Supporting Kidney Cancer Research: Lessons Learned Establishing The Stanford Kidney Cancer Biospecimen Repository
Thomas J. Metzner, MS1,2, Christian R. Hoerner, PhD2,3, Hongjuan Zhao, PhD 1, Rosalie Nolley, MS1, Sumit A. Shah, MD2,3, Sandy Srinivas, MD2,3, John P. Higgins, MD2,4, Chia-Sui Kao, MD2, Rajesh P. Shah, MD2,5,9, Joanna E. Liliental, PhD2,6, Alan E. Thong, MD MPH1,2, Harcharan S. Gill, MD1,2, Benjamin I. Chung, MD, MS1,2, Geoffrey A. Sonn, MD1,2, Eila C. Skinner, MD1,2, Wendy J. Fantl, PhD1,2, Erinn B. Rankin, PhD2,7, Amato J. Giaccia, PhD2,7, Donna M. Peehl, PhD1,8, James D. Brooks, MD1,2, Alice C. Fan, MD2,3, John T. Leppert, MD, MS1,2,9
1Department of Urology, Stanford University School of Medicine, Stanford, CA, 2Stanford Kidney Cancer Research Program, 3Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, 4Department of Pathology, Stanford University School of Medicine, Stanford, CA, 5Department of Radiology, Stanford University School of Medicine, Stanford, CA
6Department of Medicine Translational Research and Applied Medicine Program, Translational Applications Service Center,
7Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 8Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, 9Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
Key words: Renal cell carcinoma, biospecimen, repository, biopsy, biology, collection, specimen handling, research protocol, tissue banking, Clinical Research Coordinator.
Corresponding Author: John Leppert, Grant S-289, 300 Pasteur Drive, Stanford, CA, 94305 firstname.lastname@example.org
Acknowledgements: This manuscript is dedicated to the memory of Larry Lulofs, and to the hundreds of patients with renal cell carcinoma who have selflessly donated their tissues to support our research efforts in hopes of improving treatments for future patients.
Funding: This work was supported in part by the Departments of Urology and Medicine at Stanford University School of Medicine, the Stanford Cancer Institute (Translational Developmental Cancer Research Award to J.T.L. and A.C.F.), the Stanford Translational Research and Applied Medicine (TRAM) Program Pilot Grant (J.T.L., A.C.F.), the Parker Institute of Cancer Immunotherapy (W.J.F. and J.T.L.), the US National Institute of Health (CA169964 to J.T.L. and A.C.F., CA199075 to A.C.F., CA140722 to A.C.F., CA229933 to J.D.B., CA198291 to A.J.G. and E.B.R., CA217456 to D.M.P.), the Department of Defense Peer Reviewed Cancer Research Program (11981051 to J.T.L.), and an Conquer Cancer Foundation of ASCO Career Development Award (A.C.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the U.S. Department of Veterans Affairs or the U.S. Government.
Advancing our understanding of kidney cancer relies on the acquisition of biological specimens from patients with the disease. The increasing complexity of cancer biology studies necessitates a “team science” approach, leveraging input from a multidisciplinary team and often requiring multiple methods for acquiring and preparing biospecimens. Researchers face many challenges when developing infrastructure to obtain high-quality specimens, including limited access to specimens due to regulatory requirements and institutional barriers, and a lack of familiarity with clinical care environments. Clinicians also face challenges when working to collect samples outside of an individual practice, including access to multiple locations and other sub-specialty care services. The collecting of high-quality biospecimens itself is challenging, as it is important to consider patient characteristics, pre-analytic variables, collection protocols, specimen handling, and data management. The purpose of this paper is to detail our experience addressing these challenges while developing the infrastructure for a kidney cancer biospecimen repository. We believe that sharing solutions to these challenges at a single institution may assist others developing similar programs, and will aid in fostering future efforts for collaborative group banking efforts with specimen and data harmonization.
