Clinical outcomes of immune checkpoint inhibitor diabetes mellitus at a comprehensive cancer center.

Introduction: Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare adverse event. In this study, we characterize clinical outcomes of patients with ICI-DM and evaluate survival impact of this complication on melanoma patients. Research design & methods: We conducted a retrospective review of 76 patients diagnosed with ICI-DM from April 2014 to December 2020. Results: 68% of patients presented in diabetic ketoacidosis, 16% had readmissions for hyperglycemia, and hypoglycemia occurred in 70% of patients after diagnosis. Development of ICI-DM did not impact overall survival or progression-free survival in melanoma patients. Conclusion: Development of ICI-DM is associated with long-term insulin dependence and pancreatic atrophy; the use of diabetes technology in this patient population can help improve glycemic control.

Cancer treatment with immune checkpoint inhibitors can cause irreversible side effects. In this study, we describe the clinical presentations of 76 patients who developed immune checkpoint inhibitor diabetes mellitus, a rare complication of checkpoint inhibitor therapy that requires lifelong treatment with insulin therapy. Most patients presented with a life-threatening hyperglycemic emergency and had experienced weight loss and hyperglycemia several weeks prior to diagnosis. After diagnosis, these patients are at risk for high and low blood sugars, but the use of glucose monitoring devices and insulin pumps can help improve blood sugar control. In our study, the development of this complication did not affect survival for melanoma patients. We need to improve awareness of this rare complication to ensure timely treatment for patients.

A CASE OF ACQUIRED GENERALIZED LIPODYSTROPHY ASSOCIATED WITH PEMBROLIZUMAB IN A PATIENT WITH METASTATIC MALIGNANT MELANOMA.

OBJECTIVE: To describe an unusual immune-related adverse event (irAE), acquired generalized lipodystrophy (AGL), from checkpoint inhibitor therapy in a patient treated with pembrolizumab. METHODS: This is a case report of a 67-year-old male with metastatic melanoma who was treated with pembrolizumab. Prior to pembrolizumab, the patient was treated with another immune-checkpoint inhibitor and developed autoimmune hemolytic anemia. After starting pembrolizumab, he developed a scrotal mass consistent with panniculitis and after several subsequent cycles, he developed AGL. RESULTS: Loss of subcutaneous fat, unexplained weight loss in combination with worsening insulin resistance and worsening hypertriglyceridemia after initiation of pembrolizumab were consistent with AGL. Autoimmune disorders and other etiologies were ruled out. Despite this irAE, the patient continued to receive pembrolizumab given stabilization of melanoma with treatment. CONCLUSION: We report the second case of a patient who developed AGL secondary to pembrolizumab, and the fourth case to report such complication secondary to antiprogrammed cell death receptor-1 inhibitors. As use of checkpoint inhibitors becomes more common to treat several types of cancer, it is vital for clinicians to recognize these rare irreversible complications that are not frequently reported in clinical trials.

Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.

BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae. METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT. RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis. CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.

Co-Managing Patients with Type 1 Diabetes and Cancer.

The life expectancy of people with type 1 diabetes is improving and now approaches that of those without diabetes. As this population ages, a growing number will be diagnosed with and treated for cancer. Cancer treatments can drastically affect insulin requirement and glycemic control through multiple mechanisms including high doses of glucocorticoids and targeted therapies that directly interfere with cellular pathways involved in the action of insulin. Patients with cancer frequently also have alterations in gastrointestinal motility or appetite and require supplemental enteral or parenteral nutrition. Few studies have evaluated these patients directly, but data on patients with and without diabetes suggest that glycemic control may play a larger role in cancer outcomes than is often recognized. Collaboration between the treating oncologist and diabetologist allows people with diabetes to receive the most effective therapies for their cancers without undue risk of hypoglycemia or adverse outcomes due to hyperglycemia.

Safe and effective dosing of basal-bolus insulin in patients receiving high-dose steroids for hyper-cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy.

