Associations between immune-related thyroid dysfunction and efficacy of immune checkpoint inhibitors: a systematic review and meta-analysis.

BACKGROUND: There is growing evidence suggesting that the occurrence of immune-related adverse events (irAEs) may be a predictor of immune checkpoint inhibitor efficacy. Whether this association extends to all irAEs or just those within particular organs/systems is yet to be resolved. As immune-related thyroid dysfunction (thyroid irAE) is one of the most commonly reported irAEs, this study aims to summarize the available data and determine if thyroid irAE is a surrogate marker for improved cancer outcomes during ICI therapy. METHODS: PubMed, EMBASE and Cochrane Library were searched up to July 1st 2021 for studies assessing the relationship between thyroid irAE development during ICI therapy and cancer outcomes. Outcome measures of interest include overall survival (OS) and progression free survival (PFS). Sub-group analyses based on cancer type and adjustment for immortal time bias (ITB) were also performed. RESULTS: Forty-seven studies were included in the systematic review. Twenty-one studies were included in the OS meta-analysis whilst 15 were included in the PFS meta-analysis. Development of thyroid irAE during ICI therapy was associated with improved OS and PFS (OS: HR 0.52, CI 0.43-0.62, p < 0.001; PFS: HR 0.58, CI 0.50-0.67, p < 0.001). Sub-group analyses involving non-small cell lung cancer populations and studies where ITB was accounted for, observed similar results (HR 0.37, CI 0.24-0.57, p < 0.001) and (HR 0.51, CI 0.39-0.69, p < 0.001), respectively. CONCLUSION: Despite the heterogeneity and biases identified, the evidence does suggest that the development of thyroid irAE is associated with anti-tumor effects of ICIs and therefore, can be used as a surrogate marker for clinical response.

A targeted approach to phosphoinositide-3-kinase/Akt/mammalian target of rapamycin-induced hyperglycemia.

Phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway inhibitors are a novel class of antineoplastic agent available for the treatment of various cancers. With improved cancer outcomes and survival, individuals are exposed to these antineoplastic therapies for longer periods of time and therefore, the consideration of adverse effects is of increasing importance. The PI3K/Akt/mTOR signaling pathway plays a critical role in regulating cellular processes such as growth and proliferation, but also regulates the metabolic effects of insulin such as glucose uptake and glycogen synthesis. Therefore, hyperglycemia and insulin resistance are frequently reported adverse effects. There are no recent consensus guidelines on the management of hyperglycemia secondary to PI3K/Akt/mTOR inhibitors, with the latest guidelines produced in 2012 - when many of these agents were still undergoing development. As we now have a greater understanding of the underlying mechanisms and patterns in which hyperglycemia is induced and access to an increasing array of glucose-lowering agents, an update of the previous guidelines accommodating these understandings and developments is timely. This review will provide a comprehensive summary of the current literature with regards to the incidence of hyperglycemia associated with each agent, as well as the different pathways and mechanisms in which hyperglycemia is induced. Our proposed up-to-date strategy for the specific management of PI3K/Akt/mTOR inhibitor-induced hyperglycemia will also aim to facilitate management of this complex oncological population.

Teriparatide in individuals with a prior history of radiation therapy-a case series.

PURPOSE: Teriparatide is a highly effective anabolic therapy for use in patients with osteoporosis at elevated fracture risk but carries a warning about an increased risk of osteosarcoma based on findings from pre-approval animal studies. Since approval, follow-up of individuals treated with teriparatide has not shown an increased risk of osteosarcoma, but it is still recommended to avoid teriparatide in patients with risk factors for osteosarcoma. One such risk factor is radiotherapy; deciding whether to use teriparatide therapy in patients at high risk of fracture but with a history of radiotherapy is therefore a frequent clinical problem. METHODS: We sought to identify whether clinicians are using teriparatide in patients with a history of radiotherapy despite the warning and to explore the rationale for this choice. Herein, we describe six cases where the likelihood of fracture, osteosarcoma, and the benefits of teriparatide treatment are assessed to determine the appropriateness of prescribing teriparatide in the setting of prior or concurrent radiotherapy. RESULTS: All six patients had severe osteoporosis with limited treatment options. For those who completed 2 years of teriparatide, no further fractures during the follow-up period have occurred, and improvements in bone density (as measured by dual-energy X-ray absorptiometry) were observed. CONCLUSION: Despite radiotherapy being a relative contraindication to teriparatide use, there may be a role for teriparatide in select cases where osteoporosis is complex and severe and where other treatment options are not suitable or have been exhausted. The risks vs. benefits of prescribing teriparatide in this population should always be carefully considered, and both the patient and treating oncologist should be educated on the potential risk of osteosarcoma development when teriparatide is continued during radiotherapy.

Omentin-1 levels are reduced by pharmacologic doses of leptin, but remain unaffected by energy deprivation and display no day-night variation.

OBJECTIVE: To study the day-night variation of omentin-1 levels and assess whether leptin and/or short- and long-term energy deprivation alter circulating omentin-1 levels via cytokines. DESIGN AND METHODS: Omentin-1 levels were measured hourly in serum samples from six healthy men to evaluate for day-night variation. To study effects of acute energy deprivation and of leptin administration, eight healthy subjects were studied in the fasting state for 72 h with administration of either placebo or metreleptin (recombinant human leptin) in physiologic replacement doses. We evaluated the effect of leptin in pharmacologic doses on serum omentin-1 and cytokine levels, as well as on omentin-1 levels in ex vivo omental adipose tissue, in 15 healthy volunteers. To study the effect of chronic energy deprivation and weight loss on omentin-1 levels, we followed 18 obese subjects for 12 months who underwent bariatric surgery. RESULTS: There is no day-night variation in omentin-1 levels. Short-term and chronic energy deprivation, as well as ex vivo leptin administration and physiologic replacement doses of leptin, do not alter omentin-1 levels; pharmacologic doses of metreleptin reduce omentin-1 levels, whereas levels of tumor necrosis factor-α receptor II and interleukin-6 tend to increase. CONCLUSIONS: Omentin-1 levels are reduced by pharmacologic doses of metreleptin independent of effects on cytokine levels.

Thyroid dysfunction from antineoplastic agents.

Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient's quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents.