Radiogenomics of Muscle Invasive Bladder Cancer
Phase: NA
Conditions: Bladder Cancer Stage II
Sponsor: Cedars-Sinai Medical Center

IIT2020-22-Rosser-Radiogenomics 
Page 1 of 24 
 
 
Clinical Research Protocol 
 
Study Title:  Radiogenomics of muscle invasive bladder cancer 
 
Protocol Number: 
IIT2020-22-Rosser-Radiogenomics 
Current Version Number: 
1.2 
Current Version Date: 
12 July 2022 
Investigational Product:
N/A
IDE Number: 
N/A 
NCT Number:
NCT04806334
Development Phase: 
Pilot 
Funding Organization: 
Cedars-Sinai 
Principal Investigator: 
Name: Charles J. Rosser, MD, MBA  
Telephone: 310-423-0622 
Fax: 310-423-1988 
 
 
E-mail:  Charles.rosser@cshs.org 
 
Clinical Site: 
Cedars Sinai Medical Center 
8700 Beverly Blvd 
Los Angeles, CA 90048 
 
 
 

IIT2020-22-Rosser-Radiogenomics 
Page 2 of 24 
 
TABLE OF CONTENTS  
 
PROTOCOL SUMMARY ....................................................................................................................... 3 
1.0 BACKGROUND, RATIONALE ....................................................................................................... 4 
2.0 STUDY OBJECTIVES ...................................................................................................................... 6 
3.0 STUDY POPULATION .................................................................................................................... 6 
 
3.1 SELECTION OF THE STUDY POPULATION .................................................................... 6 
 
3.2 INCLUSION CRITERIA ........................................................................................................ 7 
 
3.3 SUBJECT SCREENING AND ENROLLMENT ................................................................... 8 
4.0 STUDY DESIGN AND METHODS ................................................................................................. 8 
5.0 CLINICAL ASSESSMENT………………………………………………………………………..10 
6.0 ADVERSE EVENT REPORTING AND 
DOCUMENTATION………………………………………………………………………………….11
7.0 DISCONTINUATION AND REPLACEMENT OF SUBJECTS………………………………....15 
8.0 SCHEDULE OF 
PROCEDURES……………………………………………………………………………………..…16 
9.0 DATA COLLECTION AND MANAGEMENT ........................................................................... 117 
10.0 DATA AND SAFETY MONITORING ...................................................................................... 118 
11.0 STATISTICAL CONSIDERATIONS ......................................................................................... 119 
12.0 REFERENCES............................................................................................................................... 20 
 
 

IIT2020-22-Rosser-Radiogenomics 
Page 3 of 24 
 
PROTOCOL SUMMARY  
Title: 
Radiogenomics of muscle invasive bladder cancer 
Protocol number: 
IIT2020-22-Rosser-Radiogenomics 
Phase: 
Pilot 
Study Design: 
Single center clinical trial evaluating identifying a distinct 
radiogenomic signature of muscle invasive bladder cancer (MIBC) 
 
Study Duration: 
84 weeks 
Objective: 
Primary Objective:  
To show feasibility, which we will define as know-how to create a 
radiogenomic workflow and to learn about the correlation structure 
between the radiomic and genomic parameters of interest, which will 
allow us to design future studies with adequate power. 
Number of subjects: 
20 subjects 
Main Inclusion 
criteria: 
Adults with sessile bladder masses, suspected of harboring MIBC  
Study product, dose, 
route of 
administration: 
N/A 
Statistical Analysis: 
 
We will apply a deconvolution algorithm to the genomic data from 
patients with MIBC in conjunction with magnetic resonance imaging 
(MRI) data to search for genomic and radiomic parameters that predict 
tumor stage and outcomes. 
 
 
 

IIT2020-22-Rosser-Radiogenomics 
Page 4 of 24 
 
1.0 BACKGROUND, RATIONALE  
In the US, radical cystectomy is the treatment of choice of muscle invasive bladder cancer (MIBC). 
MIBC comprises approximately 1/3 of bladder cancer (BCa) and is associated with significant 
morbidity and mortality. Accurate staging of BCa is essential to identifying the optimal treatment. 
Current NCCN guidelines recommend contrast-enhanced CT of the abdomen and pelvis to assess 
the local extent of the cancer, including regional lymph nodal. However, 1/3 of patients are 
understaged, while 1/3 of patients are overstaged with CT imaging (1). Thus, more accurate non-
invasive staging modality is necessary, which could improve medical decision making between 
various treatments (e.g., radical cystectomy vs. bladder preservation).  
 
Radiomics 
Multiparametric magnetic resonance imaging (mpMRI) is emerging as the imaging modality of 
choice in tumor staging, with a reported sensitivity of 90% in detecting BCa and 76% sensitivity 
with 89% specificity of detecting metastatic lymph nodes (2). The superior soft tissue contrast and 
versatile imaging sequences of MRI can facilitate margin definitions critical in cystectomy and 
bladder preservation strategies. In addition, 4D-MRI techniques have provided high isotropic 
resolution that was previously unachievable with standard MRI (3-5). With these images, 
extensive quantitative imaging metrics can be collected. Recently, radiomics, defined as the high-
throughput extraction of quantitative imaging metrics, has emerged as a potential diagnostic, 
capable of assessing the tumor’s aggressiveness and extent. Thus, 4D-mpMRI offers an 
opportunity to reduce staging errors through better anatomical visualization (6, 7) compared to 
traditional CT imaging (8, 9).  
 
Genomics 
Genomics has long been the mechanism of assessing a tumor’s clinical characteristics. With the 
advent of early versions of gene expression profiling and RNA sequencing, there has been a large 
amount of data available for assessing tumor morphology, molecular structure, and behavior. 
Furthermore, TCGA has reported clustering of mRNA expression converged into distinct subsets 
with differential epithelial-mesenchymal transition status (e.g., basal, luminal and 
neuroendocrine), which have been linked to outcomes and survival (10). While we may have more 
knowledge and understanding of BCa, a different approach to query its molecular underpinning is 
warranted in hopes of identifying clinically useful biomarkers to guide medical decision making.  
A previous study using single cell RNA sequencing (scRNA-seq) demonstrated 
transcriptional heterogeneity of BCa (11), suggesting that the traditional bulk RNA sequencing 
(RNA-seq), similar to what is in TCGA, may have limitations in BCa. In particular, scRNA-seq 
of BCa revealed an interesting transcriptome, a platinum resistance gene, COX7B, and its 
surrogate marker, CD63, which was previously not identified (12). Consequently, employing 
scRNA-seq of MIBC, we have identified unique gene clusters including but not limited to EGFR, 
NRG1, NRXN1, PTPRC, VWF, COL6A2, CD247, and ITGAX (unpublished data). Thus, we 
believe scRNA-seq hold a key to not only better analyze tumors for genetic defects, but to identify 
key cell lines within the tumor microenvironment.  
 
