Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis: the VISSIT randomized clinical trial.

IMPORTANCE: Intracranial stenosis is one of the most common etiologies of stroke. To our knowledge, no randomized clinical trials have compared balloon-expandable stent treatment with medical therapy in symptomatic intracranial arterial stenosis. OBJECTIVE: To evaluate the efficacy and safety of the balloon-expandable stent plus medical therapy vs medical therapy alone in patients with symptomatic intracranial stenosis (≥70%). DESIGN, SETTING, AND PATIENTS: VISSIT (the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy) trial is an international, multicenter, 1:1 randomized, parallel group trial that enrolled patients from 27 sites (January 2009-June 2012) with last follow-up in May 2013. INTERVENTIONS: Patients (N = 112) were randomized to receive balloon-expandable stent plus medical therapy (stent group; n = 59) or medical therapy alone (medical group; n = 53). PRIMARY OUTCOME MEASURE: a composite of stroke in the same territory within 12 months of randomization or hard transient ischemic attack (TIA) in the same territory day 2 through month 12 postrandomization. A hard TIA was defined as a transient episode of neurological dysfunction caused by focal brain or retinal ischemia lasting at least 10 minutes but resolving within 24 hours. Primary safety measure: a composite of any stroke, death, or intracranial hemorrhage within 30 days of randomization and any hard TIA between days 2 and 30 of randomization. Disability was measured with the modified Rankin Scale and general health status with the EuroQol-5D, both through month 12. RESULTS: Enrollment was halted by the sponsor after negative results from another trial prompted an early analysis of outcomes, which suggested futility after 112 patients of a planned sample size of 250 were enrolled. The 30-day primary safety end point occurred in more patients in the stent group (14/58; 24.1% [95% CI, 13.9%-37.2%]) vs the medical group (5/53; 9.4% [95% CI, 3.1%-20.7%]) (P = .05). Intracranial hemorrhage within 30 days occurred in more patients in the stent group (5/58; 8.6% [95% CI, 2.9%-19.0%]) vs none in the medical group (95% CI, 0%-5.5%) (P = .06). The 1-year primary outcome of stroke or hard TIA occurred in more patients in the stent group (21/58; 36.2% [95% CI, 24.0-49.9]) vs the medical group (8/53; 15.1% [95% CI, 6.7-27.6]) (P = .02). Worsening of baseline disability score (modified Rankin Scale) occurred in more patients in the stent group (14/58; 24.1% [95% CI, 13.9%-37.2%]) vs the medical group (6/53; 11.3% [95% CI, 4.3%-23.0%]) (P = .09).The EuroQol-5D showed no difference in any of the 5 dimensions between groups at 12-month follow-up. CONCLUSIONS AND RELEVANCE: Among patients with symptomatic intracranial arterial stenosis, the use of a balloon-expandable stent compared with medical therapy resulted in an increased 12-month risk of added stroke or TIA in the same territory, and increased 30-day risk of any stroke or TIA. These findings do not support the use of a balloon-expandable stent for patients with symptomatic intracranial arterial stenosis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00816166.

Design of the Vitesse Intracranial Stent Study for Ischemic Therapy (VISSIT) trial in symptomatic intracranial stenosis.

BACKGROUND: Patients with high-grade symptomatic intracranial stenosis (≥ 70%) have an increased risk of recurrent stroke despite medical treatment with antiplatelet or anticoagulant therapy. Intracranial stenting has been proposed as a viable treatment option for this high-risk patient population; however, evaluation of this therapy in randomized multicenter trials is needed. In this article, we present the design and methods of the Vitesse Intracranial Stent Study for Ischemic Therapy (VISSIT) trial for symptomatic intracranial stenosis. METHODS: The VISSIT trial is a randomized control study designed to evaluate the safety, probable benefit, and effectiveness of the PHAROS Vitesse neurovascular balloon-expandable stent system plus medical therapy versus medical therapy alone in patients with cerebral or retinal ischemia due to neurovascular stenosis (≥ 70%) for preventing the primary composite end point: stroke in the same territory (distal to the target lesion) as the presenting event within 12 months of randomization or hard transient ischemic attack in the same territory (distal to the target lesion) as the presenting event from day 2 through month 12 postrandomization. RESULTS: Enrollment began in February 2009 and was halted in January 2012 with 112 subjects enrolled into the study. Clinical follow-up will continue for the planned period of 12 months postrandomization. CONCLUSIONS: The VISSIT trial may provide valuable insight into the use of balloon-expandable intracranial stent as a treatment option for high-risk patients. Lessons learned from this trial may better guide future clinical trial design on best patient selection, stenting techniques, and periprocedural management.

