Overview and update on molecular testing in non-small cell lung carcinoma utilizing endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples

Lung carcinoma remains one of the most frequent and aggressive human neoplasms. Fortunately, in the last decades, the increasing knowledge of the molecular mechanisms leading to cancer development has allowed the use of targeted therapies with improvement of prognosis in many patients. Clinical management has also changed after the introduction of endobronchialultrasonographic bronchoscopy that allows a conservative staging of lung tumors, avoiding the need of mediastinoscopy for lymph node staging. Lung pathologists and cytopathologists are facing the challenge of giving the more comprehensive prognostic and predictive information with ever smaller tissue or cytological samples. The aim of this review is to summarize the molecular testing for non-small cell lung carcinoma and how pathologists can contribute to the patient's outcome with a conscious management of biological samples.     

MR imaging in retinoblastoma

We studied the appearance of retinoblastoma on unenhanced and gadolinium-enhanced images and the accuracy of tumour staging with MR imaging. The MR images were obtained in 18 children with retinoblastoma and compared with histopathological findings after enucleation. The MR imaging included T1-weighted and dual-echo T2-weighted images before, and T1-weighted images after, gadopentetate dimeglumine injection. The contrast between tumour and ipsilateral vitreous strongly increased (57%) after gadolinium on T1-weighted images (p=0.004). Tumour was strongly hypointense as compared with ipsilateral vitreous in all patients using heavily T2-weighted (TE=120 ms) images (p=0.001). The estimated T2 of tumour (mean 96+14 ms) did not correlate with histological grading or degree of calcification. Unenhanced T1-weighted MR images rightfully excluded extrascleral growth in 16 of 16 cases, but its presence was confirmed after enucleation in only one of 2 abnormal MR scans. Invasion of the optic nerve behind the cribriform plate was confirmed in 2 of 3 abnormal gadolinium-enhanced MR scans, but also in 1 of the 15 cases in which MR images were normal. The T2-weighted images were useful in assessing retinal detachment. We conclude that heavily T2-weighted images, unenhanced T1-weighted images and gadolinium-enhanced T1-weighted MR images are complementary in characterizing and staging retinoblastoma.     

8p21.3 deletions are rare causes of non-syndromic autism spectrum disorder

neurogenetics - A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis....     

Home literacy environment of pre‐school children with intellectual disabilities

Background For pre‐school children, the home literacy environment (HLE) plays an important role in the development of language and literacy skills. As there is little known about the HLE of children with intellectual disabilities (ID), the aim of the present study was to investigate the HLE of children with ID in comparison with children without disabilities. Method Parent questionnaires concerning aspects of the HLE were used to investigate differences between 48 children with ID, 107 children without disabilities of the same chronological age and 36 children without disabilities of the same mental age (MA). Furthermore, for the children with ID, correlations were computed between aspects of the HLE and children's non‐verbal intelligence, speech intelligibility, language and early literacy skills. Results and conclusions From the results of the multivariate analyses of variance it could be concluded that the HLE of children with ID differed from that of children in the chronological age group on almost all aspects. When compared with children in the MA group, differences in the HLE remained. However, differences mainly concerned child‐initiated activities and not parent‐initiated activities. Correlation analyses showed that children's activities with literacy materials were positively related with MA, productive syntax and vocabulary age, and book orientation skills. Also, children's involvement during storybook reading was related with their MA, receptive language age, productive syntax and vocabulary age, book orientation and rapid naming of pictures. The amount of literacy materials parents provided was related to a higher productive syntax age and level of book orientation of the children. Parent play activities were also positively related to children's speech intelligibility. The cognitive disabilities of the children were the main cause of the differences found in the HLE between children with ID and children without disabilities. Parents also adapt their level to the developmental level of their child, which may not always be the most stimulating for the children.     

Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients.