Radiogenomics 
Radiogenomics is a relatively new area of research, emerging because of the ability to associate 
radiologic imaging data to genomics data from tumors to garner a better tumor phenotype and 
predict clinical outcomes (13). Results from these radiogenomic studies have reported a strong 

IIT2020-22-Rosser-Radiogenomics 
Page 5 of 24 
 
association between radiologic parameters and genomic features, e.g., DNA mutations, mRNA 
expression, and copy number variations. Imaging parameters with strong associations to genomic 
data may serve as reliable markers for tumor diagnosis (i.e., staging), prognosis and treatment 
response. In addition, integrating radiogenomic data may a) allow the exploration of molecular 
interconnections that explain various tumor features captured by the radiologic parameters and b) 
validate the mechanistic pathways supporting such interconnections, and thereby, allowing us to 
gain a deeper understanding of the cancer and its pathophysiology.  
The Cancer Genome Atlas (TCGA) is a large publicly available genomic database of 
various human tumors. Akin to TCGA is The Cancer Imaging Archive (TCIA), a publicly 
available radiomic database of various human tumors. There are many tumors within TCGA and 
TCIA with both genomic and radiomic data. For example, Zhu et al. integrated multi-omics 
molecular data with magnetic resonance imaging (MRI) data from 91 invasive breast cancers and 
reported miRNA expression was associated with tumor size and tumor enhancement texture on 
imaging (14). Furthermore, Vargas et al. evaluated radiogenomic data from 92 high-grade serous 
ovarian adenocarcinomas and noted a significant association between mRNA expression, miRNA 
expression, promoter methylation and DNA copy number data with CT-based characteristics of 
primary ovarian masses, including size, presence of definable mesenteric implants and infiltration, 
etc. (15). Lastly, Karlo et al. reported the radiogenomic results of 233 clear cell renal cell 
carcinoma cases, which revealed VHL was associated with ill-defined tumor margins, nodular 
tumor enhancement and gross appearance of intratumoral vascularity (16).    
Interestingly, when conducting a PubMed literature search for radiogenomic and BCa, only 
one article is noted. In this study, Lin et al. report the results of bulk RNA-seq, radiomics features 
and clinical parameters of 62 BCa patients and found that the radiomics and transcriptomics 
signatures significantly stratified patients into high- and low-risk groups in terms of the 
progression-free survival (PFS) (17). 
 
Current trends in bladder cancer 
The landscape for BCa treatment options have changed dramatically over the past 5 years with the 
approval of five checkpoint inhibitors as well as Erdafitinib and Enfortumab. For MIBC, more 
attention is turning towards bladder preservation (BP). Despite improvements in systemic therapy 
options and radiation therapy technology (e.g., image guide radiation therapy (IGRT), intensity 
modulated radiation therapy (IMRT), the optimal outcomes (i.e., maintaining one’s bladder, good 
quality of life and overall survival; a.k.a. ‘trifecta’) is still elusive. There are several factors which 
may contribute to the inability to obtain this ‘trifecta’; including inadequate staging and inability 
to predict who would respond favorably to radiation therapy. Thus, a more thoughtful, phased 
approach to BP strategies need to develop and evolve in order to improve long-term outcomes for 
the growing need of patients who are ineligible for cisplatin based neoadjuvant chemotherapy 
and/or are either refusing or ineligible for radical cystectomy.  
In particular, 5-year OS for MIBC remains poor at 50% (18). However, a patient’s quality 
of life could be negatively affected by radical cystectomy (19), thus the continued intrigue with 
BP. Multiple BP options exist, although the approach of maximal transurethral resection of bladder 
tumor (TURBT) performed along with chemoradiation therapy (CRT) is the most favored (20, 21). 
BP strategies need to develop and evolve if they are to address issues related to OS. Specifically, 
improved modalities to stage patients with MIBC are needed to ensure we are identifying the 
optimal patient for BP. With this said, Cedars-Sinai Cancer (CS Cancer) has identified BP 
strategies as a major initiative from which to begin to develop a BCa center of excellence.   

IIT2020-22-Rosser-Radiogenomics 
Page 6 of 24 
 
We aim to build upon the current knowledge by correlating radiomics findings with that of 
genetic signature in order to identify a radiogenomic profile of MIBC which could be used to 
accurately stage patients (Fig. 1) leading to better medical decision making as it relates to BP 
techniques. Our central hypothesis is that a radiogenomic profile exists that a) is specifically 
associated with BCa and b) can be utilized to more effectively and accurately stage BCa. We seek 
to develop a computational algorithm that predicts, from radiographic imaging data and genetic 
alterations from RNA-seq data of a tumors, the relative proportions of predefined cancer cell 
populations, which lends to aggressiveness and BCa extent. To begin to test this hypothesis, we 
propose to conduct a pilot study of integrating radiomics data with genomics data in patients with 
localized MIBC and correlating to final pathology at the time of radical cystectomy. By improving 
our ability to better stage patients with MIBC, this work could facilitate future studies to explore 
a radiogenomic signature associated with MIBC and improve patient outcomes. 
 
2.0 STUDY OBJECTIVES  
To show feasibility, which we will define as know-how to create a radiogenomic workflow and 
to learn about the correlation structure between the radiomic and genomic parameters of interest, 
which will allow us to design future studies with adequate power. 
 
3.0 STUDY POPULATION  
 
3.1 SELECTION OF THE STUDY POPULATION 
The study will accrue patients with sessile appearing bladder masses who are felt by the treating 
physician to harbor MIBC.  

IIT2020-22-Rosser-Radiogenomics 
Page 7 of 24 
 
Prior to TURBT at Cedars-Sinai, ALL subjects will undergo axial imaging for clinical staging in 
the form of contrast enhanced MRI of the abdomen and pelvis (standard of care). The pelvic 
MRI will be multiparametric (mp)-4D MRI incorporating high resolution diffusion weighted 
imaging (HR-DWI). Both the abdominal and pelvic MRI will have an official intrepretation by a 
radiologist, thus both can be used in the care of the subject. Next, ALL subjects will undergo 
TURBT at which time, voided urine, blood and fresh frozen bladder tumor will be collected.  
 
Many subjects present to Cedars-Sinai after their transurethral resection of bladder tumor (TURBT) 
at an outside facility and a repeat TURBT is not planned at Cedars-Sinai. Such subjects will 
undergo axial imaging for clinical staging in the form of contrast enhanced MRI of the abdomen 
and pelvis (standard of care). The pelvic MRI will be multiparametric (mp)-4D MRI 
incorporating high resolution diffusion weighted imaging (HR-DWI). Both the abdominal and 
pelvic MRI will have an official interpretation by a radiologist, thus both can be used in the care 
of the subject. Next, ALL subjects will have their outside TURBT formalin fixed paraffin 
embedded (FFPE) requested, specifically 1 H&E slide and 10 unstained slides.  
 
