tumorsMalignant tumoursMalignant tumours2224-50572587-6813Rosoncoweb10.18027/2224-5057-2025-060tumors-1599Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL REPORTSЭпидемиология эндокринных иммуноопосредованных нежелательных явлений, предикторы их развития и связь с исходами злокачественных опухолейEpidemiology, Predictors, and Impact of Endocrine Immune-Related Adverse Events on Outcomes in Patients with Malignant Tumorshttps://orcid.org/0000-0001-8420-2854КожевниковА. А.KozhevnikovA. A.

Кожевников Александр Алексеевич

127006 Москва, ул. Долгоруковская, 4

Aleksandr Alekseevich Kozhevnikov

4 Dolgorukovskaya St., Moscow 127006

kaaruds@yandex.ruhttps://orcid.org/0000-0003-1316-5245МкртумянА. М.MkrtumyanA. M.

Мкртумян Ашот Мусаелович

127006 Москва, ул. Долгоруковская, 4

111123 Москва, Новогиреевская ул., 1, корп. 1

Ashot Musaelovich Mkrtumyan

4 Dolgorukovskaya St., Moscow 127006

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0003-4848-6938ЖуковаЛ. Г.ZhukovaL. G.

Жукова Людмила Григорьевна

111123 Москва, Новогиреевская ул., 1, корп. 1

Lyudmila Grigoryevna Zhukova

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0002-0616-5477ГречухинаК. С.GrechukhinaE. S.

Гречухина Катерина Сергеевна

111123 Москва, Новогиреевская ул., 1, корп. 1

Ekaterina Sergeevna Grechukhina

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0002-0340-7119ФеоктистоваП. С.FeoktistovaP. S.

Феоктистова Полина Сергеевна

111123 Москва, Новогиреевская ул., 1, корп. 1

Polina Sergeevna Feoktistova

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0002-7224-3111ФилоненкоД. А.FilonenkoD. A.

Филоненко Дарья Александровна

111123 Москва, Новогиреевская ул., 1, корп. 1

Daria Aleksandrovna Filonenko

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0001-5417-0425ПольшинаН. И.PolshinaN. I.

Польшина Наталья Ивановна

111123 Москва, Новогиреевская ул., 1, корп. 1

Natalia Ivanovna Polshina

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0003-3717-1148ВолковаЕ. И.VolkovaE. I.

Волкова Екатерина Игоревна

111123 Москва, Новогиреевская ул., 1, корп. 1

Volkova Ekaterina Igorevna

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0009-0002-0892-4315РустамоваИ. И.RustamovaI. I.

Рустамова Ирина Игоревна

111123 Москва, Новогиреевская ул., 1, корп. 1

Rustamova Irina Igorevna

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0009-0008-3295-8236КолягоЕ. М.KolyagoE. M.

Коляго Елена Максимовна

111123 Москва, Новогиреевская ул., 1, корп. 1

Kolyago Elena Maksimovna

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0009-0002-8509-5944ПасечнюкО. С.PasechnyukO. S.

Пасечнюк Ольга Сергеевна

111123 Москва, Новогиреевская ул., 1, корп. 1

Pasechnyuk Olga Sergeevna

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0001-8887-2660СмолинС. А.SmolinS. A.

Смолин Сергей Алексеевич

111123 Москва, Новогиреевская ул., 1, корп. 1

Smolin Sergey Alekseevich

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0003-2739-8875ВоронцоваК. А.VorontsovaK. A.

Воронцова Карина Андреевна

111123 Москва, Новогиреевская ул., 1, корп. 1

Vorontsova Karina Andreevna

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0002-3177-1495ЗарьяновД. А.ZaryanovD. A.

Зарьянов Дмитрий Альбертович

111123 Москва, Новогиреевская ул., 1, корп. 1

Zaryanov Dmitry Albertovich

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0002-2745-9765ИбрагимоваТ. М.IbragimovaT. M.

