Contrast-enhanced Ultrasound as a Screening Tool for Kidney Cancer in Patients With Von-Hippel Lindau

Study Overview
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Brief Summary
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The purpose of this study is to determine if contrast-enhanced ultrasound can detect abnormal features of kidney lesions in patients with Von-Hippel Lindau with the same accuracy as conventional ultrasound and contrast-enhanced magnetic resonance imaging (MRI)

Detailed Description
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This is a pilot cross-sectional study that compares contrast enhanced ultrasound to conventional ultrasound and contrasted MRI. Any patient undergoing annual imaging screening is eligible, but the investigators will target inclusion of at least 10 subjects who have at least 1 kidney lesion. Therefore, up to 5 subjects may have no current kidney lesions. Subject participation will be only for the day of CEUS study. There will be no follow-up period for this study. However, if results are encouraging, a longitudinal observational study may follow, and these same subjects would be eligible for enrollment. Eligible subjects will undergo a contrast enhanced ultrasound. Following completion of imaging, all CEUS, MRI (within 4 months) and B-mode (at time of CEUS) US studies will be de-identified. Blinded radiologists will interpret images and provide an overall assessment of risk of malignancy to each kidney using the Bosniak criteria for each kidney lesion present. The Bosniak criteria places cystic lesions into one of 5 categories (I, II, IIF, III and IV) based on lesion characteristics. CEUS based diagnosis will be compared to the diagnoses on routine B-mode US and contrast-enhanced MRI.

Official Title
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Double-Center Cross-Sectional Study of Contrast-Enhanced Ultrasound With Lumason/Definity as a Screening Tool for Kidney Cancer in Patients With Von-Hippel Lindau

Conditions
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Von-Hippel Lindau, Kidney Disease, Chronic

Intervention / Treatment
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* Drug: Perflutren lipid microsphere
* Drug: Sulfur hexafluoride lipid microspheres


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for the present study, patients must meet the following criteria: Able to provide written informed consent Willing to comply with protocol requirements At least 16 years of age Carry a diagnosis of VHL and able to undergo routine clinical screening tests for RCC Exclusion Criteria: Critically ill or medically unstable or in an intensive care setting and whose critical course during the observation period would be unpredictable Known hypersensitivity to sulfur hexafluoride or to any component of perflutren lipid (Definity®) or sulfur hexafluoride (Lumason®) Right to left shunt, severe pulmonary hypertension (Pulmonary artery pressure >90mmHg), or adult respiratory distress syndrome Active cardiac disease including any of the following: A. Severe congestive heart failure (class IV in accordance with the classification of the New York Heart Association) B.Unstable angina. C.Symptomatic arrhythmia (i.e. tachycardia, bradycardia, supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia, atrial flutter or fibrillation). D.Myocardial infarction within 14 days prior to the date of proposed microbubble administration. Has any other medical condition or other circumstances that would significantly decrease the chances of obtaining reliable data or of achieving the study objectives such as: Mental illness Drug abuse Female patient who is pregnant or lactating Obesity that limits obtainment of acceptable images

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Perflutren Lipid Microsphere or Lumason<br>Patients with Von-Hippel Lindau disease will be imaged using contrast-enhanced ultrasound with either perflutren or Lumason. | Drug: Perflutren lipid microsphere<br>* Baseline B-mode US will be performed to confirm the lesions being imaged (unless it is a subject with no lesions, then a basic B-mode US will be performed. Perflutren is a diagnostic drug that is intended to be used for contrast enhancement. The vial contains a clear, colorless, sterile, non-pyrogenic, hypertonic solution which is activated by mechanical agitation with Vialmix®.It will be dispensed in inactivated form to a study team member. The contrast agent will be activated just prior to administration (ideally to be used within 5 minutes of activation). Contrast agent Definity (or Lumason) will be activated according to package insert instructions, including use of VialMix®, the device used to activate Definity. Administration will occur IV in coordination with sonography staff trained specifically in contrast ultrasound imaging.The total imaging time is anticipated to be less than 30 minutes.<br>* Other names: • Microbubble contrast agent;Drug: Sulfur hexafluoride lipid microspheres<br>* Baseline B-mode US will be performed to confirm the lesions being imaged (unless it is a subject with no lesions, then a basic B-mode US will be performed. Lumason will be used as a secondary contrast agent only if Definity(perflutren) is unavailable.This drug will be administered using the dosing range and administration type within the Lumason prescribing information. The contrast agent will be activated just prior to administration (ideally to be used within 5 minutes of activation). Contrast agent Definity (or Lumason) will be activated according to package insert instructions, including use of VialMix®, the device used to activate Definity. Administration will occur IV in coordination with sonography staff trained specifically in contrast ultrasound imaging.The total imaging time is anticipated to be less than 30 minutes.<br>* Other names: Lumason;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Radiologist's Lesion Evaluation compared to B-mode Ultrasound (percent) | Kappas will be calculated separately for each reader for CEUS versus B-mode US using the dichotomized Bosniak score. Confidence intervals for kappas will be computed by bootstrapping subjects, accounting for potential correlations of kidneys within subjects. Differences in agreement between readers will be based on comparing reader specific kappas, with statistical significance of these differences tested via bootstrapping. An overall kappa will be computed for each paired imaging comparison by averaging kappas across readers, with a 95% interval calculated via bootstrapping. Differences in overall kappas for the 3 paired imaging comparisons will be assessed using a bootstrap test. | (Baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Radiologist's Lesion Evaluation compared to contrasted MRI (percent) | Kappas will be calculated separately for each reader for CEUS versus contrasted MRI using the dichotomized Bosniak score. Confidence intervals for kappas will be computed by bootstrapping subjects, accounting for potential correlations of kidneys within subjects. Differences in agreement between readers will be based on comparing reader specific kappas, with statistical significance of these differences tested via bootstrapping. An overall kappa will be computed for each paired imaging comparison by averaging kappas across readers, with a 95% interval calculated via bootstrapping. Differences in overall kappas for the 3 paired imaging comparisons will be assessed using a bootstrap test. | (Baseline, 4 months) |