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Supplemental material, sj-pdf-1-opp-10.1177_10781552231167824 for Immunosuppressive therapy management in cancer patients with autoimmune diseases treated with immune checkpoint inhibitors: A case series and systematic literature review by Stephanie C.M. Wuyts, Charlotte A.H. Cappelle, Marthe Verhaert, Bert Bravenboer and Sandrine Aspeslagh in Journal of Oncology Pharmacy Practice

Contains fulltext : 290940.pdf (Publisher’s version ) (Open Access) AIMS: Prescribing errors among junior doctors are common in clinical practice because many lack prescribing competence after graduation. This is in part due to inadequate education in clinical pharmacology and therapeutics (CP&T) in the undergraduate medical curriculum. To support CP&T education, it is important to determine which drugs medical undergraduates should be able to prescribe safely and effectively without direct supervision by the time they graduate. Currently, there is no such list with broad-based consensus. Therefore, the aim was to reach consensus on a list of essential drugs for undergraduate medical education in the Netherlands. METHODS: A two-round modified Delphi study was conducted among pharmacists, medical specialists, junior doctors and pharmacotherapy teachers from all eight Dutch academic hospitals. Participants were asked to indicate whether it was essential that medical graduates could prescribe specific drugs included on a preliminary list. Drugs for which ≥80% of all respondents agreed or strongly agreed were included in the final list. RESULTS: In all, 42 (65%) participants completed the two Delphi rounds. A total of 132 drugs (39%) from the preliminary list and two (3%) newly proposed drugs were included. CONCLUSIONS: This is the first Delphi consensus study to identify the drugs that Dutch junior doctors should be able to prescribe safely and effectively without direct supervision. This list can be used to harmonize and support the teaching and assessment of CP&T. Moreover, this study shows that a Delphi method is suitable to reach consensus on such a list, and could be used for a European list. 01 april 2023

Background : The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of an unprecedented scale, with an ever-growing impact on healthcare systems. The clinical presentation of coronavirus disease 2019 (COVID-19) is diverse, ranging from asymptomatic illness to respiratory failure requiring admission to the intensive care unit (ICU). Risk factors for severe presentation include old age, male gender, underlying comorbidities such as metabolic syndrome, chronic lung diseases, heart-, liver- and kidney diseases, malignancy, immunodeficiency, and pregnancy (1). Little is known about the risk of COVID-19 in patients with rare endocrine malignancies, such as pituitary carcinoma. Case presentation: We describe the case of a 43-year-old man with ACTH-secreting pituitary carcinoma (with cerebellar and cervical drop metastases) who experienced a severe COVID-19 pneumopathy. He had previously received multiple lines of treatment including surgery, radiotherapy, ketoconazole, pasireotide,cabergoline, bilateral (subtotal) adrenalectomy, and temozolomide chemotherapy, as described elsewhere (2). His most recent therapy was a combination of immune checkpoint inhibitors with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) (anti-CTLA-4 and anti-PD-1, respectively) every 3 weeks for 4 cycles, after which maintenance therapy with nivolumab (240 mg) every 2 weeks was continued. Residual endogenous cortisol production was suppressed with ketoconazole 800mg daily. He had disease stabilisation with a decrease in 08:00h plasma ACTH, urinary free cortisol, and stable radiographic findings. Surgical resection of the left adrenal remnant was planned, but could not proceed due to the development of COVID-19 infection. In March 2021, he consulted our emergency department with respiratory exhaustion due to SARS-CoV-2 infection requiring urgent endotracheal intubation. He was commenced on high dose dexamethasone for 10 days together with broad-spectrum antibiotics for positive sputum cultures containing Serratia,methicillin-susceptible S. aureus and H. Influenzae. He developed multiple organ involvement, including metabolic acidosis, acute renal failure requiring continuous veno-venous hemofiltration, acute coronary syndrome type 2, septic thrombophlebitis of the right jugular vein, and critical illness polyneuropathy. He was readmitted twice to the ICU, for ventilator-associated pneumonia and central line-associated bloodstream infection respectively. He was eventually discharged from the hospital and able to continue his rehabilitation. Regarding his endocrine treatment, a "block-replace" regimen was adopted with the continuation of ketoconazole (restarted on day 11), and the supplementation of hydrocortisone at a dose depending on the current level of stress. The consecutive daily dose of hydrocortisone and ketoconazole is demonstrated in Figure 1. Discussion: The learning points of this case are twofold. Firstly, this case illustrates the presence of many of the comorbidities for COVID-19 mortality in patients with Cushing’s disease, such as the cardiovascular risk factors of obesity, arterial hypertension, impaired glucose metabolism, as well as increased thromboembolic risk and increased susceptibility to bacterial infections. Patients with endogenous glucocorticoid excess may therefore be particularly susceptible to severe COVID-19. Secondly, a « block-replace » therapy might be preferred in this patient population, to avoid adrenal insufficiency and reduce the need for biochemical monitoring (as suggested by Newell-Price et al.) (3). References: 1. Gao Y dong, Ding M, Dong X, Zhang J jin, Kursat Azkur D, et al. Risk factors for severe and critically ill COVID-19 patients : A review. Allergy : European Journal of Allergy and Clinical Immunology. 2021. 2. Sol B, de Filette JMK, Awada G, Raeymaeckers S, Aspeslagh S, Andreescu CE, et al. Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma : A new emerging treatment ? Eur J Endocrinol.2021. 3. Newell-Price J, Nieman LK, Reincke M, Tabarin A. ENDOCRINOLOGY in the TIME of COVID-19 : Management of Cushing’s syndrome. Eur J Endocrinol.2020