Ибрагимова Тансылу Магсумовна

111123 Москва, Новогиреевская ул., 1, корп. 1

Ibragimova Tansylu Magsumovna

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0009-0004-7119-0160СуховаМ. В.SukhovaM. V.

Сухова Маргарита Витальевна

111123 Москва, Новогиреевская ул., 1, корп. 1

Sukhova Margarita Vitalievna

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0001-7564-7472ОганесянЛ. В.OganesyanL. V.

Оганесян Лиана Вачагановна

111123 Москва, Новогиреевская ул., 1, корп. 1

Oganesyan Liana Vachaganovna

Build. 1, 1 Novogireevskaya St., Moscow 111123

ФГБОУ ВО «Российский университет медицины» Минздрава РоссииРоссияRussian University of MedicineRussian FederationФГБОУ ВО «Российский университет медицины» Минздрава России; ГБУЗ г. Москвы «Московский клинический научно-практический центр им. А. С. Логинова Департамента здравоохранения г. Москвы»РоссияRussian University of Medicine; A. S. Loginov Moscow Clinical Scientific Center, Moscow Healthcare DepartmentRussian FederationГБУЗ г. Москвы «Московский клинический научно-практический центр им. А. С. Логинова Департамента здравоохранения г. Москвы»РоссияRussian University of Medicine; A. S. Loginov Moscow Clinical Scientific Center, Moscow Healthcare DepartmentRussian Federation20250302202615411–25Copyright © Кожевников А.А., Мкртумян А.М., Жукова Л.Г., Гречухина К.С., Феоктистова П.С., Филоненко Д.А., Польшина Н.И., Волкова Е.И., Рустамова И.И., Коляго Е.М., Пасечнюк О.С., Смолин С.А., Воронцова К.А., Зарьянов Д.А., Ибрагимова Т.М., Сухова М.В., Оганесян Л.В., 20262026Кожевников А.А., Мкртумян А.М., Жукова Л.Г., Гречухина К.С., Феоктистова П.С., Филоненко Д.А., Польшина Н.И., Волкова Е.И., Рустамова И.И., Коляго Е.М., Пасечнюк О.С., Смолин С.А., Воронцова К.А., Зарьянов Д.А., Ибрагимова Т.М., Сухова М.В., Оганесян Л.В.Kozhevnikov A.A., Mkrtumyan A.M., Zhukova L.G., Grechukhina E.S., Feoktistova P.S., Filonenko D.A., Polshina N.I., Volkova E.I., Rustamova I.I., Kolyago E.M., Pasechnyuk O.S., Smolin S.A., Vorontsova K.A., Zaryanov D.A., Ibragimova T.M., Sukhova M.V., Oganesyan L.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.malignanttumors.org/jour/article/view/1599

Ингибиторы иммунных контрольных точек (ИИКТ) широко применяются в лечении злокачественных опухолей (ЗО) в виде отдельного варианта терапии, или в комбинации с химиотерапией, или тирозин‑киназными ингибиторами (ТКИ). Эндокринные иммуноопосредованные нежелательные явления (эИОНЯ) являются перспективным маркером эффективности ИИКТ и выживаемости пациентов благодаря их частоте, раннему развитию, четким критериям диагностики.

Цель исследования

Цель исследования: Провести эпидемиологический анализ развития эИОНЯ, выявить предикторы их возникновения и оценить их влияние на исходы ЗО.

Материалы и методы исследования: В ретроспективное исследование были включены совершеннолетние пациенты с солидными ЗО, получившие первое введение ИИКТ совместно с химиотерапией, или c ТКИ, или без них в ГБУЗ МКНЦ им. А. С. Логинова с 01.06.2016 г. по 31.12.2022 г. Общая выживаемость (ОВ) пациентов была прослежена до 01.02.2024 г. Результаты считались значимыми при p < 0,05.