Renal cell carcinoma (RCC, kidney cancer) poses a daunting research and clinical challenge. RCC is not a single disease, but represents a group of cancers with distinct biology that happen to arise from the kidney. Moreover, each variant of RCC can manifest across a broad spectrum of risk – from slow-growing indolent lesions, to rapidly growing cancers with high metastatic potential. The study of RCC specimens has played an integral part in advancing our understanding of the biology of RCC, and has led to the global improvement in our ability to care for patients. Despite these advancements, significant opportunities remain for basic and translational research utilizing human RCC biospecimens.1 The Urology Care Foundation National Urology Research Agenda highlights the urgency of establishing “biospecimen repositories of well documented disease and normal tissue” in the National Urology Research Agenda.3 The importance of high-quality biospecimens is well established within the cancer and RCC research communities.4,5 The practice of biospecimen collection must continue to evolve to meet the needs of RCC researchers.2 To continue to improve biospecimen repositories, best practices have been proposed to ensure the collection of samples that support reproducible high-quality research.6,7
The Stanford Kidney Cancer Research Program is an interdisciplinary group of physicians and basic scientists who are dedicated to pioneering research studies to increase knowledge of the biology of, and improve treatments for, RCC. In order to support this growing research enterprise, we have collaborated to build the infrastructure necessary to collect a wide range of RCC biospecimens. Like many other institutions, we have addressed administrative and regulatory issues in building this program, and when coordinating these efforts with existing programs.
In this publication, we aim to share our experience within Stanford University and the VA Palo Alto Health Care System. Our intent is to generate discussion to broadly support RCC biospecimen collection and research, and to foster efforts for specimen and data harmonization across collaborative groups focusing on advancing our understanding of RCC.
A research enterprise devoted to the acquisition of biological specimens from patients with RCC requires key personnel to be both useful and efficient. At Stanford, the personnel who are crucial to our biospecimen banking efforts are the Principal Investigators, Clinical Research Coordinators, basic scientists, and other clinicians treating patients with RCC. (Figure 1)
We have adopted several approaches to acquiring and organizing human-subjects research protocols for kidney cancer biospecimen collection that are approved by the Stanford Institutional Review Board (IRB). While many institutions (including our own) maintain cancer tissue banks, or umbrella protocols to collect tissue across many disease states, we have worked to develop specific RCC biospecimen collection protocols led by Principal Investigators (PIs) who are clinicians that specialize in the management and care of patients with RCC. As a clinician, the PI will have a good working understanding of the clinical environment, and the complexities of conducting research in that environment, while remaining an advocate for each patient. Furthermore, clinically informed PIs will recognize opportunities for the research team to acquire biological specimens needed to answer timely clinical questions. With this knowledge and experience, a clinician-PI is also best suited to guide and train Clinical Research Coordinators to assist in the clinical sample and data collection effort.
This approach has resulted in a research protocol with a Urologist (JTL) as PI that focuses on obtaining biospecimens from patients at the time of clinical procedures, such as tissue from nephrectomies, metastasectomies, and image-guided biopsies, as well as blood and urine samples from patients with localized disease. Similarly, a research protocol is also in place with a medical oncologist (ACF) as PI, which focuses on serial blood and urine sampling, and collecting tumor biopsies from patients receiving systemic therapies to treat advanced disease. Finally, there remain broad protocols designed to enroll all patients receiving care through the Urology department, as well as a general tissue-banking protocol that is managed by the Stanford Cancer Institute. While these latter services follow a “banking model” and are designed to bank biospecimens from all patients, we have taken a more targeted approach, prospectively collecting tissues for specific research questions and also serving as a repository for future analyses.8 We have streamlined our RCC protocols to ensure that patients avoid consent fatigue, and that relevant biospecimens can be collected (even as patients transition from localized to advanced disease) without requiring enrollment on additional protocols. Further, we have intended for the RCC-specific and institutional generalized tissue banking protocols to operate symbiotically, maximizing biospecimen banking in the support of RCC research.
Clinical Research Coordinator
We have designed a unique hybrid Clinical Research Coordinator (CRC) position that combines capacities typical of a research coordinator with those of a research assistant. We attribute much of our success in obtaining specimens to this hybrid CRC position, which empowers the CRC to participate in every aspect of the tissue collection process. The CRC is responsible for tasks commonly assigned to CRC’s at other institutions, including writing protocols that allow for biospecimen acquisition, maintaining regulatory approvals, and managing study data. The CRC also obtains informed consent from participants in clinical environments, such as the outpatient clinic, inpatient wards, and pre-operative holding area. What we believe is unique at our institution, however, is that the CRC is positioned in the operating room during interventional procedures that allow for tissue harvest (nephrectomies, metastasectomies, image-guided biopsies, and ablations). For many researchers and research coordinators, clinical environments such as the operating room are daunting. This perceived, and sometimes real, barrier between the research environment and clinical care settings can impede specimen collection efforts. By being present in the operating room and interventional radiology suite, the CRC is able to communicate with the clinical staff to answer questions regarding specimen acquisition, record critical pre-analytic variables, and coordinate with research teams waiting to receive the specimens. If needed for a particular assay, our CRC’s are also able to process specimens utilizing skills acquired from past laboratory bench-based research experience. This allows for highly specialized collection protocols that extend our capacity beyond traditional tissue banks.
