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Scientific Publications
Exploiting the critical perioperative period to improve long‑term cancer outcomes
This review article was published in 2015 in the prestigious scientific journal Nature. The paper highlights the crucial importance of the short time window surrounding surgical removal of a cancerous tumor (the days before and after surgery) in determining the long-term risk of metastatic disease, even following a successful operation. The review analyzes multiple aspects of surgery and their effects on malignant tissues and the immune system. It discusses surgery-related factors such as anxiety, stress, nutrition, anesthesia, pain management, hypothermia, blood transfusions, tissue injury, and stress and sex hormones. Some of these factors may adversely affect the patient and promote cancer-related processes. By elucidating harmful mechanisms and presenting empirical data, the article outlines various therapeutic and interventional strategies that protect against these factors and improve the likelihood of avoiding metastatic disease in the long term. The paper proposes an interventional treatment based on two drugs that block biological mechanisms known to accelerate cancer progression (inhibition of adrenergic responses and prevention of prostaglandin production). With this pharmacological intervention, the perioperative period may become a window of opportunity to reduce residual cancer burden in the body and improve long-term survival.
Perioperative Biobehavioral Interventions to Prevent Cancer Recurrence Through Combined Inhibition of β-Adrenergic and Cyclooxygenase 2 Signaling
Published in 2018 in the journal Cancer, this review provides a comprehensive overview of biological and clinical processes occurring around the time of surgery in cancer patients. The article describes how these processes, although limited to a relatively short period, can influence long-term cancer outcomes. It analyzes the impact of inflammatory mechanisms and physiological and psychological stress on malignant metastatic progression. The review emphasizes the importance of administering beta-blockers and COX-2 inhibitors during the perioperative period to suppress these stress- and inflammation-related mechanisms and presents evidence from multiple clinical studies demonstrating reduced metastasis and prevention of cancer recurrence following such treatment. In addition, the article reviews the benefits of psychological stress-reduction interventions when pharmacological treatment is contraindicated for medical reasons. Overall, the review demonstrates how pharmacological and/or psychological interventions during the perioperative period can transform this high-risk window for cancer acceleration into a period in which residual disease may be controlled or eliminated, thereby improving recovery prospects.
Perioperative beta-adrenergic blockade and COX2 inhibition in colorectal cancer patients improves pro-metastatic indices in the excised tumor: EMT, tumor infiltrating lymphocytes (TILs), and gene regulatory pathways
This article, published in 2020, presents results from a clinical study conducted by our laboratory in colorectal cancer patients who received a combined anti-inflammatory and beta-adrenergic blocking treatment during the perioperative period. This treatment targets stress- and inflammation-related mechanisms that are amplified during surgery and promote cancer progression and metastasis. Patients were randomly assigned to either a treatment group or a placebo group. Tumor samples were collected for genetic analyses to characterize the effects of the drugs on tumor cells. The results demonstrated a reduction in genetic markers associated with tumor spread and metastasis, along with improved immune cell activity against the tumor. In addition, cancer recurrence after three years was substantially lower in the treatment group compared with the placebo group; however, the sample size was too small to draw definitive conclusions regarding survival outcomes. Accordingly, the study is currently being replicated in larger cohorts of colorectal cancer patients across multiple hospitals in Israel.
Perioperative COX-2 and β-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial
Perioperative Inhibition of β-Adrenergic and COX2 Signaling in a Clinical Trial in Breast Cancer Patients Improves Tumor Ki-67 Expression, Serum Cytokine Levels, and PBMCs Transcriptom
These two articles, published in peer-reviewed scientific journals, present clinical studies conducted by our laboratory in breast cancer patients. The studies examined a combined treatment of a COX-2 inhibitor and a beta-adrenergic blocker administered during the perioperative period in women with early-stage breast cancer. This treatment suppresses excessive activation of stress- and inflammation-related mechanisms that are elevated during surgery and promote cancer progression and metastasis. Patients were randomly assigned to receive either the drug treatment or placebo around the time of surgery. Tumor tissue samples and blood samples were collected to assess pro-metastatic biomarkers. The results demonstrated reductions in pro-metastatic markers, decreases in inflammatory indicators, and increases in immune factors involved in anti-tumor activity. The treatment was found to be safe and represents an effective strategy for counteracting harmful perioperative mechanisms that may lead to cancer recurrence and metastatic spread. These studies underscore the importance of perioperative drug intervention during this critical window, which has long-term implications for survival.
Stress and cancer: mechanisms, significance and future directions
This article, published in 2021 in Nature Reviews Cancer, presents a comprehensive overview of the relationship between stress and cancer progression. The authors demonstrate that physiological and psychological stress influence tumor cells, the immune system, and the tumor microenvironment through activation of adrenergic and inflammatory pathways. These responses promote pro-metastatic processes such as angiogenesis, epithelial-to-mesenchymal transition (EMT), suppression of NK cell activity, and formation of pre-metastatic niches. The article highlights the perioperative period as a particularly sensitive window during which stress and inflammation may accelerate long-term metastatic progression. Accordingly, the authors propose that interventions limiting adrenergic and inflammatory signaling during this period may improve survival and serve as an important complementary component of oncological treatment.
Peri-operative individually tailored psychological intervention in breast cancer patients improves psychological indices and molecular biomarkers of metastasis in excised tumors
In this article, published in 2024, researchers from Prof. Ben-Eliyahu’s laboratory present results from a clinical trial in breast cancer patients examining an individually tailored psychological intervention administered around the time of surgery. The intervention included identification of personal stress patterns, strengthening coping skills, and emotional support. The results demonstrated reductions in psychological distress, alongside molecular changes in tumor tissue indicative of decreased activity in pro-metastatic pathways and improvement in the local immune profile. These findings provide the first evidence that a perioperative psychological intervention may influence not only patients’ psychological well-being but also biological characteristics of the tumor associated with metastatic risk.