Interfractional reproducibility of lung tumor location using various methods of respiratory motion mitigation.

PURPOSE: To determine interfractional reproducibility of the location of lung tumors using respiratory motion mitigation. METHODS AND MATERIALS: Free-breathing four-dimensional computed tomography (CT) data sets and CT data sets during breath hold were acquired weekly for 17 patients undergoing treatment for non-small-cell lung cancer. Distances between the center of the gross tumor volume (GTV) and a reproducible bony reference point under conditions of breath hold on end inspiration (EI) and end expiration (EE) and during free breathing on the 0% phase (corresponding to EI) and 50% phase (corresponding to EE) were analyzed for interfractional reproducibility. Systematic uncertainties in tumor location were determined as the difference in distance between the GTV center on the first CT data set and the mean location of GTV centers on the subsequent data sets. Random uncertainties in tumor location were determined as the standard deviation of the distances between the GTV centers and the bony reference points. Margins to account for systematic and random interfractional variations were estimated based on these uncertainties. RESULTS: Mean values of interfractional setup uncertainties were as follows: systematic uncertainties--EI, 0.3 cm; EE, 0.2 cm; 0% phase, 0.3 cm; and 50% phase, 0.3 cm; and random uncertainties--EI, 0.3 cm; EE, 0.3 cm; 0% phase, 0.3 cm; and 50% phase, 0.3 cm. There does not appear to be any correlation between uncertainties and GTV size, but there appears to be a weak positive correlation between uncertainties and the magnitude of GTV excursion. CONCLUSIONS: Voluntary breath hold and gating on either EI or EE appear to be equally reliable methods of ensuring the reproducibility of lung tumor position. We recommend setup margins of 0.3 cm if using cone-beam CT or kilovoltage X-ray with fiducials and aligning directly to the tumor and 0.8 cm when aligning to a nearby bony surrogate using cone-beam CT or kilovoltage X-ray.

Potential dosimetric benefits of four-dimensional radiation treatment planning.

PURPOSE: To determine the extent of dosimetric differences between conventional three-dimensional (3D) dose calculations and four-dimensional (4D) dose calculations based on deformation of organ models. METHODS AND MATERIALS: Four-dimensional dose calculations were retrospectively performed on computed tomography data sets for 15 patients with Stage III non-small-cell lung cancer, using a model-based deformable registration algorithm on a research version of a commercial radiation treatment planning system. Target volume coverage and doses to critical structures calculated using the 4D methodology were compared with those calculated using conventional 3D methodology. RESULTS: For 11 of 15 patients, clinical target volume coverage was comparable in the 3D and 4D calculations, whereas for 7 of 15 patients, planning target volume coverage was comparable. For the other patients, the 4D calculation indicated a difference in target volume dose sufficiently great to warrant replanning. No correlations could be established between differences in 3D and 4D calculations and gross tumor volume size or extent of motion. Negligible differences were observed between 3D and 4D dose-volume relationships for normal anatomic structures. CONCLUSIONS: Use of 4D dose calculations, when possible, helps ensure that target volumes will not be underirradiated when respiratory motion may affect the dose distribution.

Consequences of anatomic changes and respiratory motion on radiation dose distributions in conformal radiotherapy for locally advanced non-small-cell lung cancer.