Due to this unique hybrid position, we believe the CRC must be an individual who is capable of bridging the gap between the research laboratories using the tissue specimens and the clinical environments from which the specimens are acquired. Most importantly, the CRC must be skilled in communicating with patients with cancer and their families, so they do not incur additional stress during their treatments. The CRC also must build collegial relationships with both medical and research staff, and maintain familiarity and competence in clinical environments like the operating room and gross pathology work room.
In order for a CRC to be effective in this role, he or she must be given the tools to operate with a high degree of independence. Such tools include access to the clinical environments where patients can be consented and tissues can be obtained (clinics, operating rooms, pathology gross rooms, interventional radiology suites, and hospital wards), and access to resources to identify potential cases, look up surgery times and patient visits, acquire clinical data on research patients, and perform proper research documentation. We have had CRCs shadow PIs in the operating room during training, and work with the PI in the pathology gross room to acquire tissue specimens until the CRC becomes comfortable performing these duties independently. Similarly, the CRCs have shadowed PIs in the urologic and medical oncology clinics, learning about the patient experience as well as relevant kidney cancer biology and treatment courses. The Stanford Cancer Clinical Trials Office (CCTO) has provided training for the regulatory affairs aspect of the CRC’s duties. The training in regulatory affairs and conduct of research that a CCTO can provide is invaluable in ensuring that a biospecimen harvesting research protocol is legally and ethically compliant.
The basic scientists and laboratories involved in the Stanford Kidney Cancer Research Program are the end users of the tissue specimens acquired, and are actively involved in this prospective collection model. Research laboratories interested in studying RCC approach either the PI or CRC with clinically relevant hypotheses, and propose the biospecimens that would be required to test them. In doing so, the research scientists provide crucial information regarding acquisition, processing, and storage conditions required to maintain the fidelity of the specimens and eliminate variability in the research assays for which they will be used. In this way, basic scientists at our institution play an integral role (along with the CRC) in designing tissue acquisition protocols. We have had success designating a single member of the research team to act as a point of contact for the CRC. We also encourage discussion of protocols and strategies in our bi-weekly Stanford Kidney Cancer Research Program conference. This allows for the pertinent information regarding the specimen needs of the laboratory to be communicated, and allows the CRC to help identify upcoming cases or clinical encounters to quickly satisfy the group’s tissue needs with specimens acquired under the optimal conditions. We have found that this level of communication allows the CRCs to provide specialized collection services not available through our institutional programs (e.g. collection of fresh tissue using core or fine-needle aspirate biopsies, multi-region tissue sampling, or collections in specific medium required for experiments). Moreover, this level of access to specimens has assisted with recruiting cancer biology laboratories to study RCC, as they often face challenges in acquiring biospecimens when studying other cancer types.
Treating patients with RCC requires a team that includes surgeons, oncologists, interventional radiologists, radiologists, and pathologists. Our research team involves all interested clinicians from these disciplines to maximize the acquisition of specimens, and increase the likelihood of acquisition of rare specimens. To do this, we have included multiple urologists and medical oncologists as study co-investigators on specimen acquisition protocols. Our protocol also includes pathologists as co-investigators to assist with the acquisition of tissue specimens from the gross room and re-review of histology when necessary. We encourage clinicians to also attend the aforementioned bi-weekly meetings to discuss research in progress. This has fostered trust among clinicians such that they feel comfortable in approaching their patients for enrollment to the studies, and are willing to participate in biospecimen collection even if it requires additional time and effort.
Designing Multi-Modal Biospecimen Collection Research Protocols
We have worked with the IRB to create protocols that allow collection of multiple specimen types (e.g. tissue, blood, and urine) at serial timepoints throughout the patient’s clinical course. In order to obtain permission to collect different types of biospecimens in a single protocol, we have designed a “check box system”. With this system, a patient can opt in or out of providing certain biospecimens by initialing next to each procedure outlined in the consent. This gives patients the flexibility to participate in ways that they are most comfortable. For example, a patient may consent to donating tissue harvested after a surgery is complete, but not consent to blood collection at the time of surgery. We have found that the check box system in our consent reduces patients’ anxiety associated with participating in the research study, and has increased our accrual.