Subsequently, those patients deemed to have muscle invasive, yet localized disease and are 
considered candidates for radical cystectomy by their treating physicians will proceed to radical 
cystectomy at which time another voided urine, blood and fresh frozen bladder tumor will be 
collected. Pathologic stage will be determined and reported on both the TURBT specimen and 
radical cystectomy specimen. Finally, subjects will be followed for 2 years to elicit outcome 
data.   
 
Inevitably, a portion of subjects with bladder masses who are suspected of harboring BCa will 
not have bladder cancer (10%), BCa diagnosed may not be MIBC (20%) and some subjects may 
not desire radical cystectomy for their MIBC (20%), thus we anticipate the need to enroll and 
image 20 subjects to get to our final study population of 10 MIBC who have undergone mp-4D 
MRI, TURBT and subsequent radical cystectomy.   
 
 
3.2 INCLUSION CRITERIA 
 
1. Patients must be > 18 years of age. 
 
2. Patient must have a sessile mass noted within the bladder on cystoscopy or imaging 
worrisome for bladder cancer, specifically MIBC.  
 
3. Patient must agree to undergo staging which will include mp-4D MRI HR-DWI of the 
pelvis in addition to standard axial imaging of the abdomen. 
 
4. Patient must have undergone TURBT or agree to undergo planned TURBT as part of the 
normal treatment course.  
 
5. Patients must not have known or suspected primary urothelial carcinoma of the ureter, 
urethra, or renal pelvis. 
 
6. Patients must not have known distant metastatic disease (e.g. pulmonary or hepatic 

IIT2020-22-Rosser-Radiogenomics 
Page 8 of 24 
 
metastases). Subjects with malignant lymphadenopathy in the abdomen or pelvis 
considered appropriate for radical cystectomy and lymphadenectomy with the goal of 
complete resection of all malignant disease are allowed.  
 
7. Patients must not have had prior definitive treatment for bladder cancer.  
 
8. Patients must not have clinically significant active infection or uncontrolled medical 
condition that would preclude participation in study. 
 
9. Patients must not have any active malignancy other than urothelial carcinoma of the 
bladder that, in the opinion of the treating investigator, which could interfere with 
protocol treatment. 
 
10. Patient must have adequate renal function: Serum creatinine < 2 mg/dL OR calculated 
CrCl > 30ml/min.  
 
11. Patients must not have allergy or contraindication for MRI contrast/contrast dye.  
 
12. Patients must not be under treatment with systemic immunosuppressive medications 
(including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to 
TURBT.  
 
13. Patient must not be adverse to undergo radical cystectomy as part of the normal treatment 
course if found to have MIBC.   
 
14. Patients must have the ability to understand and willingness to sign a written informed 
consent.  
 
3.3 EXCLUSION CRITERIA 
 
1. Persons with allergy to animal dander or animal-instigated asthma. 
 
2. Patient must not have undergone a bladder biopsy or limited (incomplete) TURBT within 
3 weeks (21 days) of the MRI.   
 
3.4 SUBJECT SCREENING AND ENROLLMENT 
Subjects will be recruited by investigators within the outpatient Urology Clinics at Cedars-Sinai 
Medical Center (CSMC).  Subjects will be evaluated by a clinical investigator for eligibility. The 
study rationale, and potential risks and benefits will be clearly explained; study investigators will 
obtain informed consents and enroll subjects. Only subjects who meet the inclusion/exclusion 
criteria will be enrolled. Enrolled subjects will be assigned a unique, non-identifying study 
subject ID number.  

IIT2020-22-Rosser-Radiogenomics 
Page 9 of 24 
 
 
4.0 STUDY DESIGN AND METHODS 
This is a single center non-randomized pilot clinical trial assessing radiogenomics in a cohort of 
subjects with MIBC recruited at CSMC.  
 
After signing informed consent, the subject will be scheduled for standard of care axial imaging 
of the abdomen and pelvis to include pelvic MRI imaging in the radiologic suite in Davis 
Building at CSMC.  
 
mp-4D pelvic MRI incorporating high resolution diffusion weighted imaging (HR-DWI)  
1. All imaging will be performed on a 3T clinical MR scanner (Biograph mMR, Siemens 
Medical Solutions, Erlangen, Germany) with a 32-channel phase array surface coil.  
2. During the imaging session, routine protocols including 3D T1W volumetric interpolated 
breath-hold examination (T1-VIBE) with Dixon fat saturation in axial orientation, multi-
slice T2W half-Fourier acquisition single-shot turbo spin-echo sequence (T2-HASTE) in 
axial and coronal orientations, and multi-slice single-shot echo-planar imaging (SS-EPI) 
DWI sequence will be first acquired for pancreas delineation and tumor definition.  
3. 2D Modified Look-Locker Inversion Recovery (MOLLI) sequence in oblique planes to 
cover as much PDAC tumor mass will be obtained as the reference for in-vivo T1 mapping.  
4.  Following these sequences, the Multitasking DCE 4D-MRI will be performed. The 
technique has been designed to cover the entire pelvis. Each SR period lasted 500 ms with 
84 TIs at TR 5.6 ms. One readout line will be collected per TI. The SR period will be 
repeated 1200 times in a scan of 10 min. The DCE temporal footprint was selected to be 1 
second by combining two SR periods to balance between the temporal resolution and noise 
(22).  
5. Gd contrast agent (Gadavist, 0.1 mmol/kg, Bayer Schering Pharma) will be administrated 
intravenously 2 minutes into the scan at a rate of 2 mL/s, followed by a 20 mL saline flush 
at the same rate. Immediately at the end of this sequence, post-contrast MOLLI at the same 
slice location as pre-contrast one will be collected. Detailed imaging parameters for the 
protocols are summarized in “Variables collected”.   
6. At the same time the pelvic MRI is being completed, the abdominal MRI can be performed.   
 
Next, subjects who have not had an outside TURBT will undergo TURBT in the operating room 
(mandatory). In pre-operative holding, a voided urine sample (50 mL) will be collected, while 
blood (15 mL in ACD-containing tube ) and fresh frozen tumor tissue will be collected in the 
operating room by the BioBank staff. The results of the evaluation of the TURBT will determine 
if the subject has bladder cancer and if so the histology, clinical stage and grade will be noted. If 
the subject is found not to have MIBC, then he/she would be off study. For the subjects who had 
an outside TURBT, tumor material from the TURBT will be requested from the local 
hospital/pathology, specifically, 1 H&E slide and 10 unstained slides will be requested.  
 
