Endocrine Toxicity and Outcomes in Patients With Metastatic Malignancies Treated With Immune Checkpoint Inhibitors.

CONTEXT: Immune checkpoint inhibitors (ICIs) have gained a revolutionary role in management of many advanced malignancies. However, immune-related endocrine events (irEEs), have been associated with their use. irEEs have nonspecific clinical presentations and variable timelines, making their early diagnosis challenging. OBJECTIVE: To identify risk factors, timelines, and prognosis associated with irEEs development. DESIGN AND SETTING: Retrospective observational study within the Cleveland Clinic center. PATIENTS: Metastatic cancer adult patients who received ICIs were included. METHODS: 570 charts were reviewed to obtain information on demographics, ICIs used, endocrine toxicities, cancer response to treatment with ICI, and overall survival. MAIN OUTCOME MEASURES: Incidence of irEEs, time to irEEs development and overall survival of patients who develop irEEs. RESULTS: The final cohort included 551 patients. The median time for the diagnosis of irEEs was 9 weeks. Melanoma was associated with the highest risk for irEEs (31.3%). Ipilimumab appeared to have the highest percentage of irEEs (29.4%), including the highest risk of pituitary insufficiency (11.7%), the most severe (Grade 4 in 60%) and irreversible (100%) forms of irEEs. Forty-five percent of patients with irEEs had adequate cancer response to ICI compared to 28.3% of patients without irEEs (P = 0.002). Patients with irEEs had significantly better survival compared to patients without irEEs (P < 0.001). CONCLUSIONS: In the adult population with metastatic cancer receiving treatment with ICI, irEEs development may predict tumor response to immunotherapy and a favorable prognosis. Ipilimumab use, combination ICI therapy, and melanoma are associated with a higher incidence of irEEs.

Decreased complex II respiration and HNE-modified SDH subunit in diabetic heart.

Several lines of research suggest that mitochondria play a role in the etiopathogenesis of diabetic cardiomyopathy, although the mechanisms involved are still debated. In the present study, we report that State 3 oxygen consumption decreases by approximately 35% with glutamate and by approximately 30% with succinate in mitochondria from diabetic rat hearts compared to controls. In these mitochondria the enzymatic activities of complex I and complex II are also decreased to a comparable extent. Western blot analysis of mitochondrial protein pattern using antibodies recognizing proteins modified by the lipid peroxidation product 4-hydroxynonenal indicates the FAD-containing subunit of succinate dehydrogenase as one of the targets of this highly reactive aldehyde. In rats diabetic for 6 or 12 weeks, insulin supplementation for 2 weeks decreases the level of protein modified by 4-hydroxynonenal and restores mitochondrial respiration and enzyme activity to control level. Taken together, these results: (1) indicate that 4-hydroxynonenal is endogenously produced within diabetic mitochondria and forms an adduct with selective mitochondrial proteins, (2) identify one of these proteins as a subunit of succinate dehydrogenase, and (3) provide strong evidence that insulin treatment can reverse and ameliorate free radical damage and mitochondrial function under diabetic conditions.

Hyperglycemia does not alter state 3 respiration in cardiac mitochondria from type-I diabetic rats.

Cardiovascular complications are the primary cause of death for diabetic patients. Clinically, the development of dysfunctional cardiomyopathy is one of the main complications of diabetes. Experimental evidence indicates that the mitochondrion is one of the main sites implicated in the development of cardiac dysfunction. Yet, the precise cause and mechanisms involved in the process are largely debated. We report here that heart mitochondria from streptozotocin-induced diabetic Sprague-Dawley rats present a gradual reduction in state 3 oxygen consumption that reaches 35% by the fourth week following diabetes onset. Rats presenting a level of hyperglycemia similar to diabetic animals, but not showing the marked weight loss or appearance of urinary ketones typical of the later group present no decline in state 3 mitochondrial oxygen consumption, the values being indistinguishable from those of mitochondria from control animals. Mitochondria from hyperglycemic non-ketotic rats, however, show a 15-20% increase in state 4 respiration, but only when glutamate is used as energetic substrate. Mitochondria from diabetic rats, instead, show a 40-50% increase in state 4 respiration with glutamate and 20-25% with succinate as energetic substrate. Interestingly, hyperglycemic non-ketotic animals present a level of serum insulin intermediate between those of controls and diabetic animals. These functional modifications are unrelated to the time elapsed since the onset of diabetes, as they are observed at 2, 4, 6 as well as 8 and 12 weeks after diabetes onset. Taken together, these data argue against hyperglycemia per se being a direct cause of the decline in state 3 oxygen consumption observed in cardiac mitochondria of type-I diabetic rats. Rather, they point to insulin level and subsequent metabolic alterations as a possible cause for the insurgence of mitochondrial dysfunction.

Mitochondria respiration and susceptibility to ischemia-reperfusion injury in diabetic hearts.

Cardiovascular complications are the primary cause of death for diabetic patients. Clinical and experimental observation has showed the development of dysfunctional cardiomyopathy as one of the main complications of diabetes. Whether the cardiomyopathy results from an increased susceptibility of cardiac tissue to ischemic insult or from a specific functional defect of cardiac mitochondria is a controversial issue. The investigation of possible functional defect in cardiac mitochondria from diabetic rats indicates a decline in state 3 respiration only in animals presenting a marked decrease in body weight. Mitochondria from rats presenting a level of hyperglycemia similar to diabetic animals but not the marked weight loss typical of the latter group show no decline in state 3 respiration, the values being indistinguishable from those of control mitochondria. Mitochondria from hyperglycemic rats, however, show a 15-20% increase in state 4 oxygen consumption but only when glutamate is used as energetic substrate, as compared to a 40-50% increase in state 4 respiration in mitochondria from diabetic rats under similar experimental conditions. This phenomenon is unrelated to diabetes duration, as it is observed at 2 as well as 8 weeks after diabetes onset. Taken together, these data argue against hyperglycemia per se being a direct cause of the decline in state 3 oxygen consumption observed in cardiac mitochondria of type-I diabetic rats and indicate that differences exist in cardiac mitochondrial function in rats generically labeled as diabetic. These differences can contribute to explain discrepancies in experimental results reported by various groups in the field and provide an additional parameter to be taken into consideration in evaluating the varying sensitivity of diabetic hearts to ischemia-reperfusion injury.