Proof-of-concept study linking ex vivo sensitivity testing to neoadjuvant anthracycline-based chemotherapy response in breast cancer patients.

We developed a functional ex vivo anthracycline-based sensitivity test. Surgical resection material of primary breast cancer (BC) was used to determine criteria for the ex vivo sensitivity assay based on morphology, proliferation and apoptosis. Subsequently, a proof-of-concept study was performed correlating results of this assay on primary BC biopsies with in vivo response after treatment with anthracycline-containing neoadjuvant chemotherapy (NAC). Cut off values for the ex vivo anthracycline-based sensitivity test were established based on analysis of 21 primary breast tumor samples obtained after surgery. In the proof-of-concept study based on a new set of tumor biopsies, 41 patients were included. Eight biopsies did not contain tumor cells and three patients could not be biopsied for various reasons. In the remaining 30 biopsies, the success rate of the ex vivo test was 77% (23/30); six out of seven failed tests were due to excessive apoptosis, our pre-specified test criteria. Of the 23 patients with a successful ex vivo test result, three patients did not undergo NAC after the biopsy. Here we report the ex vivo anthracycline-based sensitivity assay is feasible on biopsy material and shows 75% concordance between ex vivo outcomes and in vivo MRI response. Unfortunately, the percentage of unsuccessful tests is rather high. This study provides the foundation for further development of ex vivo sensitivity assays.

Gamma probe and ultrasound-guided fine needle aspiration cytology of the sentinel node (GULF) trial.

PURPOSE: Sentinel lymph node biopsy (SLNB) was introduced as a minimally invasive technique for nodal staging. Since associated morbidity is not negligible, it is highly relevant to pursue a more minimally invasive alternative. The purpose of this study was to prospectively evaluate the sensitivity of fine needle aspiration cytology (FNAC) with combined gamma probe and ultrasound (US) guidance in comparison with the gold standard histology of the sentinel node (SN) after SLNB for detecting metastasis. METHODS: The study was designed as a prospective, multicentre, open-label, single-arm trial enrolling patients with newly diagnosed cutaneous melanoma or breast cancer between May 2015 and August 2017. Sample radioactivity was measured using a Mini 900 scintillation monitor. After FNAC, all patients underwent SLNB. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated. RESULTS: Accrual was terminated early following an unplanned interim analysis indicating that a FNAC sensitivity of at least 80% could not be achieved. In total 58 patients of the originally planned 116 patients underwent FNAC with gamma probe and US guidance. There were no true-positive FNAC results, 14 false-negative results and one false-positive result, and thus the sensitivity, specificity, PPV and NPV of FNAC were 0%, 98%, 0% and 75%, respectively. At least 75% of the FNAC samples had a radioactivity signal higher than the background signal. CONCLUSION: FNAC with gamma probe and US guidance is not able to correctly detect metastases in the SN and is therefore not able to replace SLNB. Gamma probe-guided US is a highly accurate method for correctly identifying the SN, which offers possibilities for future research.

Gamma probe and ultrasound guided fine needle aspiration cytology of the sentinel node (GULF) trial - overview of the literature, pilot and study protocol.