BACKGROUND: Hyperglycemia occurs in cancer patients receiving high-dose steroids with cyclophosphamide, doxorubicin, vincristine, and dexamethasone (hyper-CVAD) protocol. The purpose of our study was to determine insulin requirements in patients with hyperglycemia on hyper-CVAD therapy using a systematic algorithm. SUBJECTS AND METHODS: We did a retrospective chart review of 23 leukemia inpatients with hyperglycemia (two glucose values >250 mg/dL) on hyper-CVAD chemotherapy managed by the Endocrine Diabetes Inpatient Team algorithm. We reviewed demographic and glycemic data, insulin dosages, and use of oral hypoglycemic agents. Using our algorithm, the dose of insulin for each patient was titrated daily and with each subsequent cycle of hyper-CVAD. RESULTS: Ninety-one percent of patients had known diabetes. The median body mass index was 32.5 (range, 21.6-40.9) kg/m², and median age was 61 (range, 40-80) years. The overall trend in glucose values across cycles showed a statistically significant decrease with each subsequent cycle of hyper-CVAD. Hyperglycemia accounted for 81% of glucose measurements in the first cycle and 60% of glucose values in the last cycle. Patients received 1-1.3 units/kg of insulin per cycle, and insulin requirements were similar across cycles. The distribution of basal versus bolus insulin for each cycle was 63-77% prandial and 23-37% basal. Nine of the 23 patients had at least one glucose value <70 mg/dL, which accounted for 1.3% of all recorded glucose values. None of the patients had severe hypoglycemia. CONCLUSIONS: Multiple-dose insulin therapy initiated at 1-1.2 units/kg/day, distributed as 25% basal and 75% prandial, reduced hyperglycemia in patients who were receiving high-dose dexamethasone as part of hyper-CVAD.

A randomized controlled trial of an intensive insulin regimen in patients with hyperglycemic acute lymphoblastic leukemia.

UNLABELLED: Hyperglycemia during hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine, with methylprednisolone premedication) chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL). To examine whether intensive insulin therapy could improve outcomes, a randomized trial was conducted that compared glargine plus aspart vs. conventional therapy. Intensive insulin did not improve ALL clinical outcomes despite improved glycemic control. Secondary analysis suggests that the choice of antidiabetic pharmacotherapy may influence ALL outcomes. INTRODUCTION: Hyperglycemia during hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine, with methylprednisolone premedication) chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: To examine whether an intensive insulin regimen could improve outcomes compared with conventional antidiabetic pharmacotherapy, a randomized trial was conducted that compared glargine plus aspart vs. conventional therapy (control). Between April 2004 and July 2008, 52 patients newly diagnosed with ALL, Burkitt lymphoma, or lymphoblastic lymphoma who were on hyper-CVAD in the inpatient setting and had a random serum glucose level >180 mg/dL on ≥2 occasions during chemotherapy were enrolled. RESULTS: The trial was terminated early due to futility regarding ALL clinical outcomes despite improved glycemic control. Secondary analysis revealed that molar insulin-to-C-peptide ratio (I/C) > 0.175 (a surrogate measure of exogenous insulin usage) was associated with decreased overall survival, complete remission duration and progression-free survival (PFS), whereas metformin and/or thiazolidinedione usage were associated with increased PFS. In multivariate analyses, factors that significantly predicted short overall survival included age ≥ 60 years (P = .0002), I/C ≥ 0.175 (P = .0016), and average glucose level ≥ 180 mg/dL (P = .0236). Factors that significantly predicted short PFS included age ≥ 60 years (P = .0008), I/C ≥ 0.175 (P = .0002), high systemic risk (P = .0173) and average glucose level ≥ 180 mg/dL (P = .0249). I/C ≥ 0.175 was the only significant (P = .0042) factor that predicted short complete remission duration. CONCLUSIONS: A glargine-plus-aspart intensive insulin regimen did not improve ALL outcomes in patients with hyperglycemia. Exogenous insulin may be associated with poor outcomes, whereas metformin and thiazolidinediones may be associated with improved outcomes. Analysis of these results suggests that the choice of antidiabetic pharmacotherapy may influence ALL outcomes.

Relation of severe coronary artery narrowing to insulin or thiazolidinedione use in patients with type 2 diabetes mellitus (from the Bypass Angioplasty Revascularization Investigation 2 Diabetes Study).