PURPOSE: To determine the effect of interfractional changes in anatomy on the target and normal tissue dose distributions during course of radiotherapy in non-small-cell lung cancer patients. METHODS AND MATERIALS: Weekly respiration-correlated four-dimensional computed tomography scans were acquired for 10 patients. Original beam arrangements from conventional and inverse treatment plans were transferred into each of the weekly four-dimensional computed tomography data sets, and the dose distributions were recalculated. Dosimetric changes to the target volumes and relevant normal structures relative to the baseline treatment plans were analyzed by dose-volume histograms. RESULTS: The overall difference in the mean +/- standard deviation of the doses to 95% of the planning target volume and internal target volume between the initial and weekly treatment plans was -11.9% +/- 12.1% and -2.5% +/- 3.9%, respectively. The mean +/- standard deviation change in the internal target volume receiving 95% of the prescribed dose was -2.3% +/- 4.1%. The overall differences in the mean +/- standard deviation between the initial and weekly treatment plans was 3.1% +/- 6.8% for the total lung volume exceeding 20 Gy, 2.2% +/- 4.8% for mean total lung dose, and 34.3% +/- 43.0% for the spinal cord maximal dose. CONCLUSION: Serial four-dimensional computed tomography scans provided useful anatomic information and dosimetric changes during radiotherapy. Although the observed dosimetric variations were small, on average, the interfractional changes in tumor volume, mobility, and patient setup was sometimes associated with dramatic dosimetric consequences. Therefore, for locally advanced lung cancer patients, efforts to include image-guided treatment and to perform repeated imaging during the treatment course are recommended.

Utility of four-dimensional computed tomography for analysis of intrafractional and interfractional variation in lung volumes.

PURPOSE: To assess the viability of four-dimensional (4D) computed tomography (CT) in describing intrafractional and interfractional changes in lung volumes and to determine which breathing phase, if any, produces the most highly reproducible lung volumes among fractions. METHODS AND MATERIALS: Weekly 4D CT scans were acquired for 13 patients with non-small-cell lung cancer during a course of radiotherapy. Contours delineating the right lung, left lung, and total lung were obtained by adapting library models of the anatomic structures to the CT images and propagating them to all 10 respiratory phases represented in the 4D CT image data set. Lung volumes were calculated using software tools in a commercial radiation treatment-planning system and analyzed for interfractional volume reproducibility using t tests and for phase reproducibility using a phase-dependent uncertainty curve across all patients. Probability (p) values of <0.05 were considered to indicate significant differences in all comparisons. RESULTS: The average mean coefficient of variation of tidal volume across all patients was 25.0%. The average standard deviation of tidal volumes was 5.7% relative to the lung volume at end-expiration. Total volumes measured at the 30% phase were 15% more consistent than those measured at end-inspiration (p = 0.03). CONCLUSIONS: Four-dimensional CT assesses lung volume with acceptable precision; but the technique was unable to accurately predict interfractional changes in lung volume because wide variations in intra- and interfractional breathing cause high uncertainties in 4D CT data acquisition. The most reproducible breathing phase seems to be at the 30-40% phase (just before end-expiration).

Determination of an optimal organ set to implement deformations to support four-dimensional dose calculations in radiation therapy planning.

Surface-based deformable image registration to generate a four-dimensional (4D) dose calculation in radiation treatment planning requires the selection of a set of organ contours to represent a basis set to generate anatomic deformation. The purpose of the present work was to determine the optimal set of organs needed to generate a basis set for deformation in treatment planning for thoracic tumors such that the required computations are minimized but dose accuracy is high. Using retrospectively reviewed records, we calculated 4D dose distributions based on treatment plans for 10 patients with thoracic tumors using a deformable model algorithm in a research version of a commercial radiation treatment planning system. Various combinations of organs (total lungs, heart, spinal cord, external body surface) were used to generate the basis set for deformations used in the calculations. The external surface contour did not have a noticeable effect on the dose calculation. Total lung, heart, and spinal cord together provided an adequate set of deformation organs to generate accurate dose deformations. The magnitude of calculated dose differences had no obvious relationship to tumor parameters, including site, histologic type, disease stage, extent of motion, or degree of centralization.

