Stratifying drug treatment of cognitive impairments after traumatic brain injury using neuroimaging.

Cognitive impairment is common following traumatic brain injury. Dopaminergic drugs can enhance cognition after traumatic brain injury, but individual responses are highly variable. This may be due to variability in dopaminergic damage between patients. We investigate whether measuring dopamine transporter levels using 123I-ioflupane single-photon emission computed tomography (SPECT) predicts response to methylphenidate, a stimulant with dopaminergic effects. Forty patients with moderate-severe traumatic brain injury and cognitive impairments completed a randomized, double-blind, placebo-controlled, crossover study. 123I-ioflupane SPECT, MRI and neuropsychological testing were performed. Patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Subjects received neuropsychological assessment after each block and completed daily home cognitive testing during the trial. The primary outcome measure was change in choice reaction time produced by methylphenidate and its relationship to stratification of patients into groups with normal and low dopamine transporter binding in the caudate. Overall, traumatic brain injury patients showed slow information processing speed. Patients with low caudate dopamine transporter binding showed improvement in response times with methylphenidate compared to placebo [median change = -16 ms; 95% confidence interval (CI): -28 to -3 ms; P = 0.02]. This represents a 27% improvement in the slowing produced by traumatic brain injury. Patients with normal dopamine transporter binding did not improve. Daily home-based choice reaction time results supported this: the low dopamine transporter group improved (median change -19 ms; 95% CI: -23 to -7 ms; P = 0.002) with no change in the normal dopamine transporter group (P = 0.50). The low dopamine transporter group also improved on self-reported and caregiver apathy assessments (P = 0.03 and P = 0.02, respectively). Both groups reported improvements in fatigue (P = 0.03 and P = 0.007). The cognitive effects of methylphenidate after traumatic brain injury were only seen in patients with low caudate dopamine transporter levels. This shows that identifying patients with a hypodopaminergic state after traumatic brain injury can help stratify the choice of cognitive enhancing therapy.

Optimisation and usefulness of quantitative analysis of 18F-florbetapir PET.

OBJECTIVES: This study investigates the usefulness of quantitative SUVR thresholds on sub types of typical (type A) and atypical (non-type A) positive (Aß+) and negative (Aß-) 18F-florbetapir scans and aims to optimise the thresholds. METHODS: Clinical 18F-florbetapir scans (n = 100) were categorised by sub type and visual reads were performed independently by three trained readers. Inter-reader agreement and reader-to-reference agreement were measured. Optimal SUVR thresholds were derived by ROC analysis and were compared with thresholds derived from a healthy control group and values from published literature. RESULTS: Sub type division of 18F-florbetapir PET scans improves accuracy and agreement of visual reads for type A: accuracy 90%, 96% and 70% and agreement κ > 0.7, κ ≥ 0.85 and -0.1 < κ < 0.9 for all data, type A and non-type A respectively. Sub type division also improves quantitative classification accuracy of type A: optimum mcSUVR thresholds were found to be 1.32, 1.18 and 1.48 with accuracy 86%, 92% and 76% for all data, type A and non-type A respectively. CONCLUSIONS: Aß+/Aß- mcSUVR threshold of 1.18 is suitable for classification of type A studies (sensitivity = 97%, specificity = 88%). Region-wise SUVR thresholds may improve classification accuracy in non-type A studies. Amyloid PET scans should be divided by sub type before quantification. ADVANCES IN KNOWLEDGE: We have derived and validated mcSUVR thresholds for Aß+/Aß- 18F-florbetapir studies. This work demonstrates that division into sub types improves reader accuracy and agreement and quantification accuracy in scans with typical presentation and highlights the atypical presentations not suited to global SUVR quantification.

Measurement of glomerular filtration rate in patients undergoing obesity surgery.

