Inter-rater agreement in glioma segmentations on longitudinal MRI.

BACKGROUND: Tumor segmentation of glioma on MRI is a technique to monitor, quantify and report disease progression. Manual MRI segmentation is the gold standard but very labor intensive. At present the quality of this gold standard is not known for different stages of the disease, and prior work has mainly focused on treatment-naive glioblastoma. In this paper we studied the inter-rater agreement of manual MRI segmentation of glioblastoma and WHO grade II-III glioma for novices and experts at three stages of disease. We also studied the impact of inter-observer variation on extent of resection and growth rate. METHODS: In 20 patients with WHO grade IV glioblastoma and 20 patients with WHO grade II-III glioma (defined as non-glioblastoma) both the enhancing and non-enhancing tumor elements were segmented on MRI, using specialized software, by four novices and four experts before surgery, after surgery and at time of tumor progression. We used the generalized conformity index (GCI) and the intra-class correlation coefficient (ICC) of tumor volume as main outcome measures for inter-rater agreement. RESULTS: For glioblastoma, segmentations by experts and novices were comparable. The inter-rater agreement of enhancing tumor elements was excellent before surgery (GCI 0.79, ICC 0.99) poor after surgery (GCI 0.32, ICC 0.92), and good at progression (GCI 0.65, ICC 0.91). For non-glioblastoma, the inter-rater agreement was generally higher between experts than between novices. The inter-rater agreement was excellent between experts before surgery (GCI 0.77, ICC 0.92), was reasonable after surgery (GCI 0.48, ICC 0.84), and good at progression (GCI 0.60, ICC 0.80). The inter-rater agreement was good between novices before surgery (GCI 0.66, ICC 0.73), was poor after surgery (GCI 0.33, ICC 0.55), and poor at progression (GCI 0.36, ICC 0.73). Further analysis showed that the lower inter-rater agreement of segmentation on postoperative MRI could only partly be explained by the smaller volumes and fragmentation of residual tumor. The median interquartile range of extent of resection between raters was 8.3% and of growth rate was 0.22 mm/year. CONCLUSION: Manual tumor segmentations on MRI have reasonable agreement for use in spatial and volumetric analysis. Agreement in spatial overlap is of concern with segmentation after surgery for glioblastoma and with segmentation of non-glioblastoma by non-experts.

Interrelated responses of tomato plants and the leaf miner Tuta absoluta to nitrogen supply.

Plant-insect interactions are strongly modified by environmental factors. This study evaluates the influence of nitrogen fertilisation on the tomato (Solanum lycopersicum L.) cv. Santa clara and the leafminer (Tuta absoluta (Meyrick), Lepidoptera: Gelechiidae). Greenhouse-grown tomato plants were fed hydroponically on a complete nutrient solution containing either a high nitrogen concentration (HN) sustaining maximum growth or a low nitrogen concentration (LN) limiting plant growth. Insect-free plants were compared with plants attacked by T. absoluta. Seven and 14 days after artificial oviposition leading to efficacious hatching and larvae development, we measured total carbon, nitrogen and soluble protein as well as defence compounds (phenolics, glycoalkaloids, polyphenol oxidase activity) in the HN versus LN plants. Only in the HN treatment did T. absoluta infestation slightly impair leaf growth and induce polyphenol oxidase (PPO) activity in the foliage. Neither the concentration of phenolic compounds and proteins nor the distribution of nitrogen within the plant was affected by T. absoluta infestation. In contrast, LN nutrition impaired T. absoluta-induced PPO activity. It decreased protein and total nitrogen concentration of plant organs and enhanced the accumulation of constitutive phenolics and tomatine. Moreover, LN nutrition impaired T. absoluta development by notably decreasing pupal weight and lengthening the development period from egg to adult. Adjusting the level of nitrogen nutrition may thus be a means of altering the life cycle of T. absoluta. This study provides a comprehensive dataset concerning interrelated responses of tomato plants and T. absoluta to nitrogen nutrition.

Optimizing the association between disability and biological markers in MS.