International Scientific Committee of Radionuclides in Nephrourology (ISCORN) consensus on renal transit time measurements.

This report is the conclusion of the international consensus committee on renal transit time (subcommittee of the International Scientific Committee of Radionuclides in Nephrourology) and provides recommendations on measurement, normal values, and analysis of clinical utility. Transit time is the time that a tracer remains within the kidney or within a part of the kidney (eg, parenchymal transit time). It can be obtained from a dynamic renogram and a vascular input acquired in standardized conditions by a deconvolution process. Alternatively to transit time measurement, simpler indices were proposed, such as time of maximum, normalized residual activity or renal output efficiency. Transit time has been mainly used in urinary obstruction, renal artery stenosis, or renovascular hypertension and renal transplant. Despite a large amount of published data on obstruction, only the value of normal transit is established. The value of delayed transit remains controversial, probably due to lack of a gold standard for obstruction. Transit time measurements are useful to diagnose renovascular hypertension, as are some of the simpler indices. The committee recommends further collaborative trials.

A phase II study on stereotactic body radiotherapy for stage I non-small cell lung cancer.

BACKGROUND AND PURPOSE: The outcome of stage I non-small cell lung cancer (NSCLC) patients treated with conventional radiotherapy is inferior to that of patients treated surgically. We aimed to evaluate the clinical outcome of stereotactic body radiotherapy (SBRT) in the treatment of stage I NSCLC. MATERIALS AND METHODS: We performed SBRT for 31 stage I NSCLC patients. Of these, 20 were medically inoperable, and 11 refused surgery. Nineteen tumours were T1-stage masses, and 12 tumours were T2. Median tumour size was 25 mm. SBRT was administered as 45 Gy/3 fractions; however, when the tumour was close to an organ at risk, 60 Gy/8 fractions were used. These doses were prescribed at the centre of the tumours. RESULTS: The median duration of observation for all patients was 32 months (range, 4-87 months). In 9 of the 31 cases, local recurrence was observed. The 3-year local control rates of T1 and T2 tumours were 77.9% and 40.0%, respectively. The 3-year overall and cause-specific survival rates were 71.7% and 83.5%, respectively. Although the symptoms improved with medical treatment, 5 patients developed acute pulmonary toxicity > or =grade 2. CONCLUSIONS: SBRT is safe and effective for stage I NSCLC patients. However, a more intensive treatment regimen should be considered for T2 tumours.

Assessment of gross tumor volume regression and motion changes during radiotherapy for non-small-cell lung cancer as measured by four-dimensional computed tomography.

PURPOSE: To investigate the magnitudes of the changes in mobility and volume of locally advanced non-small-cell lung cancer (NSCLC) tumors during radiotherapy, using four-dimensional computed tomography (4DCT). METHODS AND MATERIALS: Five to ten 4DCT data sets were acquired weekly for each of 8 patients throughout treatment. Gross tumor volumes (GTVs) were outlined on each data set. Volumes and coordinates of the GTV centroids were calculated at the 0 (end-inspiration) and 50% (end-expiration) respiration phases. Trends in magnitudes of intrafraction and interfraction positional variations were assessed for the GTV and internal target volume (ITV) during treatment. RESULTS: Tumor volume reduction ranged from 20% to 71% (end-inspiration) and from 15% to 70% (end-expiration). Increased tumor mobility was observed in the superior-inferior and anterior-posterior directions. However, no trends in tumor motion were observed. Motion along the superior-inferior direction was significantly greater (p < 0.001), with mean +/- SD values of 0.86 +/- 0.19 cm, as compared with 0.39 +/- 0.08 cm and 0.19 +/- 0.05 cm in the anterior-posterior and right-left directions, respectively. A marginally significant (p = 0.049) increase in total GTV positional variation was observed with increasing treatment weeks, and similar results were seen for the interfractional ITV mobility. CONCLUSIONS: Because of changes in tumor size and mobility, an explicit initial determination of the ITV may not be sufficient, especially where small setup margins are used. Repeat 4DCT scans might be warranted for highly mobile tumors to reduce the potential for missing the tumor.