BACKGROUND: Most studies on obesity surgery have measured renal function using the estimated GFR. However, due to the reduction of muscle mass, and therefore creatinine that accompanies weight loss, such measures can falsely suggest an improvement in renal function. To balance the risks of surgery versus any potential benefits on renal function, we need to be able to determine renal function using valid and reliable methodologies. In this pilot study we aimed to measure renal function in patients with CKD undergoing obesity surgery using the gold standard 51Cr-EDTA GFR clearance methodology which is independent of measures of muscle mass. METHODS: Nine consecutive obese patients with CKD underwent obesity surgery. Their renal function was assessed using 51Cr-EDTA GFR, cystatin C and serum creatinine as well as using eGFR equations including MDRD CKD Epi, Cockcroft Gault and CKD Epi cystatin before and 12 months after surgery. RESULTS: Renal function using the 51Cr-EDTA measured GFR did not change significantly after surgery. Similar results were obtained when Cystatin C, CKD Epi cystatin, CKD Epi cystatin creatinine and adjusted Cockcroft Gault Creatinine clearance methods were used. In contrast there were either trends or significant improvements in renal function measured using the MDRD and CKD Epi equations. CONCLUSIONS: In this pilot study using the gold standard 51Cr-EDTA method we found stabilisation in renal function after obesity surgery. Until further definitive data emerge it is critical to balance the risk and benefits of surgery, especially if renal function may not improve as often as previously suggested. TRIAL REGISTRATION: ClinicalTrials.gov NCT01507350 . Registered June 2011.

Dopaminergic abnormalities following traumatic brain injury.

Traumatic brain injury can reduce striatal dopamine levels. The cause of this is uncertain, but is likely to be related to damage to the nigrostriatal system. We investigated the pattern of striatal dopamine abnormalities using 123I-Ioflupane single-photon emission computed tomography (SPECT) scans and their relationship to nigrostriatal damage and clinical features. We studied 42 moderate-severe traumatic brain injury patients with cognitive impairments but no motor parkinsonism signs and 20 healthy controls. 123I-Ioflupane scanning was used to assess dopamine transporter levels. Clinical scan reports were compared to quantitative dopamine transporter results. Advanced MRI methods were used to assess the nigrostriatal system, including the area through which the nigrostriatal projections pass as defined from high-resolution Human Connectome data. Detailed clinical and neuropsychological assessments were performed. Around 20% of our moderate-severe patients had clear evidence of reduced specific binding ratios for the dopamine transporter in the striatum measured using 123I-Ioflupane SPECT. The caudate was affected more consistently than other striatal regions. Dopamine transporter abnormalities were associated with reduced substantia nigra volume. In addition, diffusion MRI provided evidence of damage to the regions through which the nigrostriatal tract passes, particularly the area traversed by dopaminergic projections to the caudate. Only a small percentage of patients had evidence of macroscopic lesions in the striatum and there was no relationship between presence of lesions and dopamine transporter specific binding ratio abnormalities. There was also no relationship between reduced volume in the striatal subregions and reduced dopamine transporter specific binding ratios. Patients with low caudate dopamine transporter specific binding ratios show impaired processing speed and executive dysfunction compared to patients with normal levels. Taken together, our results suggest that the dopaminergic system is affected by a moderate-severe traumatic brain injury in a significant proportion of patients, even in the absence of clinical motor parkinsonism. Reduced dopamine transporter levels are most commonly seen in the caudate and this is likely to reflect the pattern of nigrostriatal tract damage produced by axonal injury and associated midbrain damage.

Evaluation of breast lesions using sonographic elasticity imaging: a multicenter trial.

