Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs\u27 therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy

RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes.

Malignant tumors of the thyroid gland vary considerably in aggressiveness, ranging from a well-differentiated, clinically indolent, to an undifferentiated, often lethal phenotype. Undifferentiated (anaplastic) thyroid tumors are supposed to be derived, through a process of progression, from previously differentiated neoplasms. A common genetic alteration in thyroid tumors is the rearrangement of the tyrosine kinase-encoding RET proto-oncogene, leading to the generation of chimeric RET/PTC oncogenes. To define the characteristics of the thyroid tumor subset with RET rearrangements, we have investigated its activation by a combined immunohistochemistry and reverse transcription-PCR approach in a series of 316 well-characterized thyroid tumors representative of the main diagnostic groups. RET activation was detected in 81 of 201 (40.3\%) papillary carcinomas. It correlated with tumors exhibiting the "classic" morphological features of papillary cancer or with the microcarcinoma subtype (P = 0.017). RET activation in papillary carcinoma was not associated with clinical markers (such as large tumor size, extrathyroidal extension, or metastases) of increased morbidity. Follicular-type neoplasms (61 adenomas and 22 carcinomas), as well as the aggressive poorly differentiated (15 cases) or undifferentiated (anaplastic) carcinomas (17 cases), were negative. This study demonstrates that all thyroid carcinomas harboring activating RET rearrangements exhibit a well-differentiated phenotype, that of papillary carcinoma, and indicates that the subset of RET/PTC-positive papillary carcinomas do not progress to more aggressive, less differentiated tumor phenotypes