BACKGROUND: Sentinel node (SN) biopsy (SNB) detects clinically occult metastases of breast cancer and melanoma in 20-30%. Wound infections, seroma and lymph edema occur in up to 10%. Targeted ultrasound (US) of the SN, (with fine needle aspiration cytology (FNAC) if appropriate) has been investigated as a minimally invasive alternative, but reported sensitivity rates are too low to replace SNB. Our hypothesis is that the use of a handheld gamma probe concomitant with US may improve sensitivity. Our aim is to provide an overview of the current literature on preoperative nodal staging of clinical N0 melanoma patients, report on a pilot, and present a study protocol for a minimally invasive alternative to the SNB: Gamma probe and Ultrasound guided Fine needle aspiration cytology of the sentinel node (GULF trial). METHODS: The GULF trial is a multicenter open single arm observational trial. Newly diagnosed cT1b-4N0M0 cutaneous melanoma or cT1-3N0M0 breast cancer patients, aged >18 years, presenting for SNB are eligible. 120 patients will be included for preoperative targeted gamma probe guided US and FNAC of the SN. Afterwards all patients proceed to surgical SNB. Primary endpoint is the sensitivity of FNAC. Secondary endpoints include SN identification rate and the histopathological compatibility of Core Needle Biopsy and FNAC vs. SNB. Secondary endpoints were investigated in a pilot with 10 FNACs and marker placements, and 10 FNACs combined with Core Needle Biopsy. RESULTS: A pilot in 20 patients showed that SN identification rate was 90%, supporting the feasibility of this technique. DISCUSSION: There is broad experience with US (in combination with FNAC) prior to SNB, but sensitivity and specificity are too low to completely abandon SNB. Promising alternative techniques potentially will replace SNB in the future but more evidence is needed in the form of prospective studies. Accurate identification of the SN for US-FNAC has been proven feasible in our pilot. When adequate sensitivity can be reached, US-FNAC provides a minimally invasive alternative for the surgical SNB procedure. TRIAL REGISTRATION: The GULF trial is registered in the Netherlands Trial Registry (NTR), ID: NRT5193 . May 1st 2015.

Preoperative breast MRI can reduce the rate of tumor-positive resection margins and reoperations in patients undergoing breast-conserving surgery.

OBJECTIVE: In breast cancer patients eligible for breast-conserving surgery, we evaluated whether the information provided by preoperative MRI of the breast would result in fewer tumor-positive resection margins and fewer reoperations. SUBJECTS AND METHODS: The study group consisted of 123 consecutive patients diagnosed with either breast cancer or ductal carcinoma in situ eligible for breast-conserving surgery between April 2007 and July 2010. For these patients, a first plan for breast-conserving surgery was made on the basis of clinical examination and conventional imaging. The final surgical plan was made with knowledge of the preoperative breast MRI. The rates of tumor-positive resection margins and reoperations were compared with those of a historical control group consisting of 119 patients who underwent 123 breast-conserving procedures between January 2005 and December 2006. The percentage of change in the surgical plan was recorded. RESULTS: Preoperative breast MRI changed the surgical plan to more extensive surgery in 42 patients (34.1%), mainly to mastectomy (29 patients, 23.6%). Ninety-four patients underwent 95 breast-conserving procedures. Significantly fewer patients had tumor-positive resection margins than in the control group (15.8%, 15/95 versus 29.3%, 36/123; p < 0.01). Patients in the study group underwent significantly fewer reoperations compared with the historical control group (18.9%, 18/95 vs 37.4%, 46/123; p < 0.01). CONCLUSION: Preoperative breast MRI can substantially decrease the rate of tumor-positive resection margins and reoperations in breast cancer patients eligible for breast-conserving surgery.

Suspected carotid artery stenosis: cost-effectiveness of CT angiography in work-up of patients with recent TIA or minor ischemic stroke.

PURPOSE: To assess the effectiveness and cost-effectiveness of state-of-the-art noninvasive diagnostic imaging strategies in patients with a transient ischemic attack (TIA) or minor stroke who are suspected of having carotid artery stenosis (CAS). MATERIALS AND METHODS: All prospectively evaluated patients provided informed consent, and the local ethics committee approved this study. Diagnostic performance, treatment, long-term events, quality of life, and costs resulting from strategies employing duplex ultrasonography (US), computed tomographic (CT) angiography, contrast material-enhanced magnetic resonance (MR) angiography, and combinations of these modalities were modeled in a decision tree and Markov model. Data sources included a prospective diagnostic cohort study, a meta-analysis, and a review of the literature. Outcomes were costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, and net health benefits (QALY-equivalents), with a willingness-to-pay threshold of euro 50,000 per QALY and a societal perspective. The strategy with the highest net health benefit was considered the most cost effective. Extensive one-way, two-way, and probabilistic sensitivity analyses to explore the effect of varying parameter values were performed. The reference case analysis assumed that patients underwent surgery 2-4 weeks after the first symptoms, and the effect of earlier intervention was explored. RESULTS: The reference case analysis showed that duplex US combined with CT angiography and surgery for 70%-99% stenoses was the most cost-effective strategy, with a net health benefit of 13.587 and 15.542 QALY-equivalents in men and women, respectively. In men, the CT angiography strategy with a 70%-99% cutoff yielded slightly more QALYs, at an incremental cost of euro 71,419 per QALY, compared with duplex US combined with CT angiography. In patients with a high-risk profile, in patients with a high prior probability of disease, and when patients could be treated within 2 weeks after the first symptoms, the CT angiography strategy with surgery for 50%-99% stenoses was the most cost-effective strategy. CONCLUSION: In diagnosing CAS, duplex US should be the initial test, and, if its results are positive, CT angiography should be performed; patients with 70%-99% stenoses should then undergo carotid endarterectomy. In patients with a high-risk profile, a high probability of CAS, or who can undergo surgery without delay, immediate CT angiography and surgery for 50%-99% stenoses is indicated.