However if the subject is found to have MIBC and is deemed to be a candidate for definitive 
therapy by radical cystectomy without neoadjuvant chemotherapy or immunotherapy, then 
he/she will be scheduled for radical cystectomy within 4 weeks. At the time of radical 
cystectomy, additional voided urine (approximately 50 mL) will be collected in pre-operative 
holding and blood (15 mL in ACD-containing tube) and fresh frozen tumor tissue will be 

IIT2020-22-Rosser-Radiogenomics 
Page 10 of 24 
 
ciollected in the operating room by the Biobank staff. The results of the histological evaluation 
of the cystectomy specimen will be reported noting histological type of bladder cancer, 
pathologic stage and grade. 
 
Correlative studies  
Embedded within will be crucial correlative studies that will begin to shed light on MIBC in 
hopes of identifying a radio-molecular staging system, which is more accurate than the standard 
clinical staging.    
 
These studies will involve analyses of: 
(1) Peripheral blood specimen:  
An additional specimen of blood will be obtained beyond what is needed for clinical 
care. The amount of blood will be approximately 15 ml of extra blood collected 
from a vein into ACD-containing tubes. In the BioBank, the blood will separated 
by centrifugation into the plasma fraction and the blood cell fractions. The fractions 
will be divided into aliquots for measurements which will be done either at the time 
of the blood sample acquisition or at a designated time later on stored specimens. 
Storage will be at -800 C in a secure biorepository freezer in CSMC BioBank. 
(2) Biofluid Specimens (Urine):   
Urine sample(s) will be obtained by asking the patient to provide urine into a 
provided container or via urinary catheter placed at the time of surgery. 
Approximately 50 mL will be obtained, centrifuged, separated into cellular pellet 
and supernatant and stored at -800 C, in a secure biorepository freezer in CSMC 
BioBank. 
(3) Tissue Specimens:   
A fresh frozen tissue sample from TURBT and subsequent cystectomy speciumens 
will be obtained by CSMC BioBank personnel. The tissue samples will be snap-
frozen in liquid nitrogen and stored in -80C freezers in CSMC BioBank. When 
needed for analysis, BioBank will send a portion of the de-identified TURBT tumor 
(5mm3) to CS Genomic Core for RNA extraction, and RNA-seq.  
Or FFPE tissue sample from a TURBT will be requested. Specifically we will 
request 1 H&E from the FFPE block with tumor as well as 10 unstained slides.  
 
Using standard techniques, CS Genomic Core will perform RNA-seq. Biostatisticians and Bio-
informaticians will assess correlations between radiomics, genomics and pathology data.  
 
Table 8 
Correlative Studies timing and requirements 
Specimen 
Quantity 
MRI 
TURBT
Cystectomy
Whole Blood 
ACD tube 
1x15 mL+ 
   
  X+ 
      X+ 
Urine 
50 mL 
 
X+
X+ 

IIT2020-22-Rosser-Radiogenomics 
Page 11 of 24 
 
Bladder tissue 
(Fresh) 
~5mm3 
 
X~
X+ 
Bladder tissue 
(FFPE) 
1 H&E 
10 unstained 
 
X~ 
 
 
 
~, used for sequencing 
 
 
+, banked in Cedars’ Biobank for future use 
 
5.0 
CLINICAL ASSESSMENTS 
5.1.1 CONCOMITANT MEDICATIONS 
All concomitant medication and concurrent therapies will be documented at Baseline/Screening, 
at each study visit, and at early termination when applicable, as part of routine medical 
care/treatment. Dose, route, unit frequency of administration, and indication for administration 
and dates of medication will be captured. 
5.1.2 DEMOGRAPHICS  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
5.1.3 MEDICAL HISTORY  
Relevant medical history, including history of current disease and information regarding 
underlying diseases will be recorded at Screening. 
5.1.4 PHYSICAL EXAMINATION 
A complete physical examination will be performed by physician at screening.  
5.1.5 VITAL SIGNS 
Body temperature, blood pressure and pulse will be performed at screening.  
5.1.6 OTHER STANDARD OF CARE CLINICAL PROCEDURES 
 TURBT  
 Axial imaging of the abdomen 
 Axial imaging of the chest or 2 view chest x-rays, determined by treating physician  
 Bone scan, if medically indicated 
 Radical cystectomy. This will occur according to established clinical guidelines (e.g. 
NCCN) within 6 weeks of consenting 
 
6.0   
ADVERSE EVENT REPORTING AND DOCUMENTATION   
It is unlikely any subject will experience a study related adverse event as all elements of the 
study are part of standard of care. However if such events occur the information regarding the 
occurrence will be captured throughout the study using the CTCAE v5.0 criteria. Duration (start 
and stop dates and times), severity/grade, outcome, treatment and relation to study device and 
radiation treatment will be recorded on the case report form (CRF). 
 
6.1  
Adverse Events (AE) 
An adverse event is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse device effect 
 is associated with clinical signs or symptoms 

IIT2020-22-Rosser-Radiogenomics 
Page 12 of 24 
 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
SERIOUS ADVERSE EVENT (SAE) 
An SAE is defined as any AE occurring that results in any of the following outcomes: 
 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
 
6.2 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRSO) 
Any of the above-listed events could classify as a UPIRSO if they meet the following criteria:  
 Unexpected in nature, severity, or frequency (i.e. not described in study-related documents 
such as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
 Related or possibly related to participation in the research (i.e. possibly related means there 
is a reasonable possibility that the incident experience, or outcome may have been caused 
by the procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
6.3 
RECORDING OF UNANTICIPATED ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS  
The Investigator will probe, via discussion with the subject, for the occurrence of UADEs, AEs, 
and SAEs during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded on the study CRF/eCRF.  These events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to study drug, 
or if unrelated, the cause.  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should be recorded in the source document, though should be grouped under 
one diagnosis. Data will be collected on logs and related CRFs or eCRFs.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse device effects that are still 
ongoing at the end of the study period must be followed up to determine the final outcome.   
All SAEs that occur (whether or not related to study device) will be documented - the collection 
period for all SAEs will begin after informed consent is obtained and continue until after the 
completion of cystectomy. 
 
6.4 
AE SEVERITY & GRADING 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 should be used to assess and grade AE severity, including laboratory abnormalities 
judged to be clinically significant. The guidelines shown below should be used to grade severity 
when the event does not fit within a term/diagnosis available in the CTCAE criteria.  It should be 

IIT2020-22-Rosser-Radiogenomics 
Page 13 of 24 
 
pointed out that the term “severe” is a measure of intensity and that a severe AE is not 
necessarily serious. 
 
TABLE AE SEVERITY GRADING 
Severity (Toxicity Grade)
Description
Grade (1) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade (2) 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
 
*Instrumental ADL refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
Grade (3) 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL**. 
 
**Self-care ADL refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not 
bedridden. 
Grade (4) 
Life-threatening consequences; 
urgent intervention indicated. 
Grade (5)
Death related to AE. 
 
6.5 
AE Relationship to MRI 
The relationship of an AE to the study MRI should be assessed using the following guidelines in 
the table below 
 
TABLE AE RELATIONSHIP TO DEVICE OR RADIATION  
Definite 
The AE is clearly related to the study MRI
Probable
The AE is likely related to the study MRI
Possible
The AE may be related to the study MRI
Unlikely 
The AE is doubtfully related to the study MRI
Unrelated
The AE is clearly NOT related to the study MRI
 
Note: This includes all events that occur within 30 days of the MRI. Any event that 
occurs more than 30 days after the MRI and is attributed (possibly, probably, or 
definitely) to the agent(s) must also be reported accordingly. 
 
Determine the prior experience (expectedness) of the adverse event.  
Expected events are those that have been previously identified as resulting from TURBT and 
cystectomy. An adverse event is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in: 
 
The current known adverse events listed below  
 
TURBT Expected Adverse Events  

IIT2020-22-Rosser-Radiogenomics 
Page 14 of 24 
 
 Genitourinary: Frequency, nocturia, acute or chronic bleeding from 
the bladder mucosal surface 
 Gastrointestinal: Rectal irritation, bowel obstruction or bleeding, 
rectal ulcers, hematochezia, fistula formation, colitis, mucous-
like stools  
 Dermatologic: Erythema, loss of pubic hair which could be 
permanent  
 Gynecologic: Dyspareunia, ovarian failure and sterility 
 
Cystectomy Expected Adverse Events  
 Genitourinary: urinary tract infection (UTI), septicemia, stones in 
conduit/neobladder, incontinence, hydronephrosis, azotemia 
 Gastrointestinal: bowel obstruction, diarrhea 
 Wound: infection, dehiscence, hernia 
 
6.6 Reporting of SAEs  
Any significant adverse event will be reported to the IRB in accordance with the standard 
operating procedures and policies of the local Institutional Review Board (IRB) / Independent 
Ethics Committee (IEC). 
 
The IRB must be notified within 10 business days of “any unanticipated problems involving risk 
to subjects or others.” 
 
The Principal Investigator must report all SAEs promptly to within 48 hours of first becoming 
aware of the event. This report will be accomplished by completing a Medwatch 3500A form 
which is available on the FDA website at http://www.fda.gov.  
 
At the time of first notification of an SAE, the following information should be provided 
by the site, if available: 
 Patient’s study number and initials 
 Date of first dose of test article 
 Date of last dose of test article, if applicable 
 Protocol description (and number, if assigned) 
 Treatment regimen (dosing frequency, combination therapy) 
 Adverse event term 
 Time and date of occurrence of the event 
 A brief description of the event, severity, outcome to date and any actions 
taken 
 The seriousness criteria(on) that were met 
 Concomitant medication at onset of the event 
 Relevant past history information 
 Relevant laboratory test findings 
 Investigator’s assessment of the relationship to test article  
 

IIT2020-22-Rosser-Radiogenomics 
Page 15 of 24 
 
Any missing or additional relevant information concerning the SAE should be provided 
in a written follow-up report. 
 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require the subject’s removal from treatment. If the subject was permanently 
withdrawn from the study or investigational product due to an SAE, this information 
must be included in either the initial or follow-up SAE Report Form. 
 
The Investigator is required to comply with applicable regulations regarding the 
notification of his/her IRB or Ethics Committee. 
 
6.7 Protocol Defined Important Medical Findings Requiring Real Time Reporting 
Events that are to be reported in an expedited manner that may or may not meet the definition of 
serious are listed below.  For any of these events, the Principal Investigator and Data Safety and 
Monitoring Committee (DSMC) must be notified within 24 hours: 
1. SAE deemed to be related to the protocol. 
2. On-study deaths, including death of a research subject unless the death is expected (e.g. 
due to disease progression).  
 
6.8 
Deviations from the study protocol 
A protocol deviation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety, and primary endpoint 
criteria.  Please refer to the CSMC IRB intranet webpage to obtain IRB protocol deviation 
reportable to the IRB: 
https://web.csmc.edu/research-and-education/research/institutional-review-board/ 
 
Protocol deviations for this study may include, but are not limited to, the following: 
 Failure to meet inclusion/exclusion criteria 
 Non-compliance by the study subject with required tests and procedures (TURBT, mp-
MRI HR-DWI study, radical cystectomy, etc.)  
 Failure to comply with Good Clinical Practice (GCP) guidelines  
 When a protocol deviation occurs, Protocol Deviation Form detailing the events will be 
generated. This form will be signed by the clinical site investigator and submitted to the 
local IRB per institutional policy. A copy of the form will be filed in the site’s regulatory 
binder and sent to the DSMC. 
 
7.0   DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
7.1  Early Discontinuation of Study Participation 
A subject may be discontinued from study treatment at any time if the subject or the investigators 
feel that it is not in the subject’s best interest to continue.  The following is a list of possible 
reasons for study treatment discontinuation:  
 Subject withdrawal of consent (or assent) for any reason  
 Because the subject is too ill to proceed with radical cystectomy 
 Because the subject changes their mind about treatment and elects to not undergo radical 
cystectomy.  
 Subject is not compliant with study procedures 

IIT2020-22-Rosser-Radiogenomics 
Page 16 of 24 
 
 Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study  
 Protocol violation requiring discontinuation of study  
 Lost to follow-up 
 DSMC request for early termination of study 
 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed 
and treated by the clinical site investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents.  
 
7.2   Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject or the investigator feels 
that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
 
7.3   Replacement of Subjects 
Subjects who withdraw from the study before radical cystectomy will be replaced.   
 
8.0  
SCHEDULE OF PROCEDURES 
 

IIT2020-22-Rosser-Radiogenomics 
Page 17 of 24 
 
Procedures 
Screening  Visit
Staging
TURBT
Cystectomy
Follow-up
Informed consent 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
Medical history, baseline conditions 
X 
 
 
 
 
Vital signs ^ 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
Survival follow-up 
 
 
 
 
Every 6 months for 
3 years 
Chest CT† 
 
X 
 
 
 
Abdomen CT/MRI 
 
X 
 
 
 
Chest x-ray† 
 
X 
 
 
 
Bone scan (if indicated) 
 
X 
 
 
 
Pelvis MRI 
 
X^ 
 
 
 
Pregancy test 
X 
 
 
 
 
Hematology  
X 
 
 
 
 
  Chemistry  
X 
 
 
 
 
TURBT# 
 
 
X 
 
 
Research urine 
 
 
X 
X 
 
Research blood 
 
 
X 
X 
 
Fresh frozen tissue or FFPE# 
 
 
X 
X 
 
Cystectomy 
 
 
 
X 
 
^Heart rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
† Patients who have received a chest CT (or MRI) need not have a chest x-ray. Patients who have findings suspicious for 
metastatic disease on a chest x-ray at baseline should have a confirmatory CT of the chest at baseline. Patients who have 
findings suspicious for metastatic disease at baseline on CT should have CT scans at follow-up tumor assessments 
^ mp-4D MRI high resolution with DWI 
# could be outside TURBT with FFPE tissue 
 
9.0 DATA COLLECTION AND MANAGEMENT 
 
9.1 DATA PROCUREMENT 
 Patient medical history will be extracted from the Cedars-Sinai Medical Center EMR 
system. 
 Pathologic (histology, grade, stage) and MRI data will be extracted from the Cedars-Sinai 
Medical Center EMR system. 
 Biological specimens (blood, urine, tissue) will be collected during patients’ visits. 
 Additional information in regard to diseases status will be obtained via follow-up visits and 
chart review. 
 Information will be kept for 5 years after completion of the study. 
 
