PET Assessment of Acute Lung Transplant Rejection

Study Overview
=================
Brief Summary
-----------------
The purpose of this research study is to gain understanding of the basic responses of the lungs to inflammation and specifically if there may be a better way to detect graft inflammation using non-invasive methods as well as to determine the effectiveness of immunosuppressive treatment regimens in preventing acute rejection in lung transplant recipients.

Detailed Description
-----------------
Positron emission tomography with fluorodeoxyglucose (FDG-PET) is a potential way we can measure lung inflammation. FDG-PET imaging is a clinically accepted and FDA-approved method that is commonly used in the diagnosis and management of cancer. PET is a machine that detects radiation and generates pictures using a donut shaped scanner similar in appearance to an x-ray CAT computerized axial tomography or computed tomography (CT) scan. FDG stands for [18F] (flourine 18) fluorodeoxyglucose, a radiolabeled sugar that is used to identify areas of inflammation with the PET scanner. A CT scan takes a picture of what the lungs and airways look like. T cells are the primary cause of acute rejection of lung transplants. Because T cells must divide in order to be activated and cause rejection, imaging them while they are dividing is another way that we can determine whether acute rejection is occurring. A new PET tracer called [18F]ISO-1 (18F-labeled σ2-receptor ligand for PET, N-(4-(6,7-dimethoxy-3,-4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-18F-fluoroethoxy)-5-methylbenzamide (18F-3c), binds to dividing cells. Therefore, [18F]ISO-1 may help us measure acute rejection more accurately. [18F]ISO-1 is an investigational drug.

Official Title
-----------------
Positron Emission Tomography Assessment of Acute Lung Transplant Rejection

Conditions
-----------------
Lung Disease

Intervention / Treatment
-----------------
* Drug: [18F]FDG
* Drug: [18F]ISO-1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Double-lung transplant recipient Scheduled for bronchoscopy with transbronchial biopsy Capable of lying still and supine with arms raised above the head within the PET/CT scanner for  1.25 hours Capable of following instructions for breathing protocol during CT portion of PET/CT Able and willing to give informed consent BMI < 35 Already scheduled to undergo bronchoscopy with bronchoalveolar lavage (BAL) for clinical reasons Willing to donate a portion of BAL and biopsy specimen for laboratory testing Exclusion Criteria: Glucose level > 150 mg/dl at time of [18F]FDG PET scan (however, up to 160 mg/dl, with repeat testing showing level is stable or decreasing, is acceptable) Pregnancy (confirmed by qualitative urine human chorionic gonadotropin (hCG) pregnancy test) Lactation Presence of implanted electronic medical device Enrollment in another research study of an investigational drug Inability to lie flat with arms raised above the head for 1.5 hours for PET/CT scans or follow breathing protocol instructions for the CT portion of the PET/CT

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Grade A0<br>Double-lung transplant recipients with no evidence of rejection who undergo both [18F]FDG and [18F]ISO-1 PET imaging scans | Drug: [18F]FDG<br>* 10 millicuries (mCi) of [18F]FDG will be injected intravenously at the start of a 60-minute dynamic PET scan acquisition<br>* Other names: fluorodeoxyglucose;Drug: [18F]ISO-1<br>* 8 mCi of [18F]ISO-1 will be injected intravenously at the start of a 60-minute dynamic PET scan acquisition<br>* Other names: F-18 labeled proliferation tracer targeting PGRMC1;|
| Grades A2-3<br>Double-lung transplant recipients with mild to moderate rejection who undergo both [18F]FDG and [18F]ISO-1 PET imaging scans | Drug: [18F]FDG<br>* 10 millicuries (mCi) of [18F]FDG will be injected intravenously at the start of a 60-minute dynamic PET scan acquisition<br>* Other names: fluorodeoxyglucose;Drug: [18F]ISO-1<br>* 8 mCi of [18F]ISO-1 will be injected intravenously at the start of a 60-minute dynamic PET scan acquisition<br>* Other names: F-18 labeled proliferation tracer targeting PGRMC1;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ki, the influx constant that describes the rate of [18F]FDG uptake, in the whole lung |  | This outcome measure is assessed from the [18F]FDG scan performed on Day 1. | 
| Logan plot analysis determined distribution volume ratio (DVR) of [18F] ISO-1 uptake |  | This outcome measure is assessed from the [18F]ISO-1 PET scan performed on Day 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progesterone receptor membrane component 1 (PGRMC1) staining of biopsy tissues and bronchoalveolar lavage cells | The biopsy specimens will be stained for proliferation markers. The bronchoalveolar lavage cells will be assessed for glucose uptake with 2-NBDG ( fluorescent glucose analog that has been used to monitor glucose uptake in live cells, as an indicator of cell viability). | Assessed after the baseline clinical bronchoscopy procedure is performed 3 days prior to FDG PET/CT scan | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
[18F] fluorodeoxyglucose, [18F] ISO-1, acute lung transplant rejection, neutrophilic lung inflammation, positron emission tomography imaging