OBJECTIVES: The purpose of this study was to determine the sensitivity and specificity of real-time compression elasticity imaging in characterizing breast lesions as benign or malignant. METHODS: A cohort of 578 women scheduled for sonographically guided biopsy of breast lesions were recruited from 6 sites under an Institutional Review Board-approved protocol. All participants received an elastogram, which displayed both the B-mode and elasticity images in real time. The longest dimensions of the lesion on the B-mode and elasticity imaging were measured. An elasticity imaging/B-mode ratio of at least 1.0 was considered positive for malignant lesions. The reference standard was based on biopsy. RESULTS: A total of 635 lesions were imaged and biopsied. There were 222 (35%) malignant or borderline lesions and 413 (65%) benign lesions. The benign lesions were either cystic (145 [35%]) or solid (268 [65%]). Of the 222 malignant lesions, 219 had an elasticity imaging/B-mode ratio of at least 1.0. Of the 413 benign lesions, 361 had an elasticity imaging/B-mode ratio less than 1.0. These results corresponded to overall sensitivity of 98.6% and overall specificity of 87.4%. Individual site sensitivities ranged from 96.7% to 100% whereas specificities ranged from 66.7% to 95.4%. CONCLUSIONS: Elasticity imaging has high sensitivity in characterizing malignant lesions of the breast. Variability in specificity between sites and sonographers is possibly due to individual technique differences in performing elastography and measuring lesions. Further work in standardizing the technique is required.

Shear-wave elastography improves the specificity of breast US: the BE1 multinational study of 939 masses.

PURPOSE: To determine whether adding shear-wave (SW) elastographic features could improve accuracy of ultrasonographic (US) assessment of breast masses. MATERIALS AND METHODS: From September 2008 to September 2010, 958 women consented to repeat standard breast US supplemented by quantitative SW elastographic examination in this prospective multicenter institutional review board-approved, HIPAA-compliant protocol. B-mode Breast Imaging Reporting and Data System (BI-RADS) features and assessments were recorded. SW elastographic evaluation (mean, maximum, and minimum elasticity of stiffest portion of mass and surrounding tissue; lesion-to-fat elasticity ratio; ratio of SW elastographic-to-B-mode lesion diameter or area; SW elastographic lesion shape and homogeneity) was performed. Qualitative color SW elastographic stiffness was assessed independently. Nine hundred thirty-nine masses were analyzable; 102 BI-RADS category 2 masses were assumed to be benign; reference standard was available for 837 category 3 or higher lesions. Considering BI-RADS category 4a or higher as test positive for malignancy, effect of SW elastographic features on area under the receiver operating characteristic curve (AUC), sensitivity, and specificity after reclassifying category 3 and 4a masses was determined. RESULTS: Median participant age was 50 years; 289 of 939 (30.8%) masses were malignant (median mass size, 12 mm). B-mode BI-RADS AUC was 0.950; eight of 303 (2.6%) BI-RADS category 3 masses, 18 of 193 (9.3%) category 4a lesions, 41 of 97 (42%) category 4b lesions, 42 of 57 (74%) category 4c lesions, and 180 of 187 (96.3%) category 5 lesions were malignant. By using visual color stiffness to selectively upgrade category 3 and lack of stiffness to downgrade category 4a masses, specificity improved from 61.1% (397 of 650) to 78.5% (510 of 650) (P<.001); AUC increased to 0.962 (P=.005). Oval shape on SW elastographic images and quantitative maximum elasticity of 80 kPa (5.2 m/sec) or less improved specificity (69.4% [451 of 650] and 77.4% [503 of 650], P<.001 for both), without significant improvement in sensitivity or AUC. CONCLUSION: Adding SW elastographic features to BI-RADS feature analysis improved specificity of breast US mass assessment without loss of sensitivity.

Differentiating benign from malignant solid breast masses with US strain imaging.

