereditary and most sporadic colon tumours, components of the Wnt pathway are mutated. The Wnt target MET has been implicated in the development of colon cancer. Here, we show that overexpression of wild-type or a constitutively activated form of MET in colon epithelial cells leads to increased transformation irrespective of Wnt signalling. Fetal human colon epithelial cells without aberrant Wnt signalling were transfected with wild-type or mutated MET constructs. Expression of these constructs leads to increased phosphorylation of MET and its downstream targets PKB and MAPK. Upon stimulation with HGF, the expression of E-cadherin is downregulated in wild-type MET-transfected cells, whereas cells expressing mutated MET show low E-cadherin levels independent of stimulation with ligand. This implies a higher migratory propensity of these cells. Furthermore, fetal human colon epithelial cells expressing the mutated form of MET have colony-forming capacity in soft agar, while cells expressing wild-type MET show an intermediate phenotype. Subcutaneous injection of mutated MET-transfected cells in nude mice leads to the formation of tumours within 12 days in all mice injected. At this time point, mock-transfected cells do not form tumours, while wild-type MET-transfected cells form subcutaneous tumours in one out of five mice. We thus show that MET signalling can lead to increased transformation of colon epithelial cells independent of Wnt signalling and in this way could play an essential role in the onset and progression of colorectal cancer.

Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal anti-inflammatory drugs appear to inhibit the initial stages of the adenoma-carcinoma sequence, suggesting a link to the APC/beta-catenin/TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) beta-catenin and beta-catenin/TCF-mediated transcription was investigated. Nuclear beta-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on beta-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear beta-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated beta-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated beta-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear beta-catenin localisation and beta-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAIDs.

Use of safety dental syringes in British and Irish dental schools.

AIM: The aim of the present study was to determine what types of dental syringes were being used in British dental schools and whether recent studies on the use of safety syringes had had any impact. INTRODUCTION: In 2001 a controlled trial showed that avoidable needlestick injuries could be reduced with the introduction of safety syringes which did not require the re-sheathing or removal of a needle from its syringe. METHOD: A self complete questionnaire asking about safety syringe use was distributed through the deans of all 16 dental schools in the UK and Ireland. RESULTS: Fifteen schools formally replied and data are available for the missing one. Two schools have totally converted to the use of safety syringes and in seven schools some departments are using them. Six schools are not considering a change, four others are hoping to change and four are undecided as to whether they are going to change. Five schools had tried them previously. All acknowledge that extensive training is essential, there is also considerable staff resistance and the safety syringes currently available are still not ideal. CONCLUSION: All dental schools should determine their avoidable needlestick injuries rates, reconsider their views on the use of safety syringes and contribute to the development of the ideal model.

Successful treatment of fulminant pneumococcal sepsis with recombinant tissue plasminogen activator.

This case report describes a patient with a rapidly progressive pneumococcal septic shock and purpura fulminans. Despite maximal conventional treatment, the patient developed progressive multiple organ failure with imminent necrosis of the extremities. This extremely rare, but often fatal, disease responded dramatically to the infusion of recombinant tissue plasminogen activator.

[Poisoning with organophosphate compounds]. / Intoxicatie met organofosforverbindingen.

A 50-year-old man swallowed 200 ml of an insecticide containing the organophosphates dimethoate and phenitrotion in an attempted suicide. On admission, signs of a cholinergic syndrome were observed: miosis, rhinorrhoea, and fasciculations. This was followed by bradycardia with hypotension and vomiting. The patient was treated with the antidotes atropine and obidoxime. Decreasing consciousness necessitated intubation, mechanical ventilation and other supportive measures. Although the serum concentrations of both organophosphate compounds rapidly decreased, the activity of cholinesterase showed a prolonged inhibition. The clinical course was complicated by hypotension, acute respiratory distress syndrome, nosocomial pneumonia, and an epileptic seizure. A period with muscle weakness and a persisting depressive disorder then followed. This case is characteristic for acute intoxications with irreversible acetylcholinesterase inhibitors, such as organophosphate compounds. The treatment of these potentially severe intoxications includes rapid decontamination and the administration of high doses of atropine followed by obidoxime. Mechanical ventilation and circulatory support are also indicated.

Mutation detection by electrocatalysis at DNA-modified electrodes.

Detection of mutations and damaged DNA bases is important for the early diagnosis of genetic disease. Here we describe an electrocatalytic method for the detection of single-base mismatches as well as DNA base lesions in fully hybridized duplexes, based on charge transport through DNA films. Gold electrodes modified with preassembled DNA duplexes are used to monitor the electrocatalytic signal of methylene blue, a redox-active DNA intercalator, coupled to [Fe(CN)6]3-. The presence of mismatched or damaged DNA bases substantially diminishes the electrocatalytic signal. Because this assay is not a measure of differential hybridization, all single-base mismatches, including thermodynamically stable GT and GA mismatches, can be detected without stringent hybridization conditions. Furthermore, many common DNA lesions and "hot spot" mutations in the human p53 genome can be distinguished from perfect duplexes. Finally, we have demonstrated the application of this technology in a chip-based format. This system provides a sensitive method for probing the integrity of DNA sequences and a completely new approach to single-base mismatch detection.