The management of differentiated thyroid cancer using 123I for imaging to assess the need for 131I therapy.

BACKGROUND: Follow-up of 131I whole-body scanning after 131I ablation is associated with potential stunning. Previous studies have suggested that, for scanning, 123I is more sensitive than 131I in identifying thyroid tissue, but its specificity when positive is less certain. AIM: The use of 123I as an imaging agent in place of serial 131I imaging has been evaluated in the surveillance and treatment of differentiated thyroid carcinoma. RESULTS: A total of 186 studies in 136 patients with differentiated thyroid carcinoma were evaluated after total or near total thyroidectomy followed by 131I ablation. In 125 studies 123I scanning was negative and no 131I therapy was given; four patients were positive on 123I scanning but for other reasons no 131I therapy was given. In 48/49 patients a positive 123I scan was followed by positive 131I therapeutic uptake. Only one patient failed to show positive uptake of I when first treated and she subsequently demonstrated uptake on a second therapy. CONCLUSION: High-dose 123I imaging is the correct predictor of the 131I post-therapy scan findings in most cases, at an administered activity that avoids stunning. As a diagnostic agent it is preferable to 131I in differentiated thyroid carcinoma.

The prospective clinical and scintigraphic assessment of patients with preserved left ventricular systolic function after transmyocardial laser revascularisation.

AIM: To analyse the clinical outcome and myocardial perfusion and function after transmyocardial revascularisation (TMR) in patients with normal left ventricular function and multivessel coronary artery disease non-amenable for standard revascularisation. METHOD AND RESULTS: Twenty three severely symptomatic patients (CCS score median 4) with normal left ventricular systolic function but coronaries non-amenable for either PTCA or CABG were subjected to TMR. The angina score, left ventricular systolic and diastolic function in radionuclide ventriculography at rest, exercise tolerance and myocardial perfusion--Thallium-201 SPECT (adenosine stress 74 and 37 MBq under nitrate cover) were evaluated before and 3, 6, 12 months post-operatively. After an average of 40 +/- 12 (range 14-56) TMR channels angina score decreased significantly (p< 0.0001) and the exercise tolerance increased (from 6.0 +/- 4.5 to 9.1 +/- 4.6 after 6 months, p< 0.05) in 21 patients. During the follow up period two patients had a myocardial infarction and one committed suicide after 6 months. Ejection fraction dropped significantly only after 1 year post-TMR from 70 +/- 13 to 63 +/- 0.13%, p < 0.05. The overall perfusion improved initially in 14 patients with subsequent deterioration in time. The changes in segmental perfusion were not associated with the symptomatic improvement. CONCLUSION: Transmyocardial revascularisation in patients with normal ejection fraction may improve the angina class, exercise tolerance and overall but not segmental perfusion and does not show any immediate effect on left ventricular function.

Imaging with radiolabelled monoclonal antibody (MUJ591) to prostate-specific membrane antigen in staging of clinically localized prostatic carcinoma: comparison with clinical, surgical and histological staging.

OBJECTIVE: To evaluate the reliability of prostate scintigraphy using a radiolabelled antibody (MUJ591) raised against the external domain of prostate-specific membrane antigen (PSMA) in the staging of early prostate cancer. PATIENTS AND METHODS: This was a prospective study of 16 patients who had radical retropubic prostatectomies (median PSA 9.75 ng/mL). All patients underwent PSMA imaging using MUJ591 radiolabelled with (99m)Tc using a photo-reduction technique. RESULTS: The findings of prostate imaging and histology were identical in seven patients. Scans showed understaging and overstaging in six and three patients, respectively. CONCLUSIONS: PSMA scintigraphy using (99m)Tc-labelled MUJ591 identifies the presence of prostate cancer, but is not sensitive in delineating micro-invasion of the capsule, seminal vesicles or bladder neck. As in other studies it seems to be useful in detecting prostate bed recurrence and distant micrometastasis.

