{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T06:07:16Z","timestamp":1789106836642,"version":"build-2803163510"},"reference-count":164,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Health Serv."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Low- to intermediate-suspicion breast nodules (BI-RADS 2\u20134B) generate diagnostic uncertainty, prolonged surveillance, and emotional and operational burden, often without established low-risk interventions designed to support short-interval physiological modulation. Given the redox, endocrine, vascular, and microenvironmental dependencies of benign breast lesions, physiology-guided outpatient modulation may contribute to response-oriented decision-making before conventional oncologic escalation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A structured translational outpatient protocol was developed through mechanistic evidence synthesis, multicriteria translational prioritization, protocol structuring, and exploratory clinical implementation. The workflow integrated Evidence-Informed Design, Work Breakdown Structure, multicriteria decision analysis (MCDA), and DesignThinking\/Open Innovation. Systematic reviews of molecular iodine and dimethyl sulfoxide (DMSO) identified translational response domains and mechanistic convergence pathways associated with tissue accessibility, redox modulation, and outpatient feasibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The translational synthesis identified redox modulation, vascular responsiveness, microenvironmental stabilization, tissue accessibility, and immune-related physiological modulation as principal mechanistic domains associated with iodine-responsive breast-tissue modulation. Comparative prioritization identified the transdermal route as the most operationally feasible outpatient configuration. The finalized protocol\u20142.5\u2005mL of Lugol's solution (5% iodine) combined with 2.5\u2005mL of pharmaceutical-grade DMSO (99.9%), applied transdermally twice weekly for five weeks\u2014was implemented in three exploratory BI-RADS 4B cases using short-interval MRI and ultrasound reassessment. Two cases demonstrated complete radiologic resolution accompanied by vascular-signal normalization and stromal remodeling, including simultaneous remodeling of contralateral BI-RADS 2 nodules; one remained lesion-free during 12-month follow-up. A third case demonstrated a partial imaging-response pattern and was referred for fine-needle aspiration according to predefined reassessment criteria. No major adverse effects or tolerability-related discontinuations occurred; the intervention was discontinued after six sessions in the third case according to the predefined imaging-based stopping rule.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The framework integrates physiological modulation with response-oriented imaging reassessment while preserving compatibility with conventional oncologic workflows. Its low-complexity and reproducible outpatient architecture may possess translational relevance within resource-sensitive and Value-Based Healthcare-oriented breast-care settings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The exploratory implementation of the iodine\u2013DMSO transdermal protocol yielded biologically coherent, imaging-detectable, and operationally reproducible response patterns compatible with short-interval physiological modulation. These findings support controlled outpatient and implementation-oriented investigations evaluating reproducibility, scalability, cost impact, and broader translational applicability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD420251122511<\/jats:ext-link>\n                      , PROSPERO CRD420251122511;\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD420251123805<\/jats:ext-link>\n                      , PROSPERO CRD420251123805.\n                    <\/jats:p>\n                  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