{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T03:00:21Z","timestamp":1777950021128,"version":"3.51.4"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"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. Immunol."],"abstract":"<jats:p>\n                    Adrenocortical carcinoma (ACC) is a rare malignancy with limited therapeutic options following the failure of standard adjuvant therapies. We present a 54-year-old female with stage IV cortisol-secreting ACC that progressed despite radical adrenalectomy, adjuvant radiation, and mitotane therapy. Comprehensive genomic profiling revealed a complex molecular landscape: a \u201cdouble hit\u201d driving hypercortisolism (\n                    <jats:italic>GNAS<\/jats:italic>\n                    activation and\n                    <jats:italic>HSD11B2<\/jats:italic>\n                    alteration) and a high tumor mutational burden (11.6 mutations\/megabase) driven by converging instability mechanisms (\n                    <jats:italic>MSH6, TP53, DAXX, DNMT3A<\/jats:italic>\n                    , and\n                    <jats:italic>KMT2A<\/jats:italic>\n                    somatic mutations, and\n                    <jats:italic>TOP2A<\/jats:italic>\n                    overexpression), despite stable microsatellite status. Guided by this profile, a salvage regimen of pembrolizumab, ipilimumab and lenvatinib was initiated. The patient achieved a profound clinical response with resolution of Cushing\u2019s syndrome and induction of adrenal insufficiency. Follow-up 18F-FDG PET\/CT confirmed a sustained partial response per response evaluation criteria in solid tumors (RECIST) 1.1, accompanied by significant metabolic improvement with regression of metastatic burden with evident central photopenia in peritoneal lesions. This case illustrates how multi-faceted genomic analysis can rationalize aggressive combination immunotherapy in refractory ACC.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1819473","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T05:34:25Z","timestamp":1777872865000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: triple therapy with pembrolizumab, ipilimumab, and lenvatinib in mitotane- and radiation-refractory, cortisol-secreting stage IV adrenocortical carcinoma: a genomically guided approach"],"prefix":"10.3389","volume":"17","author":[{"given":"Afif","family":"Nakhleh","sequence":"first","affiliation":[{"name":"Diabetes and Endocrinology Clinic, Maccabi Healthcare Services","place":["Haifa, Israel"]},{"name":"Institute of Endocrinology, Diabetes and Metabolism, Rambam Health Care Campus","place":["Haifa, Israel"]},{"name":"Azrieli Faculty of Medicine, Bar-Ilan University","place":["Safed, Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmad","family":"Mahamid","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine, Technion Israel Institute of Technology","place":["Haifa, Israel"]},{"name":"Department of Surgery, Carmel Medical Center","place":["Haifa, Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaniv","family":"Yechiel","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine, Technion Israel Institute of Technology","place":["Haifa, Israel"]},{"name":"Department of Nuclear Medicine, Rambam Health Care Campus","place":["Haifa, Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonard","family":"Saiegh","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine, Technion Israel Institute of Technology","place":["Haifa, Israel"]},{"name":"Institute of Endocrinology, Bnai Zion Medical Center","place":["Haifa, Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sagit","family":"Zolotov","sequence":"additional","affiliation":[{"name":"Diabetes and Endocrinology Clinic, Maccabi Healthcare Services","place":["Haifa, Israel"]},{"name":"Institute of Endocrinology, Diabetes and Metabolism, Rambam Health Care Campus","place":["Haifa, Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salomon M.","family":"Stemmer","sequence":"additional","affiliation":[{"name":"Davidoff Center, Rabin Medical Center","place":["Petah Tikva, Israel"]},{"name":"Faculty of Medicine, Tel Aviv University","place":["Tel Aviv, Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(24)00378-4","article-title":"Adrenocortical carcinoma: a practical guide for 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