9.2 VARIABLES COLLECTED  
The following data points/variables will be collected:  
 

IIT2020-22-Rosser-Radiogenomics 
Page 18 of 24 
 
1. RNA-seq of bladder tumor 
2. Imaging Measurement Tools: 
• 
MRI Pelvis protocol with modified sequences 
• 
T1 and T2 imaging (relaxation differences between tumor/tissue) 
• 
3D imaging of abdomen (w/o contrast) 
• 
DWI multi-b value (cellularity, density) 
• 
3D imaging of abdomen (w/o contrast) 
• 
ADC maps for slow and fast diffusion components 
• 
DCE-MRI (microvascular density, vascularity, vascular permeability) 
• 
3D imaging of abdomen (w/ contrast) 
• 
Kinetic parameter maps, Ktrans, kep, ve, AUC 
• 
Fractional blood volume, vp 
 
9.3 SOURCE DOCUMENTS 
Cedars-Sinai Medical Center EMR system will constitute source documents. In particular, EMR 
will be reviewed for patient demography and indication for procedure, MRI data, pathology data, 
clinical diagnosis information and outcomes.  
 
9.4 DATA COLLECTION AND STORAGE  
All electronic data will be stored electronically in password protected Cedars-Sinai Medical Center 
encrypted computers within a dedicate RedCap database. Hard copy research records will be stored 
in secure location (e.g. locked cabinet, office). Biological specimens will be stored in freezers at 
secure location (locked room or space accessible only to study team) within Cedars-Sinai BioBank.  
 
The data will be accessible only by the study team. 
 
On the day of consent, a de-identifier ID will be generated and assigned to each patient. The study 
database will not include identifiers. Only designated study team members will have the key that 
links the de-identifier ID with patient name, MRN or other direct identifiers. 
 
9.5 CONFIDENTIALITY AND SECURITY OF DATA 
The following measures will be taken in order to maintain confidentiality of any information 
obtained from or about the subjects:  
 
Identifiable Information and Linking Lists/Files 
 A de-identifier ID will be generated and assigned to each patient. The linking lists with de-
identifier ID, name and Medical Record Number of the patient will be maintained 
separately from research data in RedCap. Access to the list/file will be limited to approved 
research personnel. The study data coded upon abstraction, and any direct identifiers, will 
be maintained separately from data 
 Collection of sensitive information about subjects (PHI) is exclusively limited to the 
amount necessary to achieve the aims of the research study and no unneeded sensitive 
information will be collected 
 Only the minimum health information pertaining to the study will be collected. This will 
include clinical, procedure, and disease-related factors affecting the study outcomes. 

IIT2020-22-Rosser-Radiogenomics 
Page 19 of 24 
 
 Identifiable information will be destroyed as soon as possible after it is no longer needed 
for research purposes 
 Identifiable information will not be used or disclosed for any purposes not described in this 
application 
 
Research Records and Data Storage 
 Electronic research records will be stored in shared network folder on Cedars-Sinai network 
(no storage on non-CSMC computer) 
 All laptops used for collecting and storing research data or patient information will be 
encrypted in accordance with EIS standards. Laptops purchased with grant or other Cedars-
Sinai funds will be processed through EIS to register and encrypt the laptop 
 The data will only be made available to certified research personnel with IRB approval for 
access, through the use of passwords and encryption (No downloading to unencrypted 
portable devices, such as flash drive, personal laptop, etc.) 
 Access will be only at Cedars-Sinai or through approved VPN access 
 Hard copy research records will be stored in secure location (e.g. locked cabinet, office); 
Paper records with PHI will not be removed from Cedars-Sinai premises. 
 
10.0  DATA AND SAFETY MONITORING  
10.1 DATA MONITORING AND QUALITY ASSURANCE 
 
Minimal Risk Monitoring 
Adherence to the protocol, Good Clinical Practices (GCP), and institutional policy will be 
monitored by the PI during the course of the study through routine Disease Research Group 
(DRG) meetings (or equivalent). In addition, the SOCCI Cancer Clinical Trials Office (CCTO) 
Quality Management Core (QMC) will conduct focused internal monitoring visits and audits for 
data quality and protocol adherence. QMC reports will be forwarded to the SOCCI Data and 
Safety Monitoring Committee (DSMC). Refer to the DSMC Charter for more details. For any 
protocol, QMC has the authority to request more frequent reviews or focused safety monitoring 
if it is deemed appropriate for any reason.  
10.2 SAFETY MONITORING 
 
Minimal Risk Monitoring 
Oversight of the progress and safety of the study will be provided by the PI. The PI will maintain 
continuous safety monitoring for the duration of the study by reviewing subject/study data. 
Adverse events and unanticipated problems are not expected, but if they occur, they will be 
documented and reported according to CS-IRB policies and procedures. If the PI becomes aware 
of any new safety information that may place subjects at increased risk than what was previously 
known, the IRB will be promptly notified and if warranted, enrollment may be held until the PI 
determines whether a modification to the study is necessary and/or the informed consent 
documents are updated accordingly. It is the responsibility of the principal investigator to adhere 
to the Data Safety Monitoring Plan throughout the life of the study. 
In addition, this protocol will utilize the SOCCI Data and Safety Monitoring Committee will 
provide another layer of data and safety oversight. DSMC membership and responsibilities are 
governed by the committee charter. The annual DSMC findings and recommendations will be 

IIT2020-22-Rosser-Radiogenomics 
Page 20 of 24 
 
reported in writing to the Principal Investigator as a summary letter which will be forwarded by 
the Principal Investigator or designee to the CS-IRB. The DSMC may increase or decrease the 
frequency of study review, at their discretion. Refer to the DSMC Charter for details of the 
DSMC review.  
 
