A preclinical model to investigate the role of surgically-induced inflammation in tumor responses to intraoperative photodynamic therapy

Our plain-English summary of A preclinical model to investigate the role of surgically-induced inflammation in tumor responses to intraoperative photodynamic therapy, by R.W. Davis, E. Papasavvas, A. Klampatsa, et al (Lasers in Surgery and Medicine, 2018).

The study

• Authors: R.W. Davis, E. Papasavvas, A. Klampatsa, M. Putt, L.J. Montaner, M.J. Culligan, S. McNulty, J.S. Friedberg, C.B. Simone, S. Singhal, S.M. Albelda, K.A. Cengel, T.M. Busch
• Journal: Lasers in Surgery and Medicine
• Published: 2018;50(5):440-450
• Type of article: Randomized trial
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objective: Inflammation is a well-known consequence of surgery. Although surgical debulking of tumor is beneficial to patients, the onset of inflammation in injured tissue may impede the success of adjuvant therapies. One marker for postoperative inflammation is IL-6, which is released as a consequence of surgical injuries. IL-6 is predictive of response to many cancer therapies, and it is linked to various molecular and cellular resistance mechanisms. The purpose of this study was to establish a murine model by which therapeutic responses to photodynamic therapy (PDT) can be studied in the context of surgical inflammation.

Materials And Methods: Murine models with AB12 mesothelioma tumors were treated with either surgical resection or sham surgery with tumor incision but no resection. The timing and extent of IL-6 release in the tumor and/or serum was measured using enzyme-linked immunosorbent assay (ELISA) and compared to that measured in the serum of 27 consecutive, prospectively enrolled patients with malignant pleural mesothelioma (MPM) who underwent macroscopic complete resection (MCR).

Results: MPM patients showed a significant increase in IL-6 at the time MCR was completed. Similarly, IL-6 increased in the tumor and serum of mice treated with surgical resections. However, investigations that combine resection with another therapy make it necessary to grow tumors for resection to a larger volume than those that receive secondary therapy alone. As the larger size may alter tumor biology independent of the effects of surgical injury, we assessed the tumor incision model. In this model, tumor levels of IL-6 significantly increased after tumor incision.

Conclusion: The tumor incision model induces IL-6 release as is seen in the surgical setting, yet it avoids the limitations of surgical resection models. Potential mechanisms by which surgical induction of inflammation and IL-6 could alter the nature and efficacy of tumor response to PDT are reviewed. These include a wide spectrum of molecular and cellular mechanisms through which surgically-induced IL-6 could change the effectiveness of therapies that are combined with surgery. The tumor incision model can be employed for novel investigations of the effects of surgically-induced, acute inflammation on therapeutic response to PDT (or potentially other therapies). Lasers Surg. Med. 50:440-450, 2018. © 2018 Wiley Periodicals, Inc.

© 2018 Wiley Periodicals, Inc.

In plain English

This paper described a new mouse model for studying whether inflammation caused by surgery affects photodynamic therapy (PDT), a light-activated treatment given during surgery for malignant pleural mesothelioma. It also reviewed published research on possible mechanisms. The authors used blood from 26 of the first 27 consecutive patients with epithelioid malignant pleural mesothelioma on a phase II clinical trial. In these patients, serum levels of the inflammation marker IL-6 (mean plus or minus standard error) were 212 plus or minus 22 pg/ml when surgery had removed all visible tumor. Five to seven days before surgery they were 30 plus or minus 7 pg/ml. In mice with AB12 mesothelioma flank tumors, partly removing the tumor raised IL-6 in blood and in the remaining tumor 4 hours later. Cutting into the tumor without removing any raised tumor IL-6 from 42 plus or minus 3 to 138 plus or minus 38 pg/mg at 4 hours. Levels fell back to baseline from 6 hours on. The authors concluded that the incision model reproduces surgical IL-6 release without the need to grow larger tumors. PDT results were not reported; that work was ongoing.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Development of a mouse (preclinical) tumor model, compared with blood measurements from patients on a clinical trial, plus a literature review of possible mechanisms
• Who was studied: Patients: subjects with epithelioid malignant pleural mesothelioma on a randomized phase II trial of lung-sparing pleurectomy/decortication and post-operative chemotherapy with or without intraoperative PDT. Blood came from 26 of the first 27 consecutive subjects (22 of 26 male; 8 had neoadjuvant pemetrexed and platinum-based chemotherapy). 24 of 27 were operated at the Hospital of the University of Pennsylvania and 3 at Roswell Park Cancer Institute, June 2014 to June 2017. Mice: BALB/c mice with AB12 mouse mesothelioma tumors grown on the right flank, in small groups (3 to 6 mice in the incision experiments).
• Exposure: No asbestos exposure was studied. The exposures were surgery in patients (macroscopic complete resection) and, in mice, either surgical resection of tumors grown to 300 cubic millimeters down to 80 cubic millimeters, or a sham 'tumor incision' of 80 cubic millimeter tumors cut to half their depth with nothing removed.
• Main results:
  • Patients: serum IL-6 (mean plus or minus SE) was 212 plus or minus 22 pg/ml at completion of macroscopic complete resection, compared with 30 plus or minus 7 pg/ml at baseline (5 to 7 days before surgery)
  • Patients: PGE2 levels did not change after resection compared with baseline
  • Mice, surgical resection: serum IL-6 was 49 plus or minus 4 pg/ml at 4 hours after surgery, compared with 11 plus or minus 7 pg/ml in mice whose tumors were not resected. It remained high at 6 hours and declined at 16 hours.
  • Mice, surgical resection: tumor IL-6 rose from 34 plus or minus 8 pg/mg in unresected tumor to 149 plus or minus 29 pg/mg in residual tumor at 4 hours after resection, and remained high through 16 hours
  • Mice, tumor incision: tumor IL-6 increased from 42 plus or minus 3 pg/mg in untreated tumors to 138 plus or minus 38 pg/mg at 4 hours after incision, then declined to baseline levels at 6 hours and later
• The authors' conclusion: The authors concluded that the tumor incision model raises IL-6 as seen in the clinical surgical setting while avoiding the need to grow larger tumors for resection. They stated it can be used to study how surgically induced inflammation affects response to PDT, and that this use was ongoing.
• Limitations the authors state:
  • The source of the IL-6 was unknown in both the patient and mouse studies
  • In the surgical resection model, tumors must be grown larger, which may introduce confounding factors beyond surgical trauma (the reason the incision model was developed)

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Inflammation, Mesothelioma, Surgical Resection, Pleural Mesothelioma.

Related studies

• Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma — J.S. Friedberg, M.J. Culligan, et al. (2012)
• A dual role for the immune response in a mouse model of inflammation-associated lung cancer — M. Dougan, D. Li, et al. (2011)
• 3D Culture Models of Malignant Mesothelioma Reveal a Powerful Interplay Between Photodynamic Therapy and Kinase Suppression Offering Hope to Reduce Tumor Recurrence — B.Q. Spring, D. Kessel (2019)
• Photodynamic therapy as adjuvant therapy in surgically treated pleural malignancies — P. Baas, L. Murrer, et al. (1997)
• Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma — H.I. Pass, B.K. Temeck, et al. (1997)
• Preclinical investigation of folate receptor-targeted nanoparticles for photodynamic therapy of malignant pleural mesothelioma — T. Kato, C.S. Jin, et al. (2018)

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