PURPOSE: To prospectively evaluate the sensitivity and specificity of ultrasonographic (US) strain imaging for distinguishing between benign and malignant solid breast masses, with biopsy results as the reference standard. MATERIALS AND METHODS: The study was institutional review board approved and HIPAA compliant. Informed consent was obtained from all participating patients. US strain imaging of 403 breast masses was performed. The 50 malignant and 48 benign lesions (in patients aged 19-83 years; mean age, 49 years +/- 17 [standard deviation]) with the highest quality were selected for the reader study. Three observers blinded to the pathologic outcomes first described the B-mode image findings by using US Breast Imaging Reporting and Data System descriptors and derived a probability of malignancy. They then updated the probability by assessing strain images. Receiver operating characteristic (ROC) curves were constructed by using these probabilities. Areas under the ROC curve, sensitivities, and specificities were calculated and compared. Interobserver variability and the correlation between automated and subjective image quality assessment were analyzed. RESULTS: The average area under the ROC curve for all three readers after US strain imaging (0.903) was greater than that after B-mode US alone (0.876, P = .014). With use of a 2% probability of malignancy threshold, strain imaging-as compared with B-mode US alone-had improved average specificity (0.257 vs 0.132, P < .001) and high sensitivity (0.993 vs 0.987, P > .99). Significant interobserver variability was observed (P < .001). The ability to assess strain image quality appeared to correlate with the highest observer performance. CONCLUSION: US strain imaging can facilitate improved classification of benign and malignant breast masses. However, interobserver variability and image quality influence observer performance.

Acrometastasis to the foot: an unusual presentation of transitional cell carcinoma of the bladder.

Metastases from bladder cancer to the bones of the hands or feet are rare and usually present after the diagnosis of the primary lesion has been made. This case report describes a 76-year-old man presenting with initial signs of infection of the right foot. Subsequent bone scan revealed multiple bony metastases and hydronephrosis raising the possibility of a primary bladder tumour that was later confirmed by urine cytology and fine needle aspiration of the foot.

A quantitative lymphoscintigraphic evaluation of lymphatic function in the swollen hands of women with lymphoedema following breast cancer treatment.

In BCRL (breast cancer-related lymphoedema), arm swelling is unevenly distributed and some regions are partly or entirely spared. In particular, the hand may or not be swollen, but when involved functional impairment can be substantial. We have found previously that, when the ipsilateral hand is spared of swelling (in a limb with swelling proximal to the hand), the local lymph drainage rate constant (k) is at least as high as in the contralateral hand, contrary to the traditional 'stopcock' concept of reduced lymph drainage from the whole limb. In the light of this finding, we have investigated lymph drainage in the hands of eight women with BCRL and moderate-to-severe hand swelling, using gamma-camera quantitative lymphoscintigraphy. Images showed pronounced superficial activity in the ipsilateral swollen arms of most patients, indicating dermal backflow. k for 99mTc-labelled hIgG (human IgG) measured over 5 h in the subcutis of the ipsilateral swollen hand was 34+/-24% less than in the contralateral hand (P=0.013). Activity measured in the ipsilateral swollen forearm increased progressively, but there was very little increase in the contralateral forearm, indicating retention of 99mTc-labelled hIgG in the swollen forearm. It is concluded that lymphatic function in the swollen hand is impaired, and that there appears to be two populations of women with BCRL, i.e. spared-hand and swollen-hand, irrespective of the cancer treatment received.

Invasive ductal carcinoma of the breast with large central acellular zones (ring carcinoma): imaging and clinical findings in eight cases.

OBJECTIVE: To review the mammographic and ultrasound appearances in patients who have invasive ductal carcinoma with a central acellular zone (ring carcinoma), as this feature has been reported to be associated with a poorer outcome. MATERIALS: Eight patients were identified with ring carcinomas. Two breast radiologists reviewed their mammograms and ultrasound images. Patient records were reviewed to assess outcome. RESULTS: All patients had lesions deep within the breast, adjacent to the chest wall, five lesions were incompletely visualised on mammography. The appearance was of a circumscribed or obscured mass, without microcalcification. Five patients had ultrasound demonstrating a solid well-circumscribed hypoechoic microlobulated lesion. CONCLUSION: In our series of patients who have a ring carcinoma of the breast, mammographic and ultrasound appearances were similar in all cases and lacked the typical features of malignancy.

Idiopathic benign breast calcification.

A 56-year-old woman who came in for screening mammography was found to have extensive unilateral calcification of her left breast which had developed since her previous screening mammogram. The calcification had a ductal and lobular appearance. Possible known etiologies are discussed, but these do not explain the appearance in this case, implying that the cause is idiopathic.