11.0 STATISTICAL CONSIDERATIONS  
 
11.1 STUDY OUTCOME MEASURES 
We have previously performed RNA-seq on 25 MIBCs, to identify 3 key bladder tumor cell 
populations that are differentially represented across tumors. These cells show major molecular 
differences and their proportions within a tumor are strong predictors of the aggressiveness of the 
disease, as measured by time to recurrence. Further, we have applied this data to develop a 
deconvolution algorithm that is able to predict their proportions in other tumors within TCGA 
based on bulk RNA-seq data. Now, we will apply this deconvolution algorithm to the RNA-seq 
data from 10 tumors in conjunction with imaging data to search for image and genomic parameters 
that predict tumor stage, outcomes and the presence of each of the cancer cell types, as well as 
fibroblasts and different immune infiltrates.  
Querying a small population for numerous parameters can lead to high false positive rates, 
thus from our retrospective work, we will apply 30 radiomics parameters and no more than 40 
genes in our network analyses, prioritization of genes and their interactions will be done using 
Lynx, PINTA and String algorithms to perform annotation, clustering, enrichment analysis, and 
prediction of high-confidence triggers and mediators in various cell populations of interest. 
Predictions of gene interactions and reconstruction of molecular pathways for the phenotypes of 
interest will be done using PINTA and STRING algorithms. These pipelines will be executed at 
scale using cloud resources. In addition to cloud resources, we will leverage the existing 
infrastructure available to the Knott lab. The results will be annotated with information from Lynx 
knowledge base integrating > 35 biological databases and publicly presented for revision and 
analysis via Web-based user interface developed in the course of the project. Biostatistical and 
bioinformatic comparisons of the molecular profiles with MRI imaging characteristics will be 
performed using a variety of publicly available and locally developed software applications.  
 
 11.2 SAMPLE SIZE CONSIDERATIONS  
The main hypothesis to be tested is whether there is association between radiogenomic features 
and pathologic stage. The prospective study is a pilot study to: a) generate high quality data and 
b) show feasibility, which we will define as know-how to create a radiogenomic workflow and to 
learn about the correlation structure of the radiogenomics parameters of interest, which will allow 
us to design future studies with adequate power. Pearson's Correlation hypothesis tests with 5% 
significance level (two-sided) and 80% power allows sample sizes of 10 patients to detect a 
difference between the null hypothesis correlation of zero and the alternative hypothesis 
correlation of 0.76 (23). In addition, sensitivity and specificity of several potential predictors will 
be estimated. The maximum width of the 95% confidence interval for proportions (sensitivities or 
specificities) associated with sample sizes of 10 patients are 0.63 (24). We anticipate 50% of 
subjects presumed to have MIBC at the time of TURBT and/or presumed not to have metastatic 
disease to not complete the study, i.e., undergo radical cystectomy, which will denote true 
pathologic stage. Thus, our final sample size to enroll is 20.   
 

IIT2020-22-Rosser-Radiogenomics 
Page 21 of 24 
 
12.0  REFERENCES 
1. 
Nepple KG, O'Donnell MA. The optimal management of T1 high-grade bladder cancer. 
Can Urol Assoc J. 2009;3(6 Suppl 4):S188-92. Epub 2009/12/19. PubMed PMID: 20019983; 
PMCID: PMC2792452. 
2. 
Malayeri AA, Pattanayak P, Apolo AB. Imaging muscle-invasive and metastatic 
urothelial carcinoma. Curr Opin Urol. 2015;25(5):441-8. Epub 2015/07/30. doi: 
10.1097/MOU.0000000000000208. PubMed PMID: 26222929; PMCID: PMC6771285. 
3. 
Stemkens B, Tijssen RH, de Senneville BD, Heerkens HD, van Vulpen M, Lagendijk JJ, 
van den Berg CA. Optimizing 4-dimensional magnetic resonance imaging data sampling for 
respiratory motion analysis of pancreatic tumors. Int J Radiat Oncol Biol Phys. 2015;91(3):571-
8. Epub 2015/01/18. doi: 10.1016/j.ijrobp.2014.10.050. PubMed PMID: 25596109. 
4. 
Deng Z, Pang J, Yang W, Yue Y, Sharif B, Tuli R, Li D, Fraass B, Fan Z. Four-
dimensional MRI using three-dimensional radial sampling with respiratory self-gating to 
characterize temporal phase-resolved respiratory motion in the abdomen. Magn Reson Med. 
2016;75(4):1574-85. Epub 2015/05/20. doi: 10.1002/mrm.25753. PubMed PMID: 25981762; 
PMCID: PMC4644523. 
5. 
Han F, Zhou Z, Cao M, Yang Y, Sheng K, Hu P. Respiratory motion-resolved, self-gated 
4D-MRI using rotating cartesian k-space (ROCK). Med Phys. 2017;44(4):1359-68. Epub 
2017/01/31. doi: 10.1002/mp.12139. PubMed PMID: 28133752; PMCID: PMC5462449. 
6. 
Woo S, Suh CH, Kim SY, Cho JY, Kim SH. Diagnostic performance of MRI for 
prediction of muscle-invasiveness of bladder cancer: A systematic review and meta-analysis. Eur 
J Radiol. 2017;95:46-55. Epub 2017/10/11. doi: 10.1016/j.ejrad.2017.07.021. PubMed PMID: 
28987698. 
7. 
Huang L, Kong Q, Liu Z, Wang J, Kang Z, Zhu Y. The Diagnostic Value of MR Imaging 
in Differentiating T Staging of Bladder Cancer: A Meta-Analysis. Radiology. 2018;286(2):502-
11. Epub 2017/12/06. doi: 10.1148/radiol.2017171028. PubMed PMID: 29206594. 
8. 
Ficarra V, Dalpiaz O, Alrabi N, Novara G, Galfano A, Artibani W. Correlation between 
clinical and pathological staging in a series of radical cystectomies for bladder carcinoma. BJU 
Int. 2005;95(6):786-90. Epub 2005/03/30. doi: 10.1111/j.1464-410X.2005.05401.x. PubMed 
PMID: 15794783. 
9. 
Kim JK, Park SY, Ahn HJ, Kim CS, Cho KS. Bladder cancer: analysis of multi-detector 
row helical CT enhancement pattern and accuracy in tumor detection and perivesical staging. 
Radiology. 2004;231(3):725-31. Epub 2004/05/01. doi: 10.1148/radiol.2313021253. PubMed 
PMID: 15118111. 
10. 
Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, Hinoue T, 
Laird PW, Hoadley KA, Akbani R, Castro MAA, Gibb EA, Kanchi RS, Gordenin DA, Shukla 
SA, Sanchez-Vega F, Hansel DE, Czerniak BA, Reuter VE, Su X, de Sa Carvalho B, Chagas VS, 
Mungall KL, Sadeghi S, Pedamallu CS, Lu Y, Klimczak LJ, Zhang J, Choo C, Ojesina AI, 
Bullman S, Leraas KM, Lichtenberg TM, Wu CJ, Schultz N, Getz G, Meyerson M, Mills GB, 
McConkey DJ, Network TR, Weinstein JN, Kwiatkowski DJ, Lerner SP. Comprehensive 
Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2017;171(3):540-56 e25. 
doi: 10.1016/j.cell.2017.09.007. PubMed PMID: 28988769; PMCID: PMC5687509. 
11. 
Zhang X, Zhang M, Hou Y, Xu L, Li W, Zou Z, Liu C, Xu A, Wu S. Single-cell analyses 
of transcriptional heterogeneity in squamous cell carcinoma of urinary bladder. Oncotarget. 
2016;7(40):66069-76. Epub 2016/09/08. doi: 10.18632/oncotarget.11803. PubMed PMID: 
27602771; PMCID: PMC5323215. 