OBJECTIVE: Axonal damage is an important feature of MS pathology and the likely substrate of development of progressive disability. Brain volume measurement on MRI can be used as an overall marker of tissue damage and axonal loss. The authors studied the relation of brain volume measurements with the MS Functional Composite (MSFC) in an attempt to improve the clinico-radiologic association. METHODS: In 137 patients with MS (80 relapsing-remitting [RR], 36 secondary progressive [SP], and 21 primary progressive [PP]) and 12 healthy controls, a brain MRI scan was obtained. Patients also underwent MSFC and Expanded Disability Status Scale (EDSS) assessments. MRI analysis included determination of hypointense T1- and hyperintense T2-weighted lesion load, and two brain volume measurements: 1) the parenchymal fraction (PF): whole brain parenchyma/intracranial volume; and 2) the ventricular fraction (VF): ventricular volume/whole brain parenchyma. RESULTS: The median PF was smaller and the median VF larger in the patient group (0.81 for PF and 0.029 for VF) than in the control group (0.87 for PF, p < 0.001; and 0.013 for VF, p < 0.01). For the patient population, moderate correlations were found between brain volume measurements and MSFC (0.36 for PF and -0.40 for VF). Patients with short disease duration showed a correlation of MSFC with both brain and lesion volume measurements on MRI, whereas patients with long disease duration only showed a correlation with brain volume measurements. CONCLUSION: Brain volume measurements are correlated with disability as assessed by the MSFC. Although in the early phase of the disease the amount of focal demyelination is important, the residual brain volume seems to be more relevant in determining disability in later phases of the disease.

Axonal damage in the spinal cord of MS patients occurs largely independent of T2 MRI lesions.

OBJECTIVE: To determine the degree of axonal damage in relationship to signal abnormalities on T2-weighted high-resolution MRI in spinal cord tissue of patients with MS. METHODS: Spinal cord specimens of nine patients with MS and four controls were imaged at high resolution (4.7 T) in an axial plane and scored for lesions with increased signal intensity (SI). Histopathologic sections were cut and immunostained with NE14 (neurofilament marker) and Luxol fast blue (myelin stain). For each area, axonal density and diameter were quantified; axonal irregularity, NE14 axonal staining intensity, and myelin content were semiquantitatively scored. Included were 209 areas from MS cases and 109 areas from control cases distributed over lateral, posterior, and anterior columns. RESULTS: In control cases, no SI changes were found, average density of axons was 26,989/mm(2), average diameter was 1.1 micro m, and all scores for axonal irregularity, NE14 staining intensity, and myelin were normal. In MS cases, areas with increased SI were found, average axonal density was 11,807/mm(2) (p < 0.0001), and average axonal diameter 2.0 micro m (p = 0.001). Areas with high SI on MRI had lowest axonal density (average count: 10,504/mm(2); range: 3,433 to 26,325/mm(2)), largest diameter (average: 2.3 micro m; range: 1.0 to 4.0 micro m), and highest axonal irregularity and NE14 staining intensity compared to normal appearing cord tissue (NACT). However, NACT of MS cases also had lower axonal density (14,158/mm(2)) and higher average axonal diameter (1.6 micro m) than controls. CONCLUSIONS: Marked axonal loss occurs in MS spinal cords, largely independent of the degree of signal abnormality on T2-weighted MRI.

An experimental set-up to study carbon, water, and nitrate uptake rates by hydroponically grown plants.

The experimental system described allows concomitant hourly measurements of CO2, H2O, and NO3 uptake rates by plants grown hydroponically in a greenhouse. Plants are enclosed in an airtight chamber through which air flows at a controlled speed. Carbon dioxide exchange and transpiration rates are determined from respective differences of concentrations of CO2 and water vapor of the air at the system inlet and outlet. This set-up is based on the "open-system" principle with improvements made on existing systems. For instance, propeller anemometers are used to monitor air flow rates in the chamber. From their signal it is possible to continuously adjust air speed to changing environmental conditions and plant activity. The air temperature inside the system therefore never rises above that outside. Water and NO3 uptake rates are calculated at time intervals from changes in the volume and the NO3 concentration of the nutrient solution in contact with the roots. The precise measurement of the volume of solution is achieved using a balance which has a higher precision than any liquid level sensors. Nitrate concentration is determined in the laboratory from aliquots of solution sampled at time intervals. A number of test runs are reported which validate the measurements and confirm undisturbed conditions within the system. Results of typical diurnal changes in CO2, H2O, and NO3 uptake rates by fruiting tomato plants are also presented.

