Development of a Systematic Review Protocol and a Scoping Review of Ultrasound-Induced Immune Effects in Peripheral Tumors

Abstract

Purpose: Publication numbers reporting that ultrasound can stimulate immune reactions in tumors steadily increase. However, the presented data are partially conflicting, and mechanisms are difficult to identify from single publications. These shortcomings can be addressed by a systematic review and meta-analysis of current literature. As a first step, we here present the methodology and protocol for a systematic review to answer the following research question: Does ultrasound alter the immune reaction of peripheral solid tumors in humans and animals compared to control conditions without ultrasound?

Procedures: We designed a protocol to perform a systematic review and meta-analysis. The suitability of the protocol to detect and sort relevant literature was tested using a subset of publications. We extracted study characteristics, ultrasound parameters, and study outcomes to pre-evaluate the differences between publications and present the data as a scoping review.

Results: From 6532 publications detected by our preliminary literature search, 320 were selected for testing our systematic review protocol. Of the latter, 15 publications were eligible for data extraction. There, we found large differences between study characteristics (e.g., tumor type, age) and ultrasound settings (e.g., wavelength 0.5-9.5 MHz, acoustic pressure 0.0001-15,000 W/cm²). Finally, study outcomes included reports on cells of the innate (e.g., dendritic cells, macrophages) and adaptive immune system (e.g., CD8-/CD4-positive T cells).

Conclusion: We designed a protocol to identify relevant literature and perform a systematic review and meta-analysis. The differences between extracted features between publications show the necessity for a comprehensive search and selection strategy in the systematic review to get a complete overview of the literature. Meta-analyses of the extracted outcomes can then enable evidence-based conclusions.

Keywords: CEUS; Diagnostic ultrasound; Immune system; Microbubbles; Scoping review; Systematic review protocol; Therapeutic ultrasound.