Evaluation of inter- and intrafraction organ motion during intensity modulated radiation therapy (IMRT) for localized prostate cancer measured by a newly developed on-board image-guided system.

PURPOSE: To investigate prostatic organ motion at both setup and intrafraction using an onboard image-guided system. An intrafraction field-based repositioning method also was evaluated. MATERIALS AND METHODS: A dual fluoroscopy with amorphous-silicon flat panel (DFFP) system was used for the three-dimensional registration of implanted markers in the prostate of eight organ-confined cancer patients planned for treatment with intensity modulated radiation therapy (IMRT). Day-to-day motion errors were quantified and intrafraction displacements of more than +/-1 mm were corrected. RESULTS: Among 214 fractions and 565 system views, day-to-day mean magnitude of marker discrepancy +/- standard deviation (SD) was 1.76 +/- 1.4 mm, 3.14 +/- 1.6 mm, and 3.78 +/- 2.4 mm in the right-left, cranial-caudal, and anterior-posterior directions, respectively. The intrafractional mean magnitude +/- SD of marker displacement was 0.45 +/- 0.7 mm, 1.08 +/- 1.38 mm and 1.45 +/- 1.70 mm in the right-left, cranial-caudal, and anterior-posterior directions, respectively. Intrafraction corrected sessions (84/214) showed a median (range) of motion of 0.1 mm (-1.2 to 0.7 mm), -0.2 mm (-2.1 to 1.1 mm), and -0.2 mm (-1.7 to 2.0 mm) in the right-left, cranial-caudal, and anterior-posterior directions, respectively. CONCLUSION: Motion uncertainty can be considerably decreased with daily use of the DFFP system. Reduced intrafraction organ motion clearly endorsed the value of the repositioning approach, allowing a safer dose escalation protocol.

Elimination of the influence of total renal function on renal output efficiency and normalized residual activity.

UNLABELLED: One of the potential limitations in the usefulness of both renal output efficiency (ROE) and normalized residual activity (NORA) is their residual dependence on total renal function. The purpose of this study was to present and examine a new quantitative method whereby the effects of this dependence may be removed. METHODS: The analytic method involves the determination of a retention function using an unconstrained matrix algorithm deconvolution technique followed by reconvolution with a chosen standard input function to yield a new secondary renal activity time (A/T) curve from which normalized values of ROE and NORA, denoted as N_ROE and N_NORA, respectively, can then be obtained using conventional definitions. The method has been applied in a series of 50 patient studies, which had been acquired using (99m)Tc-mercaptoacetyltriglycine (99(m)Tc-MAG3) and a standard F+18 furosemide protocol, with values of the ratio of plasma clearance to plasma volume (C/V) in the range 0.013-0.242 min(-1). RESULTS: Pre- and postnormalization values of NORA, calculated at 30 min after injection, showed a significant difference in mean values (paired t test; P < 0.001), with a maximum observed difference, DeltaNORA(30), of -4.82 (-482%) and with a SD on the paired differences, DeltaNORA(30), of 0.56 (56%) or 0.63 (63%) if background subtraction on the input function (BSIF) had been performed. In contrast, corresponding values of ROE showed a nonsignificant difference in means (P > 0.05) and a SD on the paired differences, DeltaROE(30), of 3.7% or 3.2% with and without BSIF, respectively. The normalized parameters N_ROE and N_NORA were found to be strongly linearly correlated (r = -0.99; P < 0.001), in agreement with theoretical predictions. CONCLUSION: These results suggest that renal function affects NORA significantly more than ROE. The effects can be corrected by our normalization technique, resulting in equivalent values of normalized ROE and normalized NORA.