Organ-specific responses of tomato growth and phenolic metabolism to nitrate limitation.

Phenolic compounds are secondary metabolites involved in plant innate chemical defence against pests and diseases. Their concentration varies depending on plant tissue and also on genetic and environmental factors, e.g. availability of nutrient resources. This study examines specific effects of low (LN) and high (HN) nitrogen supply on organ (root, stem and leaf) growth and accumulation of major phenolics [chlorogenic acid (CGA); rutin; kaempferol rutinoside (KR)] in nine hydroponically grown tomato cultivars. LN limited shoot growth but did not affect root growth, and increased concentrations of each individual phenolic in all organs. The strength of the response was organ-dependent, roots being more responsive than leaves and stems. Significant differences were observed between genotypes. Nitrogen limitation did not change the phenolic content in shoots, whereas it stimulated accumulation in roots. The results show that this trade-off between growth and defence in a LN environment can be discussed within the framework of the growth-differentiation balance hypothesis (i.e. GDBH), but highlight the need to integrate all plant organs in future modelling approaches regarding the impact of nitrogen limitation on primary and secondary metabolism.

The predictive value of 3D time-of-flight MR angiography in assessment of brain arteriovenous malformation obliteration after radiosurgery.

BACKGROUND AND PURPOSE: The purpose of radiosurgery of bAVMs is complete angiographic obliteration of its nidus. We assessed the diagnostic accuracy of 1.5T T2-weighted MR imaging and TOF-MRA images for detecting nidus obliteration after radiosurgery. MATERIALS AND METHODS: The pre- and postradiosurgery MR images and DSA images from 120 patients who were radiosurgically treated for a bAVM were re-evaluated by 2 observers for patency of the nidus (preradiosurgery) and obliteration (postradiosurgery: final follow-up MR imaging), by using a 3-point scale of confidence. Consensus reading of the DSA after radiosurgery was considered the criterion standard for obliteration. Sensitivity, specificity, PPVs, and NPVs, and overall diagnostic performance by using ROC were determined. RESULTS: Mean bAVM volume during radiosurgery was 3.4 mL (95% CI, 2.6-4.3 mL). Sixty-six patients (55%) had undergone previous endovascular embolization. The mean intervals between radiosurgery and follow-up MR imaging and for DSA, respectively, were 35.6 months (95% CI, 32.3-38.9 months) and 42.1 months (95% CI, 40.3-44.0 months). With ROC, an area under curve of 0.81-0.83 was found. PPVs of final follow-up MR-imaging for definitive obliteration varied between 0.89 [corrected] and 0.95. NPV was 0.52 [corrected] . An average false-positive rate, meaning overestimation of nidus obliteration of 0.10 [corrected] and an average false-negative rate, meaning underestimation of nidus obliteration of 0.42 [corrected] were found. CONCLUSIONS: MRA is insufficient to diagnose obliteration in the follow-up of bAVMs after radiosurgery. A remaining nidus diameter <10 mm seems to be the major limiting factor for reliable assessment of obliteration. We highly recommend follow-up DSA for definitive diagnosis of complete obliteration.

Spinal cord grey matter lesions in multiple sclerosis detected by post-mortem high field MR imaging.

BACKGROUND: Post-mortem studies demonstrate extensive grey matter demyelination in MS, both in the brain and in the spinal cord. However the clinical significance of these plaques is unclear, largely because they are grossly underestimated by MR imaging at conventional field strengths. Indeed post-mortem MR studies suggest the great majority of lesions in the cerebral cortex go undetected, even when performed at high field. Similar studies have not been performed using post-mortem spinal cord material. AIM: To assess the sensitivity of high field post-mortem MRI for detecting grey matter lesions in the spinal cord in MS. METHODS: Autopsy material was obtained from 11 MS cases and 2 controls. Proton Density-weighted images of this formalin-fixed material were acquired at 4.7 Tesla before the tissue was sectioned and stained for Myelin Basic Protein. Both the tissue sections and the MR images were scored for grey matter and white matter plaques, with the readers of the MR images being blinded to the histopathology results. RESULTS: Our results indicate that post-mortem imaging at 4.7 Tesla is highly sensitive for cord lesions, detecting 87% of white matter lesions and 73% of grey matter lesions. The MR changes were highly specific for demyelination, with all lesions scored on MRI corresponding to areas of demyelination. CONCLUSION: Our work suggests that spinal cord grey matter lesions may be detected on MRI more readily than GM lesions in the brain, making the cord a promising site to study the functional consequences of grey matter demyelination in MS.

At the heart of primary progressive multiple sclerosis: three cases with diffuse MRI abnormalities only.

We present three patients with a clinical course and cerebrospinal fluid findings consistent with a diagnosis of primary progressive multiple sclerosis (PPMS). Extensive and repeated magnetic resonance imaging (MRI) examinations showed only diffuse abnormality in brain and spinal cord, but no focal lesions. We propose that these cases represent the most pure form of PPMS, even though according to currently applied criteria this diagnosis can not be made in the absence of focal lesions on MRI.

Spinal cord abnormalities in recently diagnosed MS patients: added value of spinal MRI examination.

OBJECTIVE: The most recent diagnostic criteria for multiple sclerosis (MS) ascertain that findings from spinal cord MRI can be used to demonstrate dissemination in space. Because little is known about the prevalence and characteristics of cord lesions early in the disease, the authors studied the prevalence of spinal cord abnormalities in patients with early-stage MS and assessed their impact on diagnostic classification. METHODS: The brains and spinal cords of 104 recently diagnosed patients with MS were examined. Median interval between first symptom and diagnosis was 18.4 months. The brain MRI protocol included before and after gadolinium axial T1-weighted conventional spin-echo sequences and dual-echo spin-echo images. For spinal cord MRI, sagittal cardiac-triggered dual-echo T2-weighted and sagittal T1-weighted spin-echo images were included. Clinical assessment for each patient included age, sex, clinical signs for spinal cord involvement, and Expanded Disability Status Scale. RESULTS: Abnormal cord MRIs were found in 83% of patients, usually with only focal lesions. Diffuse cord abnormalities were found in 13% of patients, although in isolation they were found in only three patients. Focal cord lesions were often multiple (median number, 3.0), small (median, 0.8 vertebral segments), and primarily (56.4%) situated in the cervical spinal cord. In 68 of 104 patients (65.4%), two or more focal lesions were visible on spinal cord images. The criteria for dissemination in space, as defined in the McDonald criteria for the brain, were met in only 66.3% of the patients. This percentage increased to 84.6% when spinal cord MRI abnormalities were also included. CONCLUSION: Spinal cord abnormalities are prevalent in patients with early-stage MS, have distinct morphologic characteristics, and help to determine dissemination in space at time of diagnosis.

Comparison of a conventional cardiac-triggered dual spin-echo and a fast STIR sequence in detection of spinal cord lesions in multiple sclerosis.

The current optimal imaging protocol in spinal cord MR imaging in patients with multiple sclerosis includes a long TR conventional spin-echo (CSE) sequence, requiring long acquisition times. Using short tau inversion recovery fast spin-echo (fast STIR) sequences both acquisition time can be shortened and sensitivity in the detection of multiple sclerosis (MS) abnormalities can be increased. This study compares both sequences for the potential to detect both focal and diffuse spinal abnormalities. Spinal cords of 5 volunteers and 20 MS patients were studied at 1.0 T. Magnetic resonance imaging included cardiac-gated sagittal dual-echo CSE and a cardiac-gated fast STIR sequence. Images were scored regarding number, size, and location of focal lesions, diffuse abnormalities and presence/hindrance of artifacts by two experienced radiologists. Examinations were scored as being definitely normal, indeterminate, or definitely abnormal. Interobserver agreement regarding focal lesions was higher for CSE (kappa = 0.67) than for fast STIR (kappa = 0.57) but did not differ significantly. Of all focal lesions scored in consensus, 47% were scored on both sequences, 31% were only detected by fast STIR, and 22% only by dual-echo CSE (n.s.). Interobserver agreement for diffuse abnormalities was lower with fast STIR (kappa = 0.48) than dual-echo CSE (kappa = 0.65; n. s.). After consensus, fast STIR showed in 10 patients diffuse abnormalities and dual-echo CSE in 3. After consensus, in 19 of 20 patients dual-echo CSE scans were considered as definitely abnormal compared with 17 for fast STIR. The fast STIR sequence is a useful adjunct to dual-echo CSE in detecting focal abnormalities and is helpful in detecting diffuse MS abnormalities in the spinal cord. Due to the frequent occurrence of artifacts and the lower observer concordance, fast STIR cannot be used alone.