Результаты

Результаты: В исследование было включено 214 участников. Средний возраст — 62,6 лет (от 32 лет до 91 года). эИОНЯ были зарегистрированы у 45,3 % участников, в том числе у 6,5 % — 2 вида эИОНЯ. В 25,7 % выявлялся первичный гипотиреоз, 7,9 % — тиреотоксикоз, 7,5 % — тиреоидит, 7,5 % — вторичная надпочечниковая недостаточность, 1,4 % — ИИКТ‑индуцированный сахарный диабет, у 1 пациента — вторичный гипотиреоз. 64,2 % эИОНЯ было выявлено в первые 26 нед. после начала терапии ИИКТ.

Развитие эИОНЯ коррелировало с лучшей 1‑летней OВ (11,52 мес. против 10,85 мес., log‑rank p = 0,027), особенно среди пациентов с тиреоидными осложнениями (11,6 мес. против 10,82 мес., log‑rank p = 0,009).

В подгруппах участников, не принимавших ТКИ, был на 44 % выше шанс достижения стабилизации (immune stable disease (iSD), р = 0,04) и на 45 % — клинической пользы (clinical benefit rate (CBR), р = 0,03). эИОНЯ чаще развивались при сопутствующем приеме препаратов инкретинового ряда, блокаторов медленных кальциевых каналов и антигистаминных средств, и реже — при производном отношении нейтрофилов к лейкоцитам (derived neutrophil‑tolymphocyte ratio, dNLR)) ≥ 3 исходно и перед вторым введением ИИКТ и dNLR > 2,2 перед вторым введением ИИКТ. эИОНЯ ≥ 2 степени в 2,09 раза чаще регистрировались у пациентов ≥ 60 лет. Комбинация ИИКТ и ТКИ повышает риск развития первичного гипотиреоза в 2,3 раза (р = 0,035).

Заключение

Заключение: Результаты исследования свидетельствуют о частой встречаемости эИОНЯ. Определены возможные факторы риска их развития. Требуется подтверждение данных в проспективных исследованиях.

Immune checkpoint inhibitors (ICIs) are widely used in the treatment of malignant tumors, either as monotherapy or in combination with chemotherapy or tyrosine kinase inhibitors (TKIs). Endocrine immune-related adverse events (e-irAEs) are a promising marker of ICI efficacy and patient survival due to their high frequency, early onset, and clear diagnostic criteria.

Objective

Objective: To conduct an epidemiological analysis of the development of e-irAEs, identify their predictors, and evaluate their impact on cancer outcomes.

Materials and methods

Materials and methods: This retrospective cohort study included adult patients with solid malignant tumors who received their first administration of ICIs (as monotherapy or in combination with chemotherapy or TKIs) at the SBIH Moscow Clinical Scientific and Practical Center named after A. S. Loginov of DHM from June 1, 2016, to December 31, 2022. Overall survival (OS) was followed up until February 1, 2024. Results were considered statistically significant at p < 0.05.

Results

Results: The study included 214 participants with a mean age of 62.6 years (range: 32–91). e-irAEs were reported in 45.3 % of participants, with 6.5 % experiencing two types of e-irAEs. The most common events were primary hypothyroidism (25.7 %), thyrotoxicosis (7.9 %), thyroiditis (7.5 %), secondary adrenal insufficiency (7.5 %), and ICI-induced diabetes mellitus (1.4 %); one patient developed secondary hypothyroidism. 64.2 % of e-irAEs occurred within the first 26 weeks of ICI therapy.

The development of e-irAEs correlated with better 1-year OS (11.52 vs. 10.85 months, log-rank p = 0.027), especially among patients with thyroid-related complications (11.6 vs. 10.82 months, log-rank p = 0.009).

In the subgroup of participants not receiving TKIs, there was a 44 % higher chance of achieving immune stable disease (iSD, p = 0.04) and a 45 % higher chance of clinical benefit (CBR, p = 0.03). e-irAEs occurred more frequently with concomitant use of incretin-based drugs, calcium channel blockers and antihistamines, and less frequently in patients with a derived neutrophil-to-lymphocyte ratio (dNLR) ≥ 3 at baseline and before the second ICI infusion, and a dNLR > 2.2 before the second ICI infusion. e-irAEs grade ≥ 2 were 2.09 times more often recorded in patients ≥ 60 years old. The combination of ICIs and TKIs increased the risk of primary hypothyroidism 2.3-fold (p = 0.035).

