PSM
non-CME
Tracey Pu, MD
Research Fellow
National Cancer Institute | National Institutes of Health, United States
Disclosure information not submitted.
Tracey Pu, MD
Research Fellow
National Cancer Institute | National Institutes of Health, United States
Disclosure information not submitted.
Kirsten Remmert, PhD
Staff Scientist
National Cancer Institute | National Institutes of Health, United States
Disclosure information not submitted.
Andrew Massey, PhD
Postdoctoral Fellow
NIBIB/IRP, United States
Disclosure information not submitted.
Stephanie N. Gregory, MD
Surgical Oncology Research Fellow
National Institutes of Health, National Cancer Institute, United States
Disclosure information not submitted.
Sarfraz R. Akmal, BS
Medical Student
National Cancer Institute | National Institutes of Health, United States
Disclosure information not submitted.
Moira McCormick, BS
Post-Baccalaureate Fellow
NIBIB/IRP, United States
Disclosure information not submitted.
Jeremy L. Davis, MD
Surgical Oncology
National Cancer Institute
Bethesda, Maryland, United States
Disclosure information not submitted.
David Kleiner, MD, PhD
Senior Research Physician
NCI/NIH, United States
Disclosure information not submitted.
Andrew M. Blakely, MD
Program Director
Surgical Oncology Program, National Institutes of Health, United States
Disclosure information not submitted.
Alexander Cartagena-Rivera, PhD
Senior Scientist
NIBIB/IRP, United States
Disclosure information not submitted.
Jonathan M. Hernandez, MD
Principal Investigator
National Institutes of Health
Bethesda, Maryland, United States
Disclosure information not submitted.
Hyperthermic intraperitoneal chemotherapy(HIPEC) is employed after cytoreductive surgery (CRS) to prolong survival in peritoneal carcinomatosis patients. However, peritoneal metastatic disease almost invariably recurs suggesting additional treatment measures are required. We estimate that synergistic combination therapy must be based on a clear understanding of resulting alterations in treated tumor microenvironment (TME), including biophysical architectural properties and immune cell activity, which are not captured in available co-culture and organoid models.
Methods:
Tumor-bearing peritoneum was procured from patients undergoing CRS-HIPEC on an IRB-approved protocol (NCT04847063) immediately prior to AND following completion of intraperitoneal chemotherapy perfusion. Tissue was immediately affixed to customized 3D-printed autoclavable photopolymer resin platforms and analyzed by atomic force microscopy (AFM) and live-cell imaging with aid of customized 3D-printed adaptors. Fixed samples were analyzed by immunofluorescence (IF) staining.
Results:
Compared to peritoneal metastases obtained prior to HIPEC (pre-HIPEC), peritoneal metastases obtained after HIPEC (post-HIPEC) demonstrated an 8-fold reduction in tissue stiffness when evaluated with AFM. The reduction resulted in tumor stiffness similar to that of normal peritoneum. Concurrently, IF evaluation revealed an increased wave index in both Type I and Type IV collagen, with 50% greater loss of Type IV collagen post-HIPEC peritoneal metastases as compared to pre-HIPEC peritoneal metastases.
Compared to peritoneal metastases obtained prior to HIPEC (pre-HIPEC), post-HIPEC peritoneal metastases demonstrated increased lymphocyte density in tumor-adjacent areas, suggesting tumor injury response . Average distance between lymphocytes in the tumor-adjacent areas decreased from 45 µM to 30 µM (p < 0.001). Lymphocyte density within the tumor (tumor-infiltrating lymphocytes, TILS) was unchanged with HIPEC as was TIL mobility (0.75 µM/s vs. 0.75 µM/s, p=0.98). Intriguingly, we observed an increase in proliferation among tumor-adjacent lymphocytes, TILS, and tumor cells in post-HIPEC peritoneal metastases as compared to pre-HIPEC peritoneal metastases, suggesting global response to therapy.
Conclusions:
HIPEC restores physiologic stiffness to tumor-bearing peritoneum, stimulates immune cell recruitment, and globally activates cell proliferation. Immunomodulatory agents may synergize with HIPEC and should be evaluated in a clinical trial setting.