Assessment of atherosclerotic carotid plaque volume with multidetector computed tomography angiography.

PURPOSE: The amount of atherosclerotic plaque and its components (calcifications, fibrous tissue, and lipid core) could be better predictors of acute events than the now currently used degree of stenosis. Therefore, we evaluated a dedicated software tool for volume measurements of atherosclerotic carotid plaque and its components in multidetector computed tomography angiography (MDCTA) images. MATERIALS AND METHODS: Data acquisition was approved by the Institutional Review Board and all patients gave written informed consent. MDCTA images of 56 carotid arteries were analyzed by three observers. Plaque volumes were assessed by manual drawing of the outer vessel contour. The luminal boundary was determined based on a Hounsfield-Unit (HU) threshold. The contribution of different components was measured by the number of voxels within defined ranges of HU-values (calcification >130 HU, fibrous tissue 60-130 HU, lipid core <60 HU). Interobserver variability (IOV) was assessed. RESULTS: Plaque volume was 1,259 +/- 621 mm3. The calcified, fibrous and lipid volumes were 238 +/- 252 mm3, 647 +/- 277 mm3 and 376 +/- 283 mm3, respectively. IOV was moderate with interclass correlation coefficients (ICC) ranging from 0.76 to 0.99 and coefficients of variation (COV) ranging from 3% to 47%. CONCLUSION: Atherosclerotic carotid plaque volume and plaque component volumes can be assessed with MDCTA with a reasonable observer variability.

Is a fetal origin of the posterior cerebral artery a risk factor for TIA or ischemic stroke? A study with 16-multidetector-row CT angiography.

BACKGROUND AND PURPOSE: Fetal origin of the posterior cerebral artery (PCA) is not uncommon. Whether patients with this anomaly have a higher risk of ischemic stroke in the territory of the PCA is not known. The clinical benefit of screening for a fetal origin in patients with TIA or stroke in the territory of the PCA and an ipsilateral atherosclerotic carotid stenosis is not clear. This study assessed the frequency of a fetal origin of the PCA in patients with a TIA or infarct in the territory of the PCA with 16-multidetector-row CT angiography (CTA). METHODS: 82 patients (52 male; mean age = 64; range 19 to 90 years) with isolated homonymous hemianopia and/or a PCA infarct underwent CTA of the carotid artery and circle of Willis. RESULTS: A fetal origin of the PCA at the symptomatic side was present in 14 patients (17 %) and at the asymptomatic side in 18 patients (22%) (OR: 0.7; 95 % CI: 0.3 to 1.7). Severity of stenosis (NASCET criteria) of the ICA at the symptomatic side was < 30%, 30-49% and > or = 50% in 72, 2 and 8 patients, respectively. Number and frequency of a fetal origin in these groups were 12 (17 %), 0 (0%) and 2 (25 %), respectively. There was no association between a severe carotid stenosis and a fetal origin of the PCA at the symptomatic side. CONCLUSION: This study does not provide arguments for an increased risk of ischemic stroke in the territory of the PCA in patients with a fetal origin of the PCA. A few patients with a TIA or infarct in the territory of the PCA have a fetal origin of the PCA in combination with a high-grade stenosis of the ipsilateral ICA, but not more often than one would expect from chance. Nevertheless, these patients may benefit from carotid endarterectomy.