Loss of heterozygosity on chromosome 2q: possibly a poor prognostic factor in head and neck cancer.

BACKGROUND: Loss of heterozygosity (LOH) correlates with inactivated tumor suppressor genes. The aim of this study was to see if LOH on chromosomes 2q, 3p, 5q, 9p, and 17p correlated with survival in early squamous cell carcinoma of the head and neck (SCCHN). METHODS: A case control study was performed. Ten patients with stage I or II tumors who ultimately died of their disease were identified and matched with suitable controls. None of the controls had a local recurrence and at time of last follow-up were alive with no evidence of disease or had died of an unrelated illness. The deoxyribonucleic acid (DNA) was extracted from paraffin blocks, and LOH studies were performed using microsatellite markers. RESULTS: The respective incidence of allelic loss for the index and control patients was as follows: chromosome 2q, 75% and 20% (p = .03); chromosome 3p, 71% and 57%, respectively (not significant); chromosome arm 5q, 30% and 25% (not significant); chromosome arm 9p, 71% and 73% (not significant); and chromosome arm 17p, 75% and 46% (not significant). Therefore, loss on chromosome 2q strongly correlated with poor survival (odds ratio = 10.4). CONCLUSION: Loss of heterozygosity on chromosome 2q may correlate with a poor prognosis in early-stage SCCHN.

Post-mortem high-resolution MRI of the spinal cord in multiple sclerosis: a correlative study with conventional MRI, histopathology and clinical phenotype.

We used high-resolution MRI to study the post-mortem appearance of spinal cord multiple sclerosis in relation to histopathology and low-resolution images. Fifty-nine 3 cm long formalin-fixed spinal cord specimens from 19 multiple sclerosis patients and three controls were studied. Clinical characteristics of each patient were reviewed. High-field MRI consisted of proton-density weighted spin-echo imaging with an in-plane resolution of 80 microm. Specimens were also imaged at 1.0 T, with 1 mm pixel resolution. After MRI, the specimens were cut at 5 mm intervals and stained for myelin (Luxol fast blue/cresyl violet) and axons (Bodian method). Two observers scored the MRIs for abnormalities and divided them into (i) well-delineated areas of high signal intensity (SI) and (ii) poorly defined areas of mildly increased SI. Abnormalities were scored semiquantitatively, white matter and grey matter separately. In 81 sections the total area of abnormalities per section was measured on both histopathology sections and on matched high-field MRIs. Abnormalities ranged from just a few abnormal areas to complete involvement of the spinal cord specimen. Patients with an aggressive disease course had more abnormalities than patients with a mild or intermediate disease course. Areas of mildly increased SI were seen in all specimens, and were often found around focal high-SI lesions. However, in six patients, areas of mildly increased SI were the predominant finding on the MRIs, correlating with a primary progressive disease course. Histopathologically, high-SI areas correlated with complete demyelination, while mildly increased SI corresponded with partial demyelination. All areas scored as abnormal by the neuropathologist were also found on the MRIs, and sizes measured using both methods correlated well (r = 0.85, P<0.01). On conventional MRIs, abnormalities could be recognized fairly well. However, better differentiation could be made between high-SI and mildly increased SI abnormalities on the 4.7 T images. In conclusion, high-resolution MRI revealed a great range of abnormalities in spinal cord multiple sclerosis, which related to disease course during life. Furthermore, we found very good correlation between the extent of abnormalities shown by histopathology and the SI changes on proton-density MRIs, mainly relating to demyelination revealed histopathologically.