Differential targets of CpG island hypermethylation in primary and metastatic head and neck squamous cell carcinoma (HNSCC)

Head and neck squamous cell carcinomas (HNSCC) often metastasise to the cervical lymph nodes. It is known for HNSCC as well as other cancers that progression from normal tissue to primary tumour and finally to metastatic tumour is characterised by an accumulation of genetic mutations. DNA methylation, an epigenetic modification, can result in loss of gene function in cancer, similar to genetic mutations such as deletions and point mutations. We have investigated the DNA methylation phenotypes of both primary HNSCC and metastatic tumours from 13 patients using restriction landmark genomic scanning (RLGS). With this technique, we were able to assess the methylation status of an average of nearly 1300 CpG islands for each tumour. We observed that the number of CpG islands hypermethylated in metastatic tumours is significantly greater than what is found in the primary tumours overall, but not in every patient. Interestingly, the data also clearly show that many loci methylated in a patient's primary tumour are no longer methylated in the metastatic tumour of the same patient. Thus, even though metastatic HNSCC methylate a greater proportion of CpG islands than do the primary tumours, they do so at different subsets of loci. These data show an unanticipated variability in the methylation state of loci in primary and metastatic HNSCCs within the same patient. We discuss two possible explanations for how different epigenetic events might arise between the primary tumour and the metastatic tumour of a person.     

Spontaneous aberrant crypt foci in Apc1638N mice with a mutant Apc allele

The Apc1638N/+ mouse has a chain-terminating mutation in one allele of the adenomatous polyposis coli (Apc) gene that is similar to most mutations observed in the human familial adenomatous polyposis syndrome. Aberrant crypt foci (ACF), the earliest identified neoplastic lesions in the colon, are morphologically abnormal structures that are identifiedmicroscopically in the grossly normal colonic mucosas of rodents treated with colon carcinogens and of human patients. The colons and cecums of 62 Apc1638N/+ mice were evaluated for the spontaneous occurrence of ACF and tumors. Both male and female mice were killed at different times between 5 and 28 weeks of age. Wild-type littermates, ie, Apc(+/+) mice, at 22 to 26 weeks of age served as controls. ACF were identified in 97% of the Apc1638N/+ mice starting at 5 weeks of age and not in any wild-type littermates. Although the number of ACF increased with age (P < 0.0001), the average number of crypts per focus of the ACF did not increase significantly. In addition, wild-type Apc protein was detected by immunohistochemistry in all 22 ACF evaluated. Together these data suggest that heterozygous loss of Apc may be sufficient to initiate ACF in these mice and that these mice may be suitable models to study the interaction of environmental factors with an inherited mutation of the Apc gene that is associated with colon cancer.     

Chromosomal alterations in osteosarcoma cell lines revealed by comparative genomic hybridization and multicolor karyotyping

We characterized the chromosomal alterations in eight osteosarcoma cell lines (OST, HOS, U-2 OS, ZK-58, MG-63, SJSA-1, Saos-2, and MNNG) by comparative genomic hybridization (CGH); gains and losses of DNA sequences were defined as chromosomal regions with a fluorescence ratio, wherein all of the 95% confidence interval was above 1.25 and below 0.75, respectively. In four of 8 cell lines, multicolor karyotyping (MK) was added. CGH revealed the average number of aberrations per cell line was 20.8 (range: 10–31); the average numbers of gains and losses were 11.1 and 9.6, respectively. The frequent gains were identified on 1p21q24, 1q25q31, 7p21, 7q31, 8q23q24, and 14q21; frequent losses were at 18q21q22, 18q12, 19p, and 3p12p14. High-level gains were observed on 8q23q24, 5p, and 1p21p22. MK revealed the most common translocations in the four cell lines were t(8;9), t(1;3), t(3;5), t(1;13), t(2;6), t(3;17), t(1;15), t(10;20), and t(6;20). Chromosomes 1, 3, 8, 9, and 20 were most frequently involved in translocation events. The concordance rate of aberrations in CGH and translocations in MK was 76%. MK was useful to identify the chromosomal alterations and as a supplement to the CGH results in three of four chromosomes.     

The potential of comparative genomic hybridization as a tool in the differential diagnosis of matrix-producing bone lesions

Matrix-producing bone lesions consist of a wide variety of benign and malignant conditions. With respect to morphology, an overlap exists between benign and malignant bone tumors that causes difficulties in the final determination of the tumor. This study was conducted to show the potential of comparative genomic hybridization as a tool in the differential diagnosis of matrix-producing bone lesions. Thirty benign bone tumors were evaluated by conventional comparative genomic hybridization. To test its diagnostic reliability, 5 additional cases were analyzed, all with differential diagnostic difficulties related to morphology and radiology. All were ultimately diagnosed as malignant sarcomas, and unbalanced alterations were detected. In contrast benign tumors or tumor-like lesions did not reveal any chromosomal alterations. Comparative genomic hybridization is a useful adjunct in the complicated differential diagnostic algorithms of matrix-producing bone tumors.     