Conclusion

Conclusion: The study results indicate a high incidence of e-irAEs. Potential risk factors for their development have been identified. Further validation in prospective studies is required.

иммуноопосредованые нежелательные явленияингибиторы иммунных контрольных точекэндокринологиягипотиреозтиреоидиттиреотоксикознадпочечниковая недостаточностьгипофизитсахарный диабетниволумабипилимумабатезолизумабпембролизумабпролголимабimmune-relates adverse eventsimmune checkpoint inhibitorsendocrinologyhypothyroidismthyroiditisthyrotoxicosisadrenal insufficiencyhypophysitisdiabetes mellitusnivolumabipilimumabatezolizumabpembrolizumabprolgolimabReferencesZhou X., Yao Z., Yang H., et al. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Medicine 2020;18(1):87. https://doi.org/10.1186/s12916-020-01549-2Zhou X., Yao Z., Yang H., et al. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Medicine 2020;18(1):87. https://doi.org/10.1186/s12916-020-01549-2Martins F., Sofiya L., Sykiotis G.P., et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16;(9):563–580. https://doi.org/10.1038/s41571-019-0218-0Martins F., Sofiya L., Sykiotis G.P., et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16;(9):563–580. https://doi.org/10.1038/s41571-019-0218-0Ruste V., Goldschmidt V., Laparra A., et al. The determinants of very severe immune-related adverse events associated with immune checkpoint inhibitors: A prospective study of the French REISAMIC registry. Eur J Cancer 2021;158:217–224. https://doi.org/10.1016/j.ejca.2021.08.048Ruste V., Goldschmidt V., Laparra A., et al. The determinants of very severe immune-related adverse events associated with immune checkpoint inhibitors: A prospective study of the French REISAMIC registry. Eur J Cancer 2021;158:217–224. https://doi.org/10.1016/j.ejca.2021.08.048Patrinely J.R., Johnson R., Lawless A.R., et al. Chronic immune-related adverse events following adjuvant Anti-PD-1 therapy for high-risk resected melanoma. JAMA Oncol 2021;7;(5):744–748. https://doi.org/10.1001/jamaoncol.2021.0051Patrinely J.R., Johnson R., Lawless A.R., et al. Chronic immune-related adverse events following adjuvant Anti-PD-1 therapy for high-risk resected melanoma. JAMA Oncol 2021;7;(5):744–748. https://doi.org/10.1001/jamaoncol.2021.0051Schneider B.J., Naidoo J., Santomasso B.D., et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol: Official Journal of the American Society of Clinical Oncology 2021;39;(36):4073–4126. https://doi.org/10.1200/JCO.21.01440Schneider B.J., Naidoo J., Santomasso B.D., et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol: Official Journal of the American Society of Clinical Oncology 2021;39;(36):4073–4126. https://doi.org/10.1200/JCO.21.01440Seymour L., Bogaerts J., Perrone A., et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18;(3):e143–e152. https://doi.org/10.1016/S1470-2045(17)30074-8Seymour L., Bogaerts J., Perrone A., et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18;(3):e143–e152. https://doi.org/10.1016/S1470-2045(17)30074-8Delgado A., Guddati A.K. Clinical endpoints in oncology - a primer. Am J Cancer Res 2021;11;(4):1121–1131Delgado A., Guddati A.K. Clinical endpoints in oncology - a primer. Am J Cancer Res 2021;11;(4):1121–1131Поддубская Е.В., Секачева М.И., Гурьянова А.А. Эндокринологические осложнения ингибиторов контрольных точек иммунитета: результаты одноцентрового исследования. Сеченовский вестник 2019;10;(4):4–11. https://doi.org/10.47093/22187332.2019.4.4-11.Poddubskaya E.V., Sekacheva M.I., Guryanova A.A. Endocrine adverse events of immune checkpoint inhibitors: results of a single-center study. Sechenov Medical Journal. 