Background: Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 and its ligand (PD-1/PD-L1) are the current standard-of-care for many advanced cancers (1). This novel therapeutic approach comes with its costs in the form of immune-related adverse events (irAE). The underlying mechanisms are not yet fully understood. We explore the role of HLA in endocrinopathy related to ICI therapy using an interesting patient. Case presentation: A 63-year-old woman was diagnosed in May 2019 with stage IIIB non-small cell lung carcinoma of the right superior lobe with PD-L1 expression > 50%. The patient had a partial therapeutic response on two cycles of radio-chemotherapy with carboplatin and vinorelbine, with persistence of mild hypermetabolism in pulmonary nodules. She was started on consolidation immunotherapy with durvalumab (anti-PD-L1), 10 mg/kg every two weeks, with the intended treatment duration of one year. A routine blood sampling performed before the first chemotherapy showed normal thyroid function with a TSH 1.37 mU/L (reference range: 0.27-4.20) and free T4 19.0 pmol/l (reference range: 12.0-22.0). The thyroid function was not rechecked before the first durvalumab dosing. In December 2019, after three cycles, the patient presented herself at the pneumology department with fatigue, weight loss (2 kg in two months) and increased shortness of breath. Laboratory analysis showed a mild hyperthyroidism with decreased TSH (0.23 mU/L) and increased free T4 (29.4 pmol/l). Approximately 6 weeks later, levothyroxine 50 mg daily was started because of an evolution towards hypothyroidism (with TSH 37.90 mU/L; free T4 5.8 pmol/l), as shown in Figure 1. Thyroperoxidase antibodies were positive (216 kUI/L, reference range: < 34), while the TSH receptor antibodies (TRAb, analysis of stimulating and blocking) were negative. Ultrasound examination of the thyroid was normal. Thyroid scintigraphy was not performed. HLA analysis showed A*02, -; B*15,*40; C*03,*07; the DR haplotypes: DRB1*04,*13, and the DQ haplotypes: DQB1*03,*06. Discussion: This case report illustrates that more attention should be given to the immunogenetic background of oncology patients treated with immunotherapy (2). HLA polymorphisms have been implicated for ‘conventional’ autoimmune thyroid disease (AITD), such as DR4 (susceptible), DR7 and DR13 (protective) for Hashimoto, and DR3 (susceptible) for Graves’ disease. Our patient has a mixed HLA susceptibility, with the presence of both HLA-DR4 (susceptible) and DR13 (protective). A variety fo other HLA associations have been described in patients with endocrinopathy related to immune therapy, such as DR4 in diabetes mellitus; DR4-DQ4 and DR9-DQ9 in diabetes mellitus of Asian origin (3); HLA-A2, A24, B7, DR1 and DR4 (lymphocytic hypophysitis) in two cases of nivolumab-induced hypophysitis, DRB1*04 : 05-DQA1*03 :03-DQB1*04 :01 (autoimmune polyglandular syndrome with pituitary disorder in a Japanese population) in a patient with isolated adrenocorticotropin deficiency by nivolumab-induced hypophysitis. Conclusion: In summary, our case of patient with thyroiditis associated with the PD-L1 inhibitor durvalumab highlights not only the need for proactive monitoring of thyroid function, but also identifying biomarkers associated with an increased risk of ICI-induced side effects for better patient selection, optimal management and improved understanding of the mechanisms involved. References: 1. Sammamed MF, Chen L. A Paradigm Shift in Cancer Immunotherapy : From Enhancement to Normalization. Cell. 2018. 2. Correale P, Saladino RE, Nardone V, Giannicola R, Agostino R, Pirtoli L, et al. Could PD-1/PDL1 immune checkpoints be linked to HLA signature ? Immunotherapy. 2019. 3. De Filette JMK, Pen JJ, Decoster L, Vissers T, Bravenboer B, Van Der Auwera BJ, et al. Immune checkpoint inhibitors and type 1 diabetes mellitus : A case report and systematic review. European Journal of Endocrinology. 2019.

Traditionally, geriatric patients with musculoskeletal or osteoarticular problems will be admitted to an orthopedic ward and will be treated by sur- geons. However, these patients often suffer from comorbidities requiring geriatric management. In this study, the orthogeriatric co-management (OG- CM) model is compared to traditional orthopedic care model in a retrospective pilot study. In this study, two patients groups were compared during two similar time periods : (1) Group 1 consisted of 119 geriatric patients admitted to an orthopedic (trauma) ward who were treated, with conventional geriatric care on demand (before OG- CM ; October 1-December 31, 2013) and (2) Group 2 consisted of 132 geriatric patients who were admitted after the implementation of the OG-CM model (after OG-CM ; October 1-December 31, 2014). Outcomes measured were : quality of care outcome, mortality and costs. After the introduction of OG-CM, the number of diagnoses increased (P = 0.011) adjusting for sex, age, length of stay (LOS), urgency and getting surgery (yes/ no). However, this did not lead to a significant higher severity of illness (SOI). The number of readmissions within a year were significantly lower after OG-CM (0.31 per patient) compared to before OG-CM (0.89 per patient) (P < 0.001). No significant difference in in-house and reported mortality after 3 months was observed. Costs increased, but no significant differences were found. The OG-CM model demonstrated an increase in quality of care. This was indicated by an increased number of medical diagnoses resulting in having less readmissions, without affecting the mortality rates and the LOS. Future randomized multi-centered studies are required to enable causal relationships.