MDCT detection of fibromuscular dysplasia of the internal carotid artery.

OBJECTIVE: The purpose of this article is to describe two cases in which fibromuscular dysplasia of the internal carotid artery was diagnosed with CT angiography. CONCLUSIONS: CT angiography can depict the characteristic findings of fibromuscular dysplasia. If patients with cerebrovascular symptoms undergo screening with CT angiography of the supraaortic vessels, more cases of fibromuscular dysplasia will be recognized as a cause of neurologic symptoms.

Evaluation of an improved technique for lumen path definition and lumen segmentation of atherosclerotic vessels in CT angiography.

Vessel image analysis is crucial when considering therapeutical options for (cardio-) vascular diseases. Our method, VAMPIRE (Vascular Analysis using Multiscale Paths Inferred from Ridges and Edges), involves two parts: a user defines a start- and endpoint upon which a lumen path is automatically defined, and which is used for initialization; the automatic segmentation of the vessel lumen on computed tomographic angiography (CTA) images. Both parts are based on the detection of vessel-like structures by analyzing intensity, edge, and ridge information. A multi-observer evaluation study was performed to compare VAMPIRE with a conventional method on the CTA data of 15 patients with carotid artery stenosis. In addition to the start- and endpoint, the two radiologists required on average 2.5 (SD: 1.9) additional points to define a lumen path when using the conventional method, and 0.1 (SD: 0.3) when using VAMPIRE. The segmentation results were quantitatively evaluated using Similarity Indices, which were slightly lower between VAMPIRE and the two radiologists (respectively 0.90 and 0.88) compared with the Similarity Index between the radiologists (0.92). The evaluation shows that the improved definition of a lumen path requires minimal user interaction, and that using this path as initialization leads to good automatic lumen segmentation results.

Optimization of CT angiography of the carotid artery with a 16-MDCT scanner: craniocaudal scan direction reduces contrast material-related perivenous artifacts.

OBJECTIVE: The objective of our study was to compare the effect of a caudocranial scan direction versus a craniocaudal scan direction on arterial enhancement and perivenous artifacts in 16-MDCT angiography of the supraaortic arteries. SUBJECTS AND METHODS: Eighty consecutive patients (51 men; mean age, 62 years; age range, 28-89 years) underwent scanning in the caudocranial direction (group 1; n = 40) or the craniocaudal direction (group 2; n = 40). All patients received 80 mL of contrast material followed by a 40-mL saline chaser bolus, both administered IV at 4 mL/sec. Bolus tracking was used. Attenuation inside the arterial lumen was measured at intervals of 1 sec throughout the data set. Attenuation in the superior vena cava (SVC) was measured. Contrast material-related perivenous artifacts were graded on a scale of 0-3 (none to extensive). RESULTS: Attenuation in the ascending aorta, carotid bifurcation, and intracranial arteries was slightly lower in group 2 versus group 1 (231 +/- 64 H, 348 +/- 52 H, and 258 +/- 48 H vs 282 +/- 43 H, 381 +/- 73 H, and 291 +/- 77 H, respectively; p < 0.05). Maximum and mean arterial attenuations were slightly lower in group 2 versus group 1 (369 +/- 58 H and 303 +/- 48 H vs 401 +/- 71 H and 334 +/- 58 H; p < 0.05). Attenuation in the SVC was much lower in group 2 versus group 1 (169 +/- 39 H vs 783 +/- 330 H; p < 0.001). Mean streak artifact score was much lower in group 2 versus group 1 (1.3 +/- 0.9 vs 2.5 +/- 0.6; p < 0.001). CONCLUSION: Use of a craniocaudal scan direction results in slightly lower attenuation of the carotid artery and much lower attenuation of the SVC. Streak artifacts are significantly reduced. This technique allows better evaluation of the ascending aorta and supraaortic arteries.

High iodine concentration contrast material for noninvasive multislice computed tomography coronary angiography: iopromide 370 versus iomeprol 400.