Patients with diabetes continue to die of coronary artery disease (CAD) at rates 2 to 4 times higher than patients without diabetes, despite advances in treatment of cardiovascular disease. The role of glycemic control therapies, independent of their glucose-lowering effects, on cardiovascular disease is a recurring question. We examined the association of glycemic control therapies with extent of CAD as measured by coronary angiogram obtained at baseline in 1,803 subjects in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial who had type 2 diabetes mellitus, documented moderate to severe CAD, and no previous cardiac revascularization procedures. The association between glycemic control therapy use recorded at baseline and percent coronary artery stenosis and myocardial jeopardy index was analyzed by multiple regression models. Insulin use at study entry was associated with 23% fewer highly stenotic lesions (> or =70%) (p <0.001) and a significantly lower myocardial jeopardy index compared with subjects not on insulin, despite a worse cardiac risk factor profile, more unstable angina, and increased inflammatory markers in insulin users. Subjects taking thiazolidinediones (TZDs) for > or =6 months had 17% fewer highly stenotic lesions (p = 0.02) and significantly lower C-reactive protein, fibrinogen, and plasminogen activator inhibitor-1 levels compared with those not taking TZDs. In conclusion, this cross-sectional study of patients with type 2 diabetes mellitus and CAD showed that treatment with insulin or TZDs was associated with fewer highly stenotic lesions, independent of disease duration, glycemic control, and other risk factors.

Pituitary apoplexy after leuprolide.

Clinically unsuspected pituitary adenomas are common among adults on autopsy and MRI survey. Acute pituitary hemorrhage is far more rare. We report a case of a 61-year-old male patient with locally advanced prostate cancer who presented with an acute picture of pituitary apoplexy after his first dose of leuprolide. He developed headache and neck pain within a few hours of treatment followed by nausea, vomiting, ptosis and diplopia. Pituitary apoplexy is a potentially life threatening medical emergency. Although the pathophysiology is poorly defined, various conditions and treatments have been reported to trigger apoplexy. Apoplexy has been reported in response to pituitary stimulation by GnRH or GnRH-agonists. Initial stimulatory effects of gonadotropin releasing hormone (GnRH) analogue may induce apoplexy in patients with asymptomatic gonadotroph adenomas.

Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.

OBJECTIVE: Milk-alkali syndrome, once a common cause of hypercalcaemia, is now considered rare. Our aim was to estimate the prevalence of milk-alkali syndrome among hypercalcaemic, non-end-stage renal disease (non-ESRD) inpatients of a University Hospital and identify patients' and syndrome characteristics. DESIGN AND PATIENTS: In this retrospective chart review study, we identified patients hospitalized with possible hypercalcaemia between November 1998 and October 2003 by a computer search of admission, discharge and consultation diagnoses. Patients with renal transplantation, stage 5 chronic kidney disease (CKD-5) and those admitted for parathyroidectomy were excluded. The remaining patients' charts were reviewed for confirmation of hypercalcaemia and identification of the cause. In patients with milk-alkali syndrome, additional historical, clinical, laboratory and imaging data were collected. RESULTS: We identified 125 patients with hypercalcaemia, 11 (8.8%) of whom had milk-alkali syndrome, 42 (33.6%) had malignancy and 37 (29.6%) hyperparathyroidism. Thirty-five patients had severe hypercalcaemia, defined as corrected serum calcium 3.5 mmol/l. Malignancy accounted for 13 of those patients (37.1%) and milk-alkali for nine (25.7%). Conditions prevalent among the milk-alkali inpatients were female gender, hypertension, chronic kidney disease, osteoporosis, upper gastrointestinal diseases, diuretic treatment and vitamin D derivative supplementation. Five of the patients with milk-alkali syndrome were treated with bisphosphonates and all five developed hypocalcaemia, compared to one of the five who received conventional treatment (P = 0.047). CONCLUSION: Milk-alkali was the third leading cause of hypercalcaemia of any degree and the second cause of severe hypercalcaemia among inpatients without ESRD. In milk-alkali syndrome, treatment with bisphosphonates contributes to post-treatment hypocalcaemia.

Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone.

OBJECTIVE: To attempt to confirm a previous report of superior effectiveness of using two thyroid hormones rather than one hormone to treat hypothyroidism. METHODS: This trial attempted to replicate prior findings, which suggested that substituting 12.5 microg of liothyronine (LT(3)) for 50 microg of levothyroxine (LT(4)) might improve mood, cognition, and physical symptoms in patients with primary hypothyroidism. Additionally, this trial aimed to extend the previous findings to fatigue and to assess for differential effects in subjects with low fatigue and high fatigue at baseline. A randomized, double-blind, two-period, crossover design was used. At an endocrinology and diabetes clinic, 30 adult subjects with primary hypothyroidism stabilized on LT(4) were recruited. Patients randomly assigned to treatment sequence 1 received their standard LT(4) dose in one capsule and placebo in another. Patients assigned to sequence 2 received their usual LT(4) dose minus 50 microg in one capsule and 10 microg of LT(3) in the other. At the end of the first 6 weeks, subjects were crossed over to receive the other treatment. Carryover and treatment effects were assessed by t tests. RESULTS: Of the 30 enrolled study subjects, 27 completed the trial. The mean LT(4) dose was 121 +/- 26 microg/day at baseline. No significant differences in fatigue and symptoms of depression were found between treatments. Measures of working memory were unchanged. During substitution treatment, the free thyroxine index was reduced by 0.7 (P<0.001), total serum thyroxine was reduced by 3.0 microg/dL (P<0.001), and total serum triiodothyronine was increased by 20.5 ng/dL (P = 0.004). CONCLUSION: With regard to the outcomes measured, substitution of LT(3) at a 1:5 ratio for a portion of baseline LT(4) yielded no better results than did treatment with the original dose of LT(4) alone.

Milk-alkali syndrome in pregnancy.

BACKGROUND: Severe hypercalcemia, a potentially life-threatening medical emergency, is rare in pregnancy. CASE: We report a 32-year-old woman presenting early in the second trimester with severe hypercalcemia (total calcium 22 mg/dL), alkalosis, and acute renal insufficiency resulting from excessive ingestion of calcium carbonate-containing antacid for gastroesophageal reflux. The patient was treated with aggressive hydration and furosemide, and received 1 dose of intravenous etidronate, leading to short-term symptomatic hypocalcemia. To our knowledge, this is the third reported case of milk-alkali syndrome in pregnancy. CONCLUSION: Milk-alkali syndrome is an uncommon cause of hypercalcemia in pregnancy. Intravenous hydration with saline should be the cornerstone of treatment, reserving bisphosphonates for selected cases.

Characterization of an aquaporin-2 water channel gene mutation causing partial nephrogenic diabetes insipidus in a Mexican family: evidence of increased frequency of the mutation in the town of origin.

A Mexican family with partial congenital nephrogenic diabetes insipidus (NDI) that resulted from a mutation in the aquaporin-2 water channel (AQP2) was characterized, and the source of this rare mutation was traced to the family's town of origin in Mexico. Affected individuals with profound polyuria and polydipsia were homozygous for an autosomal recessive missense V168M mutation in the AQP2 gene. Expression in oocytes revealed that, although retained in the endoplasmic reticulum (ER) to a great extent, a considerable amount of the partially functional AQP2-V168M was expressed at the plasma membrane, and that its ER retention was less than AQP2-T126M, a functional mutant in severe recessive NDI. None of the affected AQP2-V168M individuals had neurologic deficits, which also suggested a milder form of the disease. The homozygous individuals reported subjective improvement in polyuria and polydipsia with the use of dDAVP (1-desamino-8-D-arginine-vasopressin). When clinically tested, infusion of dDAVP at variable doses produced a partial increase in the urinary osmolality in homozygous individuals and decreased their water intake. Heterozygotes were unaffected when compared with controls. Samples were obtained from the population of the Mexican town of origin of the family; 30% of the population was heterozygous for the V168M AQP2 mutation and 1% was homozygous for the mutation. The high frequency of this rare mutation in the town provides evidence for an important health care problem in the village with consequences for future generations.