Vinodh Radhakrishnan, PhD
Senior Project Scientist
University of California, Irvine
Orange, California, United States
Fatemeh Tajik, MD
Research Assistant Specialist
University of California, Irvine
Orange, California, United States
Aaqil Khan, MS
Lab Manager & Research Assistant
University of California, Irvine
Orange, California, United States
Melanie Roman, MD
Research Assistant
Loma Linda University Health
Loma Linda, California, United States
Michael P. O'Leary, MD
Assistant Professor of Surgery
University of California, Irvine
Orange, California, United States
Oliver S. Eng, MD (he/him/his)
Associate Professor of Surgery
University of California, Irvine
Orange, California, United States
Maheswari Senthil, MD, FACS, FSSO (she/her/hers)
Professor of Surgery
University of California Irvine
Irvine, California, United States
Alex N. Dang, MD (he/him/his)
Resident Physician
University of California, Irvine
Long Beach, California, United States
Previous work from our group has shown that exosomes are abundantly present in the peritoneal lavage (PL) fluid from patients with gastrointestinal peritoneal carcinomatosis (GI PC). Given the significance of exosomes in premetastatic niche creation and cancer progression, we sought to evaluate the association of PL exosomes quantity, distribution, and gene expression with outcomes in GI PC.
Methods: PL samples from patients with GI PC were obtained at the time of diagnostic laparoscopy or cytoreductive surgery (CRS) and were grouped based on primary tumor site (gastric, appendix, or colon) and receipt of systemic therapy (ST) (pre-or post-ST). Patient demographics, tumor characteristics, and clinical outcomes were collected. Patients were grouped as poor or good prognosis based on recurrence and/or death. Exosomes were isolated from PL. Distribution (0.5-99.5nm and 100.5-199.5nm) and quantity of exosomes were assessed by nanoparticle tracking analysis (NTA). Exosome RNA was extracted and analyzed utilizing NanoString’s gene PanCancer Progression Panel (770 genes). Differential gene expressions were performed with log2 fold expression change cutoff of ≥1.5 to ≤ -1.5 with p-value of ≤ 0.05.
Results: A total of 34 patients with GI PC were included: appendiceal (n =12), colon (n =16), and gastric (n =8). Median age was 61.5; 53% were female; pre-ST (n=16) and post-ST (n=18). Median peritoneal cancer index (PCI) was 19 (range 1 – 39). CRS was performed in 18 patients. Recurrence or death occurred in 21/34 (61.7%). The quantity of exosomes was significantly higher in the pre-ST PL (n=12) compared to post-ST (n=14) across all primary sites (p< 0.0001). In the poor prognosis group, the quantity of exosomes post-ST was significantly higher compared to the good prognosis group (p< 0.0001). Poor prognosis group also showed significant differential overexpression of genes associated with epithelial mesenchymal transition, extracellular matrix structure, cell motility, and inhibition of apoptosis (COL1A1, VIM, RPS27A, SPARCL1, TPM2, UBA52, OGN, TXNIP, CCDC80 and STAT3).
Conclusions:
PL exosomes quantity and gene expression pattern post ST were predictive of outcomes in patients with GI PC. These results highlight the utility of PL exosomes as a predictive liquid biopsy tool for PC prognostication.