2019;10(4):4–11 (In Russ.). https://doi.org/10.47093/22187332.2019.4.4-11Юдин Д.И., Лактионов К.К., Саранцева К.А., и соавт. Иммуноопосредованная эндокринопатия у пациентов на фоне лечения ингибиторами контрольных точек. Медицинский Совет 2020;(9):16–24. https://doi.org/10.21518/2079701X-2020-9-16-24.Yudin D.I., Laktionov K.K., Sarantseva K.A., et al. Immuno-related endocrinopathy in patients treated with immune checkpoint inhibitors. Meditsinskiy sovet = Medical Council. 2020;(9):16–24 (In Russ.). https://doi.org/10.21518/2079701X-2020-9-16-24Del Rivero J., Cordes L.M., Klubo-Gwiezdzinska J., et al. Endocrine-Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management. Oncologist 2020;25;(4):290–300. https://doi.org/10.1634/theoncologist.2018-0470Del Rivero J., Cordes L.M., Klubo-Gwiezdzinska J., et al. Endocrine-Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management. Oncologist 2020;25;(4):290–300. https://doi.org/10.1634/theoncologist.2018-0470Morganstein D.L., Lai Z., Spain L., et al. Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clin Endocrinol 2017;86;(4):614–620. https://doi.org/10.1111/cen.13297Morganstein D.L., Lai Z., Spain L., et al. Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clin Endocrinol 2017;86;(4):614–620. https://doi.org/10.1111/cen.13297Iyer P.C., Cabanillas M.E., Waguespack S.G., et al. Immune-related thyroiditis with immune checkpoint inhibitors. Thyroid: Official Journal of the American Thyroid Association 2018;28;(10):1243–1251. https://doi.org/10.1089/thy.2018.0116Iyer P.C., Cabanillas M.E., Waguespack S.G., et al. Immune-related thyroiditis with immune checkpoint inhibitors. Thyroid: Official Journal of the American Thyroid Association 2018;28;(10):1243–1251. https://doi.org/10.1089/thy.2018.0116Barroso-Sousa R., Barry W.T., Garrido-Castro A.C., et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 2018;4(2):173–182. https://doi.org/10.1001/jamaoncol.2017.3064Barroso-Sousa R., Barry W.T., Garrido-Castro A.C., et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 2018;4(2):173–182. https://doi.org/10.1001/jamaoncol.2017.3064Manaka K., Sato J., Takeuchi M., et al. Immune checkpoint inhibitor combination therapies very frequently induce secondary adrenal insufficiency. Sci Rep 2021;11(1):11617. https://doi.org/10.1038/s41598-021-91032-6Manaka K., Sato J., Takeuchi M., et al. Immune checkpoint inhibitor combination therapies very frequently induce secondary adrenal insufficiency. Sci Rep 2021;11(1):11617. https://doi.org/10.1038/s41598-021-91032-6Helderman N.C., Lucas M.W., Blank C.U. Autoantibodies involved in primary and secondary adrenal insufficiency following treatment with immune checkpoint inhibitors. Immunooncol Technol 2023;17:100374. https://doi.org/10.1016/j.iotech.2023.100374Helderman N.C., Lucas M.W., Blank C.U. Autoantibodies involved in primary and secondary adrenal insufficiency following treatment with immune checkpoint inhibitors. Immunooncol Technol 2023;17:100374. https://doi.org/10.1016/j.iotech.2023.100374Zhou J.-M., Xiong H.-F., Chen X.-P., et al. Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: A retrospective study. World J Gastrointest Oncol 2023;15(4):689–699. https://doi.org/10.4251/wjgo.v15.i4.689Zhou J.-M., Xiong H.-F., Chen X.-P., et al. Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: A retrospective study. World J Gastrointest Oncol 2023;15(4):689–699. https://doi.org/10.4251/wjgo.v15.i4.689Lechner M.G., Vyas C.M., Hamnvik O.