Background: Physical forces exerted by expanding brain tumors - specifically the compressive stresses propagated through solid tissue structures - reduces brain perfusion and neurological function, but heretofore has not been directly measured in patients in vivo. Solid stress levels estimated from tumor growth patterns are negatively correlated with neurological performance in patients. We hypothesize that measurements of solid stress can be used to inform clinical management of brain tumors. Methods: We developed an intraoperative technique to quantitatively estimate solid stress and brain replacement by the tumor. In 30 patients we made topographic measurements of brain deformation through the craniotomy site with a neuronavigation system during surgical workflows immediately preceding tumor resection (< 5 minutes in the OR). Utilizing these measurements in conjunction with finite element modeling, we calculated solid stress within the tumor and the brain, and estimated the amount of brain tissue replaced, i.e., lost, by the tumor growth. Results: Mean solid stresses were in the range of 10 to 600 Pa, and the amount of tissue replacement was up to 10% of the brain. Brain tissue loss in patients delineated glioblastoma from brain metastatic tumors, and in mice solid stress was a sensitive biomarker of chemotherapy response. Conclusions: We present here a quantitative approach to intraoperatively measure solid stress in patients that can be readily adopted into standard clinical workflows. Brain tissue loss due to tumor growth is a novel mechanical-based biomarker that, in addition to solid stress, may inform personalized management in future clinical studies in brain cancer.

SC is consultant at Guidepoint and Coleman Research. LLM owns equity in Bayer AG and is a consultant for SimBiosys. RKJ is a Consultant for Cur, Elpis, Innocoll, SPARC, SynDevRx, Twentyeight-Seven Therapeutics; owns equity in Accurius, Enlight, SynDevRx; Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund and received a research Grant from Boehringer Ingelheim. No funding or reagents from these organizations were used in this study.

MD: National Institutes of Health grants K22-CA258410, R35-GM151041, American Association for Cancer Research-Loxo Oncology postdoctoral fellowship 19-40-50-DATT); ASK: Agency for Science Technology and Research National Science Scholarship; SC: American Brain Tumor Association Basic Research Fellowship, MGH Fund for Medical Discovery Award, Pediatric Cancer Research Foundation Young Investigators Award; RKJ: R35-CA197743), U01-CA224348, R01-CA259253, R01-CA208205, R01-NS118929, U01CA261842, Ludwig Cancer Center at Harvard, Nile Albright Research Foundation, Jane's Trust Foundation, National Foundation for Cancer Research

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