OBJECTIVE: The objective of this study was to compare intracoronary attenuation on 16-row multislice computed tomography (16-MSCT) coronary angiography using 2 contrast materials (CM) with high iodine concentration. MATERIAL AND METHODS: Forty consecutive patients (29 male, 11 female; mean age, 61+/-11 years) with suspected coronary artery disease were randomized to 2 groups to receive 100 mL of either iopromide 370 (group 1: Ultravist 370, 370 mg iodine/mL; Schering AG, Berlin, Germany) or iomeprol 400 (group 2: Iomeron 400, 400 mg iodine/mL; Bracco Imaging SpA, Milan, Italy). Both CM were administered at a rate of 4 mL/s. All patients underwent 16-MSCT coronary angiography (Sensation 16; Siemens, Germany) with collimation 16 x 0.75 mm and rotation time 375 ms. The attenuation in Hounsfield units (HU) achieved after each CM was determined at regions of interest (ROIs) placed at the origin of coronary arteries and on the ascending aorta, descending aorta, and pulmonary artery. Differences in mean attenuation in the coronary arteries and on the ascending aorta, descending aorta, and pulmonary artery were evaluated using Student t test. RESULTS: The mean attenuation achieved at each anatomic site was consistently greater after iomeprol 400 than after iopromide 370. At the origin of coronary arteries, the mean attenuation after iomeprol 400 (340+/-53 HU) was greater (P<0.05) than that after iopromide 370 (313+/- 42 HU). Similar findings were noted for the mean attenuation in the ascending aorta, descending aorta, and pulmonary artery. CONCLUSION: The intravenous administration of iomeprol 400 provides higher attenuation of the coronary arteries and of the great arteries of the thorax as compared with iopromide 370 using the same injection parameters.

Evaluation of an improved technique for automated center lumen line definition in cardiovascular image data.

The aim of the study was to evaluate a new method for automated definition of a center lumen line in vessels in cardiovascular image data. This method, called VAMPIRE, is based on improved detection of vessel-like structures. A multiobserver evaluation study was conducted involving 40 tracings in clinical CTA data of carotid arteries to compare VAMPIRE with an established technique. This comparison showed that VAMPIRE yields considerably more successful tracings and improved handling of stenosis, calcifications, multiple vessels, and nearby bone structures. We conclude that VAMPIRE is highly suitable for automated definition of center lumen lines in vessels in cardiovascular image data.

Sixteen-detector row CT angiography of carotid arteries: comparison of different volumes of contrast material with and without a bolus chaser.

PURPOSE: To prospectively compare different volumes of intravenously administered contrast material with and without a bolus chaser at 16-detector row computed tomographic (CT) angiography of the carotid arteries. MATERIALS AND METHODS: Institutional Review Board approval and informed consent were obtained. Seventy-five consecutive patients (44 men, 31 women; mean age, 63 years; range, 22-85 years) were allocated to one of three protocols: group 1, 80 mL of contrast material; group 2, 80 mL of contrast material followed by 40 mL of saline; and group 3, 60 mL of contrast material followed by 40 mL of saline. Bolus tracking was used to synchronize contrast material injection with CT scanning. The attenuation in Hounsfield units was measured from the ascending aorta to the intracranial arteries at 1-second intervals. Differences were tested with the Student t test. RESULTS: The maximum attenuation was reached in the proximal internal carotid artery in all groups. The addition of a bolus chaser to 80-mL contrast material resulted in a higher mean attenuation (323 HU +/- 39 vs 351 HU +/- 60, P = .06), higher maximum attenuation (393 HU +/- 53 vs 425 HU +/- 76, P = .09), and higher minimum attenuation (240 HU +/- 34 vs 264 HU +/- 48, P < .05). Group 3 had lower mean, maximum, and minimum attenuation than did groups 1 and 2 (P < .001). CONCLUSION: The addition of a bolus chaser to 80 mL of contrast material results in a slightly higher attenuation. Decreasing the volume of contrast material from 80 to 60 mL results in a significantly lower attenuation.