Our comprehensive approach to collecting specimens has also provided the opportunity for some less common tissue collection strategies not available through generalized banking programs like the Stanford Tissue Bank. For example, a radical nephrectomy specimen could provide multi-region sampling as well as an 8mm core biop-sy for preparation of xenograft models. Similarly, our prospective approach facilitates blood collections during routine clinical draws as well as research-only collections.
Practical Aspects of Specimen Acquisition
Though aspects of a biospecimen acquisition protocol will vary by institution and by research question, it is universally necessary for the specimens acquired to be collected in a way that minimizes artifact and preserves their biology to the highest degree possible, and that all aspects of collection are documented. An additional benefit of positioning a dedicated CRC where the specimen is collected is that it affords the research team the ability to record and systematically test critical pre-analytic variables that may influence the fidelity of the specimen. These include patient-level factors (e.g. specific comorbidities, prior RCC treatments), as well as pre-analytic variables specific to the procedure and tissue of interest (e.g. warm ischemia time, blood loss or hypotension during the procedure, the stabilization media used, transport and storage temperature, processing time).5 To accomplish this, the CRC carries a tissue harvesting kit to every case. The kit contains the required specimen preparation tools, but also specialized methods for documenting collection efforts, such as marking pins to denote the region where tissue is harvested from during multi-region sampling, as well as a camera to capture relevant images of the tissue harvest that can be utilized later to identify areas of gross necrosis, fibrotic tissue, and variant histology. Figure 2 illustrates some aspects of biospecimen collection, and how a surgical sample could be processed for inclusion in multiple studies such as a RCC tissue microarray,9,10 multi-region proteomic sampling,11 larger core biopsies for patient-derived xeno-grafts,12-17 or for bulk tissue acquisition for organoids and other larger-scale models and analyses.18 Utilizing this approach, we have acquired specimens from 360 resected RCC tumors, with multi-region sampling in 312 cases. We also collect paired normal tissue in all cases when possible.
Similarly, we prefer the CRC to also be present in the endoscopy and radiology suites throughout procedures involving image-guided biopsies. By being present in this way, the CRC can ensure that the specimen is properly labelled if taken from multiple locations, acquired and stored in the proper medium, and that aspects of the acquisition are documented (e.g. core vs. fine needle aspiration).19 The actual presence of the CRC during the biopsy also assures that any questions that arise regarding the research specimens can be immediately addressed, increasing the rate of successfully acquired research biopsies. To date, we have acquired tissue specimens using CT, ultrasound, or endoscopic guidance from 26 participants.
Because clinical and research blood draws can occur in multiple laboratories and even multiple campuses, it is not possible for the CRC to be present for each blood collection in the same fashion. To ensure that research collections occur regardless of the location, the CRC coordinates and facilitates the placement of research blood draw orders in the patient’s electronic medical record. A research blood draw kit is assembled with blood collection tubes specific to the needs of each assay. With the orders is a set of instructions provided to the phlebotomist or nurse drawing the blood, which details the conditions under which the blood should be stored, and instructs the person drawing the blood to record the draw time and page the CRC as soon as the blood is drawn so time-sensitive samples can be processed quickly. With this coordinated effort, blood can be collected and distributed to multiple laboratories investigating different aspects of RCC. Examples of specialized studies using blood collections include the isolation of circulating tumor cells, plasma banking and cryopreservation of PBMCs, and the development of novel blood-based diagnostic assays. Our protocols also allow for blood to be collected at serial time points, with specimens being collected at the time of routine clinical lab testing, drawn from intravenous ports or lines at the time of treatment or surgery, and dedicated research-only blood sampling that is independent of a routine lab draw. Together, these efforts have resulted in a repository of 1084 total blood samples collected from 344 participants (312 patients with RCC; 32 non-cancer controls), with 227 patients contributing serial samples throughout the course of their treatment.
Equally as important as strong personnel and well-written protocols is a means by which to organize the tremendous amount of data collected. At Stanford, we utilize three databases in our research effort: a patient enrollment database, an institutional RCC clinical database, and a specimen database. Each resource has a specific purpose to meet the needs of the Kidney Cancer Research Program. Most importantly, all are encrypted and secured, allowing for the storage of Protected Health Information crucial to the clinical and translational aspects of the research effort.