-P.R., et al. Hypothyroidism during tyrosine kinase inhibitor therapy is associated with longer survival in patients with advanced nonthyroidal cancers. Thyroid: Official Journal of the American Thyroid Association 2018;28(4):445–453. https://doi.org/10.1089/thy.2017.0587Lechner M.G., Vyas C.M., Hamnvik O.-P.R., et al. Hypothyroidism during tyrosine kinase inhibitor therapy is associated with longer survival in patients with advanced nonthyroidal cancers. Thyroid: Official Journal of the American Thyroid Association 2018;28(4):445–453. https://doi.org/10.1089/thy.2017.0587Xie L., Xu J., Sun X., et al. Anorexia, hypertension, pneumothorax, and hypothyroidism: potential signs of improved clinical outcome following apatinib in advanced osteosarcoma. Cancer Management and Research 2020;12:91–102. https://doi.org/10.2147/CMAR.S232823Xie L., Xu J., Sun X., et al. Anorexia, hypertension, pneumothorax, and hypothyroidism: potential signs of improved clinical outcome following apatinib in advanced osteosarcoma. Cancer Management and Research 2020;12:91–102. https://doi.org/10.2147/CMAR.S232823Dupuis H., Merlen E., Jannin A., et al. Unexpected cure of a toxic nodule in a multinodular goiter induced by immune checkpoint inhibitors: a case report. European Thyroid Journal 2022;11;(4):e220024. https://doi.org/10.1530/ETJ-220024Dupuis H., Merlen E., Jannin A., et al. Unexpected cure of a toxic nodule in a multinodular goiter induced by immune checkpoint inhibitors: a case report. European Thyroid Journal 2022;11;(4):e220024. https://doi.org/10.1530/ETJ-220024Gauci M.-L., Boudou P., Baroudjian B., et al. Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study. Cancer immunology, immunotherapy: CII 2018;67;(8):1197–1208. https://doi.org/10.1007/s00262-018-2178-0Gauci M.-L., Boudou P., Baroudjian B., et al. Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study. Cancer immunology, immunotherapy: CII 2018;67;(8):1197–1208. https://doi.org/10.1007/s00262-018-2178-0Gauci M.-L., Boudou P., Squara P.-A., et al. Checkpoint inhibitor treatment induces an increase in HbA1c in nondiabetic patients. Melanoma Research 2019;29(3):328–332. https://doi.org/10.1097/CMR.0000000000000585Gauci M.-L., Boudou P., Squara P.-A., et al. Checkpoint inhibitor treatment induces an increase in HbA1c in nondiabetic patients. Melanoma Research 2019;29(3):328–332. https://doi.org/10.1097/CMR.0000000000000585Ohara N., Kobayashi M., Ikeda Y., et al. Non-insulin-dependent diabetes mellitus induced by immune checkpoint inhibitor therapy in an insulinoma-associated antigen-2 autoantibody-positive patient with advanced gastric cancer. Internal Medicine 2020;59(4):551–556. https://doi.org/10.2169/internalmedicine.3208-19Ohara N., Kobayashi M., Ikeda Y., et al. Non-insulin-dependent diabetes mellitus induced by immune checkpoint inhibitor therapy in an insulinoma-associated antigen-2 autoantibody-positive patient with advanced gastric cancer. Internal Medicine 2020;59(4):551–556. https://doi.org/10.2169/internalmedicine.3208-19Barreira da Silva R., Laird M.E., Yatim N., et al. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nature Immunology 2015;16(8):850–858. https://doi.org/10.1038/ni.3201Barreira da Silva R., Laird M.E., Yatim N., et al. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nature Immunology 2015;16(8):850–858. https://doi.org/10.1038/ni.3201Roy A., Sahoo J., Narayanan N., et al. Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence. World Journal of Diabetes 2021;12(9):1426–1441. https://doi.org/10.4239/wjd.v12.i9.1426Roy A., Sahoo J., Narayanan N., et al. Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence. World Journal of Diabetes 2021;12(9):1426–1441. https://doi.org/10.4239/wjd.v12.i9.1426Alam M.R., Rahman M.M., Li Z. The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy. Genes & Diseases 2024;11(1):321–334. https://doi.org/10.1016/j.gendis.2023.01.026Alam M.R., Rahman M.M., Li Z. The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy. Genes & Diseases 2024;11(1):321–334. https://doi.org/10.1016/j.gendis.2023.01.026Li C., Yao H., Wang H., et al. Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity. Oncogene 2021;40(6):1128–1146. https://doi.org/10.1038/s41388-020-01592-6Li C., Yao H., Wang H., et al. Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity. Oncogene 2021;40(6):1128–1146. https://doi.org/10.1038/s41388-020-01592-6Thuru X., Magnez R., El-Bouazzati H., et al. Drug repurposing to enhance antitumor response to PD-1/PD-L1 immune checkpoint inhibitors. Cancers 2022;14(14):3368. https://doi.org/10.3390/cancers14143368Thuru X., Magnez R., El-Bouazzati H., et al. Drug repurposing to enhance antitumor response to PD-1/PD-L1 immune checkpoint inhibitors. Cancers 2022;14(14):3368. https://doi.org/10.3390/cancers14143368Li H., Xiao Y., Li Q., et al. The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1. Cancer Cell 2022;40(1):36–52.e9. https://doi.org/10.1016/j.ccell.2021.11.002Li H., Xiao Y., Li Q., et al. The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1. Cancer Cell 2022;40(1):36–52.e9. https://doi.org/10.1016/j.ccell.2021.11.002Eylemer Mocan E., Yekedüz E., Karataş G., et al. Impact of antihistamine use on the survival outcomes of immune checkpoint inhibitors in advanced cancer patients. Anti-Cancer Drugs 2024;35(2):190–194. https://doi.org/10.1097/CAD.0000000000001498Eylemer Mocan E., Yekedüz E., Karataş G., et al. Impact of antihistamine use on the survival outcomes of immune checkpoint inhibitors in advanced cancer patients. Anti-Cancer Drugs 2024;35(2):190–194. https://doi.org/10.1097/CAD.0000000000001498Chiang C.-H., Chiang C.-H., Peng C.-Y., et al. Efficacy of cationic amphiphilic antihistamines on outcomes of patients treated with immune checkpoint inhibitors. European Journal of Cancer (Oxford, England: 1990) 2022;174:1–9. https://doi.org/10.1016/j.ejca.2022.07.006Chiang C.-H., Chiang C.-H., Peng C.-Y., et al. Efficacy of cationic amphiphilic antihistamines on outcomes of patients treated with immune checkpoint inhibitors. European Journal of Cancer (Oxford, England: 1990) 2022;174:1–9. https://doi.org/10.1016/j.ejca.2022.07.006Li H., Zhang L., Yang F., et al. Impact of concomitant medications on the efficacy of immune checkpoint inhibitors: an umbrella review. Frontiers in Immunology 2023;14:1218386. https://doi.org/10.3389/fimmu.2023.1218386Li H., Zhang L., Yang F., et al. Impact of concomitant medications on the efficacy of immune checkpoint inhibitors: an umbrella review. Frontiers in Immunology 2023;14:1218386. https://doi.org/10.3389/fimmu.2023.1218386Rizzo A., Cusmai A., Giovannelli F., et al. Impact of proton pump inhibitors and histamine-2-Receptor antagonists on non-small cell lung cancer immunotherapy: a systematic review and meta-Analysis. Cancers 2022;14;(6):1404. https://doi.org/10.3390/cancers14061404Rizzo A., Cusmai A., Giovannelli F., et al. Impact of proton pump inhibitors and histamine-2-Receptor antagonists on non-small cell lung cancer immunotherapy: a systematic review and meta-Analysis. Cancers 2022;14;(6):1404. https:// doi.org/10.3390/cancers14061404Matsukane R., Watanabe H., Minami H., et al. Continuous monitoring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events. Sci