Potential role of <Superscript>68</Superscript>Ga-DOTATOC PET/CT in screening for pancreatic neuroendocrine tumour in patients with von Hippel-Lindau disease

Purpose

Neuroendocrine tumours of the pancreas (pNET) are observed in 8 – 17 % of patients with von Hippel-Lindau disease (vHLD), and 11 – 20 % of these patients develop metastatic disease. MRI and CT have a very high resolution; however, their sensitivity and specificity for the detection of pNET amongst cystic lesions in the pancreas of vHLD patients are generally considered insufficient. In contrast, ⁶⁸Ga-DOTATOC PET/CT demonstrates a high sensitivity for the diagnosis and staging of neuroendocrine tumours. In this study we investigated the potential role of ⁶⁸Ga-DOTATOC PET/CT in screening of patients with vHLD.

Method

⁶⁸Ga-DOTATOC PET/three-phase contrast-enhanced CT was performed according to guidelines in all consecutive vHLD patients between January 2012 and November 2015. All patients underwent additional MRI imaging of the abdomen, spine, and head. Chromogranin A (CgA) was determined at the time of the PET/CT examination. A lesion seen on ⁶⁸Ga-DOTATOC PET in the pancreas was defined as positive if the uptake was visually higher than in the surrounding tissues. Lesions were quantified using maximum SUV.

Results

Overall, 20 patients (8 men, 12 women; mean age 44.7?±?11.1 years) were prospectively examined. Genetically, 12 patients had type 1 vHLD and 8 had type 2 vHLD. ⁶⁸Ga-DOTATOC PET/CT detected more pNET than morphological imaging (CT or MRI): 11 patients (55 %; 8 type 1, 3 type 2) vs. 9 patients (45 %; 6 type 1, 3 type 2). The concentration of CgA was mildly elevated in 2 of 11 patients with pNET. The mean SUVmax of the pancreatic lesions was 18.9?±?21.9 (range 5.0 – 65.6). Four patients (36.4 %) had multiple pNETs. The mean size of the lesions on CT and/or MRI was 10.4?±?8.3 mm (range 4 – 38 mm), and 41.1 % were larger than 10 mm. In addition, somatostatin receptor-positive cerebellar and spinal haemangioblastomas were detected in three patients (SUVmax 2.1 – 10.1). One patient presented with a solitary somatostatin receptor-positive lymph node metastasis. pNETs were observed more frequently in vHLD type 1 than type 2 (66.7 % vs. 37.5 %, p?=?0.089). None of the patients showed progressive disease during follow-up.

Conclusion

In this study, ⁶⁸Ga-DOTATOC PET detected pNETs in a higher proportion of patients with vHLD than found in previous studies with ¹¹¹In-octreoscan, the imaging method recommended by the NCCN. We therefore suggest ⁶⁸Ga-DOTATOC PET/CT as the more sensible screening tool.

     

Revised PROPELLER for T2-weighted imaging of the prostate at 3 Tesla: impact on lesion detection and PI-RADS classification

Purpose

To evaluate revised PROPELLER (RevPROP) for T2-weighted imaging (T2WI) of the prostate as a substitute for turbo spin echo (TSE).

Materials and methods

Three-Tesla MR images of 50 patients with 55 cancer-suspicious lesions were prospectively evaluated. Findings were correlated with histopathology after MRI-guided biopsy. T2 RevPROP, T2 TSE, diffusion-weighted imaging, dynamic contrast enhancement, and MR-spectroscopy were acquired. RevPROP was compared to TSE concerning PI-RADS scores, lesion size, lesion signal-intensity, lesion contrast, artefacts, and image quality.

Results

There were 41 carcinomas in 55 cancer-suspicious lesions. RevPROP detected 41 of 41 carcinomas (100%) and 54 of 55 lesions (98.2%). TSE detected 39 of 41 carcinomas (95.1%) and 51 of 55 lesions (92.7%). RevPROP showed fewer artefacts and higher image quality (each p?<?0.001). No differences were observed between single and overall PI-RADS scores based on RevPROP or TSE (p?=?0.106 and p?=?0.107). Lesion size was not different (p?=?0.105). T2-signal intensity of lesions was higher and T2-contrast of lesions was lower on RevPROP (each p?<?0.001).

Conclusion

For prostate cancer detection RevPROP is superior to TSE with respect to motion robustness, image quality and detection rates of lesions. Therefore, RevPROP might be used as a substitute for T2WI.

Key points

? Revised PROPELLER can be used as a substitute for T2-weighted prostate imaging.? Revised PROPELLER detected more carcinomas and more suspicious lesions than TSE.? Revised PROPELLER showed fewer artefacts and better image quality compared to TSE.? There were no significant differences in PI-RADS scores between revised PROPELLER and TSE.? The lower T2-contrast of revised PROPELLER did not impair its diagnostic quality.

     

The roles of TRPV1, TRPA1 and TRPM8 channels in chemical and thermal sensitivity of the mouse oral mucosa

Spices in food and beverages and compounds in tobacco smoke interact with sensory irritant receptors of the transient receptor potential (TRP) cation channel family. TRPV1 (vanilloid type 1), TRPA1 (ankyrin 1) and TRPM8 (melastatin 8) not only elicit action potential signaling through trigeminal nerves, eventually evoking pungent or cooling sensations, but by their calcium conductance they also stimulate the release of calcitonin gene‐related peptide (CGRP). This is measured as an index of neuronal activation to elucidate the chemo‐ and thermosensory transduction in the isolated mouse buccal mucosa of wild types and pertinent knockouts. We found that the lipophilic capsaicin, mustard oil and menthol effectively get access to the nerve endings below the multilayered squamous epithelium, while cigarette smoke and its gaseous phase were weakly effective releasing CGRP. The hydrophilic nicotine was ineffective unless applied unprotonated in alkaline (pH9) solution, activating TRPA1 and TRPV1. Also, mustard oil activated both these irritant receptors in millimolar but only TRPA1 in micromolar concentrations; in combination (1 mm ) with heat (45 °C), it showed supraadditive, that is heat sensitizing, effects in TRPV1 and TRPA1 knockouts, suggesting action on an unknown heat‐activated channel and mustard oil receptor. Menthol caused little CGRP release by itself, but in subliminal concentration (2 mm ), it enabled a robust cold response that was absent in TRPM8^?/? but retained in TRPA1^?/? and strongly reduced by TRPM8 inhibitors. In conclusion, all three relevant irritant receptors are functionally expressed in the oral mucosa and play their specific roles in inducing neurogenic inflammation and sensitization to heat and cold.     

Personality and psychopathology in children with and without loss of control over eating

Background

In children with loss of control (LOC) over eating, recent research has revealed evidence for distinct personality features, such as more impulsivity. The aim of this study was to assess parent- and child-report personality profiles in children with and without LOC over eating and to relate these profiles to general and eating-disorder psychopathology.

Method

A total of 120 children (60 with LOC over eating; 68 girls) aged 8 to 13 years were recruited from the community. Clinical interview, self-report, and parent-report questionnaires were administered to assess personality as well as both general and eating-disorder psychopathology.

Results

The group with LOC over eating showed lower self-directedness and cooperativeness compared to the group without LOC. The children with LOC were significantly more impulsive. Personality dimensions were significantly correlated with greater general but not eating-disorder psychopathology and frequency of LOC over eating.

Conclusion

A distinct pattern of personality traits in children with LOC over eating was found that is partly in line with research on binge-eating disorder, bulimia nervosa, and obesity in adulthood. The findings suggest that longitudinal studies should examine whether certain patterns of personality in children with LOC over eating account for differences in psychopathology later in life.     

Diffusion-weighted whole-body MR imaging with background body signal suppression: a feasibility study at 3.0 Tesla

The purpose was to provide a diffusion-weighted whole-body magnetic resonance (MR) imaging sequence with background body signal suppression (DWIBS) at 3.0 Tesla. A diffusion-weighted spin-echo echo-planar imaging sequence was combined with the following methods of fat suppression: short TI inversion recovery (STIR), spectral attenuated inversion recovery (SPAIR), and spectral presaturation by inversion recovery (SPIR). Optimized sequences were implemented on a 3.0- and a 1.5-Tesla system and evaluated in three healthy volunteers and six patients with various lesions in the neck, chest, and abdomen on the basis of reconstructed maximum intensity projection images. In one patient with metastases of malignant melanoma, DWIBS was compared with ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET). Good fat suppression for all regions and diagnostic image quality in all cases could be obtained at 3.0 Tesla with the STIR method. In comparison with 1.5 Tesla, DWIBS images at 3.0 Tesla were judged to provide a better lesion-to-bone tissue contrast. However, larger susceptibility-induced image distortions and signal intensity losses, stronger blurring artifacts, and more pronounced motion artifacts degraded the image quality at 3.0 Tesla. A good correlation was found between the metastases as depicted by DWIBS and those as visualized by FDG-PET. DWIBS is feasible at 3.0 Tesla with diagnostic image quality.     

Modes of information delivery in radiologic anatomy education: Impact on student performance

RATIONALE AND OBJECTIVES: This study provides a systematic assessment of different methods of delivering radiologic teaching content (lecture, printed text, and digital content delivery) under standard conditions, enabling comparison of the effectiveness of these methods. MATERIALS AND METHODS: A printed atlas of sectional anatomy was used as a standard. Digital content was developed on the basis of the printed atlas. Lecturers used both the printed and the digital content to prepare lectures. Standardized teaching material thus created was presented to second-term undergraduate students who had attended the school's anatomy course, but had not received any radiology teaching. Multiple choice examinations were used to assess the students' ability to recognize anatomical structures in known as well as unknown images. In a survey, the students' subjective experience of the learning process was assessed. RESULTS: No difference was seen between the groups regarding examination results. Students preferred a combination of digital media and lectures by enthusiastic teachers. CONCLUSIONS: The shortage of teachers requires a compromise concerning the delivery of radiologic anatomy content in a medical school setting. Based on our results, we recommend a combined approach of lecture and digital content delivery.