BACKGROUND: Patients with chronic renal failure commonly suffer from a secondary form of complex dyslipidaemia, and may benefit from lipid-lowering treatment. Atorvastatin has been shown to reduce efficiently the levels of atherogenic lipoproteins also in patients with renal failure, but pharmacokinetic data in haemodialysis patients are lacking. METHODS: In this study, hypercholesterolaemic haemodialysis patients received 40 mg (n=12) or 80 mg (n=11) atorvastatin once daily, first as a single dose and then continuously for 2 weeks. Plasma levels of atorvastatin and its active and inactive metabolites were measured by LC/MS/MS, and pharmacokinetic parameters (C(max), t(max), AUC, t(1/2)) compared between single and multiple dosing, and between the different doses. RESULTS: The pharmacokinetic parameters of the parent drug atorvastatin acid were not significantly different after single and 2-week multiple dosing; they showed dose-proportionality between the 40 and 80 mg dose, and were comparable to findings in healthy volunteers. Dose-proportionality and absence of accumulation was also observed for the major active metabolite ortho-hydroxy-atorvastatin and the inactive metabolites atorvastatin lactone and ortho-hydroxy-atorvastatin lactone, but the levels of the active metabolite were relatively lower, and the inactive metabolites higher, compared with healthy volunteers. The para-hydroxy-metabolites constituted only a minor pathway in atorvastatin's metabolic elimination. Haemodialysis did not cause enhanced clearance of atorvastatin or its metabolites, the drug was well tolerated and there were no serious adverse events. CONCLUSION: While subtle differences may exist in the metabolic processing of atorvastatin in haemodialysis patients, active drug did not accumulate nor did it show enhanced elimination, and levels were comparable to those measured in healthy volunteers. Therefore there is no need to adapt atorvastatin dosage in this particular patient population.     

Major Reduction in Axillary Lymph Node Dissections After Neoadjuvant Systemic Therapy for Node-Positive Breast Cancer by combining PET/CT and the MARI Procedure

Background

Axillary lymph node dissection (ALND) is frequently performed for node-positive (cN+) breast cancer patients. Combining positron emission tomography/computed tomography (PET/CT) before-NST and the MARI (marking axillary lymph nodes with radioactive iodine seeds) procedure after neoadjuvant systemic therapy (NST) has the potential for avoiding unnecessary ALNDs. This report presents the results from implementation of this strategy.

Methods

All breast cancer patients treated with NST at the Netherlands Cancer Institute who underwent a PET/CT and the MARI procedure from July 2014 to July 2017 were included in the study. All the patients underwent tailored axillary treatment according to a protocol based on the combined results of PET/CT before NST and the MARI procedure after NST. With this protocol, patients showing one to three FDG-avid axillary lymph nodes (ALNs) on PET/CT (cN<4) and a tumor-negative MARI node receive no further axillary treatment. All cN (<4) patients with a tumor-positive MARI node receive locoregional radiotherapy, as well as patients with four or more FDG-avid ALNs [cN(4+)] and a tumor-negative MARI node after NST. An ALND is performed only for cN(4+) patients with a tumor-positive MARI node.

Results

The data of 159 patients who received a PET/CT before NST and a MARI procedure after NST were analyzed. Of these patients, 110 had one to three FDG-avid ALNs and 49 patients showed four or more FDG-avid ALNs on PET/CT before NST. For 130 patients (82%), ALND was omitted. Locoregional radiotherapy was administered to 91 patients (57%), and 39 patients (25%) received no further axillary treatment.

Conclusion

Combining pre-NST axillary staging with PET/CT and post-NST staging with the MARI procedure resulted in an 82% reduction of ALNDs for cN?+?breast cancer patients.