IIT2020-22-Rosser-Radiogenomics 
Page 22 of 24 
 
12. 
Tanaka N, Katayama S, Reddy A, Nishimura K, Niwa N, Hongo H, Ogihara K, Kosaka 
T, Mizuno R, Kikuchi E, Mikami S, Miyakawa A, Arenas E, Kere J, Oya M, Uhlen P. Single-
cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker 
CD63. Cancer Med. 2018;7(12):6193-204. Epub 2018/10/28. doi: 10.1002/cam4.1828. PubMed 
PMID: 30367559; PMCID: PMC6308066. 
13. 
Bodalal Z, Trebeschi S, Nguyen-Kim TDL, Schats W, Beets-Tan R. Radiogenomics: 
bridging imaging and genomics. Abdom Radiol (NY). 2019;44(6):1960-84. Epub 2019/05/03. 
doi: 10.1007/s00261-019-02028-w. PubMed PMID: 31049614. 
14. 
Zhu Y, Li H, Guo W, Drukker K, Lan L, Giger ML, Ji Y. Deciphering Genomic 
Underpinnings of Quantitative MRI-based Radiomic Phenotypes of Invasive Breast Carcinoma. 
Sci Rep. 2015;5:17787. Epub 2015/12/08. doi: 10.1038/srep17787. PubMed PMID: 26639025; 
PMCID: PMC4671006. 
15. 
Vargas HA, Huang EP, Lakhman Y, Ippolito JE, Bhosale P, Mellnick V, Shinagare AB, 
Anello M, Kirby J, Fevrier-Sullivan B, Freymann J, Jaffe CC, Sala E. Radiogenomics of High-
Grade Serous Ovarian Cancer: Multireader Multi-Institutional Study from the Cancer Genome 
Atlas Ovarian Cancer Imaging Research Group. Radiology. 2017;285(2):482-92. Epub 
2017/06/24. doi: 10.1148/radiol.2017161870. PubMed PMID: 28641043; PMCID: 
PMC5673051. 
16. 
Karlo CA, Di Paolo PL, Chaim J, Hakimi AA, Ostrovnaya I, Russo P, Hricak H, Motzer 
R, Hsieh JJ, Akin O. Radiogenomics of clear cell renal cell carcinoma: associations between CT 
imaging features and mutations. Radiology. 2014;270(2):464-71. Epub 2013/09/14. doi: 
10.1148/radiol.13130663. PubMed PMID: 24029645; PMCID: PMC4011179. 
17. 
Lin P, Wen DY, Chen L, Li X, Li SH, Yan HB, He RQ, Chen G, He Y, Yang H. A 
radiogenomics signature for predicting the clinical outcome of bladder urothelial carcinoma. Eur 
Radiol. 2020;30(1):547-57. Epub 2019/08/10. doi: 10.1007/s00330-019-06371-w. PubMed 
PMID: 31396730. 
18. 
Cahn DB, Handorf EA, Ghiraldi EM, Ristau BT, Geynisman DM, Churilla TM, Horwitz 
EM, Sobczak ML, Chen DYT, Viterbo R, Greenberg RE, Kutikov A, Uzzo RG, Smaldone MC. 
Contemporary use trends and survival outcomes in patients undergoing radical cystectomy or 
bladder-preservation therapy for muscle-invasive bladder cancer. Cancer. 2017;123(22):4337-45. 
Epub 2017/07/26. doi: 10.1002/cncr.30900. PubMed PMID: 28743162. 
19. 
Yang LS, Shan BL, Shan LL, Chin P, Murray S, Ahmadi N, Saxena A. A systematic 
review and meta-analysis of quality of life outcomes after radical cystectomy for bladder cancer. 
Surg Oncol. 2016;25(3):281-97. Epub 2016/08/28. doi: 10.1016/j.suronc.2016.05.027. PubMed 
PMID: 27566035. 
20. 
Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, 
Heney NM, Zietman AL. Long-term outcomes in patients with muscle-invasive bladder cancer 
after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation 
Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 
2014;32(34):3801-9. Epub 2014/11/05. doi: 10.1200/JCO.2014.57.5548. PubMed PMID: 
25366678; PMCID: PMC4239302. 
21. 
Cancer Facts and Figures 2020: American Cancer Society; 2020. Available from: 
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-
cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. 

IIT2020-22-Rosser-Radiogenomics 
Page 23 of 24 
 
22. 
Wang N, Christodoulou AG, Xie Y, Wang Z, Deng Z, Zhou B, Lee S, Fan Z, Chang H, 
Yu W. Quantitative 3D dynamic contrast‐enhanced (DCE) MR imaging of carotid vessel wall by 
fast T1 mapping using Multitasking. Magnetic resonance in medicine. 2018. 
23. 
Guenther WC. Desk calculation of probabilities for the distribution of the sample 
correlation coefficient. The American Statistician. 1977;31(1):45-8. 
24. 
Fleiss J, Levin B, Paik M. Statistical Methods for Rates and Proportions. 3rd ed: John 
Wiley & Sons; 2003. 
 
 
 

IIT2020-22-Rosser-Radiogenomics 
Page 24 of 24 
 
13.0  STUDY SCHEMA 
 
 
Consent to study 
Routine staging of chest and abdomen 
(bone if medically indicated) 
Known sessile bladder mass, worrisome 
for muscle invasive bladder cancer 
(MIBC) – able to obtain outside TURBT 
FFPE
mp-4D pelvic MRI HR DWI 
Transurethral Resection opf Bladder 
Tumor (TURBT) at Cedars-Sinai or ability 
to obtain the above outside FFPE 
Muscle invasive bladder cancer (MIBC) 
noted
Imaging 
No evidence of advance disease 
Radical cystectomy and final pathologic 
stage 
Urine and blood collected 
and banked
Urine and blood collected 
and banked
Fresh frozen tissue 
collected – sc RNA seq 
Fresh frozen tissue 
collected and banked