Rep 2021;11(1):1324. https://doi.org/10.1038/s41598-020-79397-6Matsukane R., Watanabe H., Minami H., et al. Continuous monitoring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events. Sci Rep 2021;11(1):1324. https://doi.org/10.1038/s41598-020-79397-6Coffelt S.B., Wellenstein M.D., de Visser K.E. Neutrophils in cancer: neutral no more. Nature Reviews. Cancer 2016;16;(7):431–446. https://doi.org/10.1038/nrc.2016.52Coffelt S.B., Wellenstein M.D., de Visser K.E. Neutrophils in cancer: neutral no more. Nature Reviews. Cancer 2016;16;(7):431–446. https://doi.org/10.1038/nrc.2016.52Eun Y., Kim I.Y., Sun J.-M., et al. Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab. Sci Rep 2019;9(1):14039. https://doi.org/10.1038/s41598-019-50574-6Eun Y., Kim I.Y., Sun J.-M., et al. Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab. Sci Rep 2019;9(1):14039. https://doi.org/10.1038/s41598-019-50574-6Nakamura Y., Tanaka R., Maruyama H., et al. Correlation between blood cell count and outcome of melanoma patients treated with anti-PD-1 antibodies. Jpn J Clin Oncol 2019;49;(5):431–437. https://doi.org/10.1093/jjco/hyy201Nakamura Y., Tanaka R., Maruyama H., et al. Correlation between blood cell count and outcome of melanoma patients treated with anti-PD-1 antibodies. Jpn J Clin Oncol 2019;49;(5):431–437. https://doi.org/10.1093/jjco/hyy201Tasaki Y., Sugiyama Y., Hamamoto S., et al. Eosinophil may be a predictor of immune-related adverse events induced by different immune checkpoint inhibitor types: A retrospective multidisciplinary study. Cancer Medicine 2023;12;(24):21666–21679. https://doi.org/10.1002/cam4.6724Tasaki Y., Sugiyama Y., Hamamoto S., et al. Eosinophil may be a predictor of immune-related adverse events induced by different immune checkpoint inhibitor types: A retrospective multidisciplinary study. Cancer Medicine 2023;12;(24):21666–21679. https://doi.org/10.1002/cam4.6724Zhang W., Tan Y., Li Y., and Liu J. Neutrophil to Lymphocyte ratio as a predictor for immune-related adverse events in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Frontiers in Immunology 2023;14:1234142. P https://doi.org/10.3389/fimmu.2023.1234142Zhang W., Tan Y., Li Y., and Liu J. Neutrophil to Lymphocyte ratio as a predictor for immune-related adverse events in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Frontiers in Immunology 2023;14:1234142. P https://doi.org/10.3389/fimmu.2023.1234142Lu H.-R., Zhu P.-F., Deng Y.-Y., et al. Predictive value of NLR and PLR for immune-related adverse events: a systematic review and meta-analysis. Clinical & Translational Oncology: Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2023. https://doi.org/10.1007/s12094-023-03313-3Lu H.-R., Zhu P.-F., Deng Y.-Y., et al. Predictive value of NLR and PLR for immune-related adverse events: a systematic review and meta-analysis. Clinical & Translational Oncology: Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2023. https://doi.org/10.1007/s12094-023-03313-3Yang T., Hao L., Yang X., et al. Prognostic value of derived neutrophil-to-lymphocyte ratio (dNLR) in patients with non-small cell lung cancer receiving immune checkpoint inhibitors: a meta-analysis. BMJ Open 2021;11(9):e049123. https://doi.org/10.1136/bmjopen-2021-049123.Yang T., Hao L., Yang X., et al. Prognostic value of derived neutrophil-to-lymphocyte ratio (dNLR) in patients with non-small cell lung cancer receiving immune checkpoint inhibitors: a meta-analysis. BMJ Open 2021;11(9):e049123. https://doi.org/10.1136/bmjopen-2021-049123.

The authors declare that there are no conflicts of interest present.