     

Refining stent technologies for femoral interventions

Stents were created as a mechanical scaffold to prevent vessel recoil and luminal renarrowing after percutaneous transluminal angioplasty (PTA). In femoropopliteal arteries, indication for stent implantation remains a topic much debated on, especially in long lesion configurations. Ever since the first stents were introduced on the market, in-stent restenosis (ISR) has been an important issue. The evolution in stent design has known a major progression in the last decades from the first generation of stents, plagued with high fracture rates and low primary patency rates, to the design of newer stents to tackle these outcomes. More flexible and longer stents decreased the high fracture rates and drug-eluting stents offered a solution to the restenosis rates by local drug application. The difficult recrossibility of the lesion because of the presence of a permanent vascular scaffold is an obstacle that the drug-coated balloon (DCB) overcomes. Future perspectives in the treatment of femoropopliteal lesions are found in the bioresorbable stent implantation. The bioresorbable stent combines the advantages of a drug-eluting scaffolding stent without the remainder of a foreign object in the long-term. Further investigations in this area will eventually evolve in the creation of a superior endovascular treatment modality with high long-term patency rates and minimal detriments.     

A comparison between blood oxygenation level-dependent and cerebral blood volume contrast in the rat cerebral and cerebellar somatosensoric cortex during electrical paw stimulation

PURPOSE: To implement and optimize cerebral blood volume (CBV)-weighted functional magnetic resonance imaging (fMRI) in the rat cerebral and cerebellar cortex during electrical paw stimulation. MATERIALS AND METHODS: fMRI of the cerebral and cerebellar cortex was performed during electrical paw stimulation on a 7-T MRI system (MRRS, Guilford, UK) comparing the blood oxygenation level-dependent (BOLD) and CBV-weighted contrast with different ultrasmall particles of iron oxide (USPIO) contrast doses (NC100150, 30 mg Fe/mL; Amersham Health, Oslo, Norway) and different TE. RESULTS: Doses of 15 and 20 mg/kg USPIO at TE = T*2 or TE = 14 msec almost doubled the contrast-to-noise ratio (CNR) of the activated areas in the cerebral cortex without affecting the overall signal-to-noise ratio (SNR) or the incidence of activation (100%). In the cerebellum the SNR decreased significantly with an increasing contrast dose. At a dose of 15 mg/kg, the CNR was slightly smaller than the CNR measured in the BOLD images, but the activation incidence seemed to be doubled. At 20 mg/kg, the CNR was slightly increased, but the activation incidence was lower. At both contrast doses the venous artifacts disappeared. CONCLUSION: A USPIO contrast dose of 20 mg/kg proved to be beneficial for fMRI in the rat, even though it affected the CNR and SNR in the cerebral and the cerebellar cortex differentially.     

Assessment of diffusion-weighted MR imaging in liver fibrosis

PURPOSE: To assess whether hepatic fibrosis is associated with a restriction in the diffusion of water that can be analyzed with diffusion-weighted MR imaging (DWI) of the liver. MATERIALS AND METHODS: DWI was performed in 10 normal rats and 15 rats with liver fibrosis. Echo-planar DWI was performed in the living rats at 1.5 T and repeated immediately after the animals were killed. Afterwards the livers were explanted, fixed in Bouin solution, and imaged with a DW spin-echo sequence at 4.7 T. Fibrosis was quantified by densitometry on Sirius red-stained histological sections. RESULTS: In living rats the apparent diffusion coefficient (ADC) decreased with the severity of liver fibrosis (controls: 1535 +/- 294 mm(2)/second; CCl(4) (5 weeks) 1129 +/- 273 mm(2)/second; CCl(4) (9 weeks): 943 +/- 132 mm(2)/second; P = 0.002). An inverse correlation between ADC and liver fibrosis volume density was observed (r = -0.712, P < 0.001). In contrast, these findings were not observed in the rats after they were killed or in the fixated livers. CONCLUSION: Decreased ADC correlated with increased liver fibrosis in living rats, but not after death. These results suggest that restricted water diffusion cannot be assessed by DWI in liver fibrosis. Other factors, such as a decrease of perfusion, may explain the decrease of the hepatic ADC measured in vivo in rats with liver fibrosis.