The enrollment database tracks the screening, consent, enrollment, and withdrawal of patients from research protocols. The Stanford Cancer Institute utilizes OnCore v14.2 (Forte Research Systems, Madison, WI) as the enrollment database. This resource assigns each participant a study ID for specimen tracking and blinding, integrates with the electronic health record to pull participant demographic information, records when patients were consented and with what version of the protocol, and can track survival outcomes. It also allows for researchers to record if patients withdraw from the study and for what reason, along with any adverse events that may have occurred as part of the research procedures. We are proud to report that no patients have incurred adverse events as a result of participating in our specimen collection research protocols.
Institutional Renal Cell Carcinoma Clinical Database
The Stanford Renal Cell Carcinoma Database (RCCD), is a medical center database consisting of clinical, demographic, and outcomes data for all patients with RCC treated at Stanford from 2003 to the present. Participant data is entered into the RCCD through an automated process, and is then curated to ensure data quality. Variables include date of diagnosis, date of surgery, clinical staging, pathologic staging, pathologic features, dates and types of treatment received, response to treatment, patient performance status, adverse events, and date of death.
The specimen database is specific to our RCC specimen acquisition efforts, and is designed to track all the parameters of the samples collected using the research protocols. This database is constructed using Research Electronic Data CAPture (REDCap, https://www.project-redcap.org), a HIPAA-compliant secure web application designed to support data capture for research studies, provide an intuitive interface for validated data entry, and audit trails for tracking data manipulation and export procedures.20 Stanford maintains a version of REDCap that restricts access to users with active Stanford login credentials accessing REDCap from an on-campus computer or Stanford VPN, as well as project-specific user access to protect research information. REDCap is also approved for research for Veterans participating through the VA Palo Alto Health Care System. Within REDCap, we have implemented data collection tools to store the pre-analytic variables associated with each specimen. These tools are organized into fields that denote particular aspects of the patient’s treatment, as well as specific information about the samples that essentially tells the “story” for each sample we collect. (Figure 3) For example, one field contains all the information leading up to resection of the tumor, such as the type of procedure performed, laterality, how the patient was diagnosed, clinical stage, and RCC risk factors. The database also contains relevant pathologic data, including stage and grade, tumor size, and histologic subtype. We record all of the data pertaining to the procurement of the tissue, such as how the tissue was harvested, storage medium, and sample ischemia time. Finally, we are able to track which tissue was collected for which laboratory and research project. REDCap also can export data formatted for various statistical software packages (e.g. SAS and R) allowing for efficient analysis of the data as the study matures.
Analysis of biospecimens will be required to meet the increasing opportunities to advance our understanding of RCC biology. Current RCC research involves “team science” in the truest form, relying on clinicians, researchers, and research coordinators to succeed. As research tools increase in complexity, strategies to support these efforts with biospecimens and to collect biospecimens in novel ways must evolve in parallel. We intend to expand our internal RCC biospecimen and repository collaborations among the many laboratories studying RCC. We will continue to share standard operating procedures (SOPs) that have been optimized for specific assays. Further, we are working to share pre-analytic variables and storage parameters of residual bio-specimens after the completion of the initial experiments. In doing so, we will encourage maximal use of the collected biospecimens, but also identify opportunities to build on existing research findings with future complementary studies. By mandating that laboratories share this information in a central location, we can effectively establish a more comprehensive picture of an individual tumor’s biology by combining and examining the diverse array of information that each laboratory generates. We believe that this data will provide greater insight into the biology of RCC, and in turn fuel collaborations between researchers to answer more complex questions about RCC disease process.
We also hope to build collaborations outside of our institution, sharing SOPs, as well as granular details of available RCC specimens. The National Cancer Institute already supports on-line tools to share SOPs and research specimen information through the Biospecimen Research Database (https://brd.nci.nih.gov/brd/) and Biospecimen Pre-analytical Variables (BPV) Program (https://biospecimens.cancer.gov/programs/bpv/default.asp). These tools, or others created specifically for groups, will support collaborative studies essential to studying rare forms of RCC. We appreciate the opportunity to share our experience developing this infrastructure, and look forward to efforts within the kidney cancer research community to build biospecimen repositories to support the translational and basic research that will improve the care of patients with kidney cancer.
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