Preoperative Identification of Medullary Thyroid Carcinoma (MTC): Clinical Validation of the Afirma MTC RNA-Sequencing Classifier.

Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III-VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9-100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1-100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.

Performance of a Genomic Sequencing Classifier for the Preoperative Diagnosis of Cytologically Indeterminate Thyroid Nodules.

Importance: Use of next-generation sequencing of RNA and machine learning algorithms can classify the risk of malignancy in cytologically indeterminate thyroid nodules to limit unnecessary diagnostic surgery. Objective: To measure the performance of a genomic sequencing classifier for cytologically indeterminate thyroid nodules. Design, Setting, and Participants: A blinded validation study was conducted on a set of cytologically indeterminate thyroid nodules collected by fine-needle aspiration biopsy between June 2009 and December 2010 from 49 academic and community centers in the United States. All patients underwent surgery without genomic information and were assigned a histopathology diagnosis by an expert panel blinded to all genomic information. There were 210 potentially eligible thyroid biopsy samples with Bethesda III or IV indeterminate cytopathology that constituted a cohort previously used to validate the gene expression classifier. Of these, 191 samples (91.0%) had adequate residual RNA for validation of the genomic sequencing classifier. Algorithm development and independent validation occurred between August 2016 and May 2017. Exposures: Thyroid nodule surgical histopathology diagnosis by an expert panel blinded to all genomic data. Main Outcomes and Measures: The primary end point was measurement of genomic sequencing classifier sensitivity, specificity, and negative and positive predictive values in biopsies from Bethesda III and IV nodules. The secondary end point was measurement of classifier performance in biopsies from Bethesda II, V, and VI nodules. Results: Of the 183 included patients, 142 (77.6%) were women, and the mean (range) age was 51.7 (22.0-85.0) years. The genomic sequencing classifier had a sensitivity of 91% (95% CI, 79-98) and a specificity of 68% (95% CI, 60-76). At 24% cancer prevalence, the negative predictive value was 96% (95% CI, 90-99) and the positive predictive value was 47% (95% CI, 36-58). Conclusions and Relevance: The genomic sequencing classifier demonstrates high sensitivity and accuracy for identifying benign nodules. Its 36% increase in specificity compared with the gene expression classifier potentially increases the number of patients with benign nodules who can safely avoid unnecessary diagnostic surgery.

LIMITATIONS OF CURRENT APPROACHES FOR THE TREATMENT OF ACROMEGALY.

OBJECTIVE: Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are currently available treatment approaches for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal IGF-1 levels, reducing tumor size, improving comorbidities, and minimizing mortality risk. Although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment. METHODS: We reviewed recently published reports and present a summary of the safety and efficacy of current treatment modalities for patients with acromegaly. RESULTS: A substantial proportion of patients who receive medical therapy or radiotherapy will have persistently elevated GH and/or IGF-1. Because of the serious health consequences of continued elevation of GH and IGF-1, there is a need to improve therapeutic approaches to optimize biochemical control, particularly in high-need patient populations for whom current treatment options provide limited benefit. CONCLUSION: This review discusses current treatment options for patients with acromegaly, limitations associated with each treatment approach, and areas within the current treatment algorithm, as well as patient populations for which improved therapeutic options are needed. Novel agents in development were also highlighted, which have the potential to improve management of patients with uncontrolled or persistent acromegaly.

HISTORICAL RESPONSE RATES OF SOMATOSTATIN ANALOGUES IN THE TREATMENT OF ACROMEGALY: A SYSTEMATIC REVIEW.

OBJECTIVE: In a completed phase III study (C2305, Clinicaltrials.gov identifier: NCT00600886), the reported rate of biochemical control with octreotide long-acting release (LAR) was lower than rates historically reported in patients pretreated and/or selected for response with somatostatin analogue (SSA) therapy. To assess whether lower efficacy rates of octreotide LAR in C2305 were influenced by study design, a systematic review of the literature was performed to evaluate response rates in previously published studies in acromegaly with similar design characteristics. METHODS: PubMed was used to search for English-language clinical studies of acromegaly published through May 2014. Prospective studies of medically naïve patients (≥20) treated with SSAs for ≤12 months that reported efficacy rates using composite endpoint measures (growth hormone [GH] and insulin-like growth factor 1 [IGF-1]) were included. Two separate authors independently screened abstracts and full-length articles of each study to determine eligibility. All authors met to review and reach consensus when primary reviewers disagreed on the inclusion or exclusion of specific studies. RESULTS: A total of 9 studies (N = 354 patients) were identified, with reported mean efficacy rates of 31% (range, 20-54%). Of note, reported mean efficacy rates were lower in studies enrolling patients naïve to any form of treatment (surgery, medical, and/or radiation) than in studies that enrolled only medically naïve patients. A limitation of this analysis was that inclusion criteria restricted the number of studies analyzed. CONCLUSION: Interpretation of biochemical response rates with SSAs is critically dependent on the context of the study and should be evaluated across clinical trials with similar study design characteristics.

Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive.

Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2-related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2R, in addition to binding mannose-6-phosphate-containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non-islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non-islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.

Effect of elevated basal insulin on cancer incidence and mortality in cancer incident patients: the Israel GOH 29-year follow-up study.

OBJECTIVE: Diabetes is associated with many forms of cancer. Recent evidence has suggested that some treatments for diabetes are associated with an increased cancer risk. Less is known about the association between endogenous insulin in the prediabetes state and cancer risk. RESEARCH DESIGN AND METHODS: We investigated cumulative cancer incidence and cancer incidence density over 29 years, according to basal insulin, in a cohort of 1,695 nondiabetic men and women of four ethnic origins, aged 51.8 ± 8.0 years at baseline. Total mortality among the 317 subjects (18.7%) who developed cancer at least 2 years after baseline was assessed. RESULTS: In a Cox proportional hazards model, the all-site hazard ratio of cancer incidence comparing the highest insulin quartile with the other three quartiles was 1.09 (95% CI 0.85-1.40), adjusted for age, sex, and ethnicity. BMI, smoking, and fasting blood glucose were not statistically significant in this model. Basal insulin level was not significantly associated with cancer of specific sites (breast, prostate, colon/rectum, or bladder). Fasting insulin in the upper quartile conferred a 37% increased risk for total mortality among cancer patients, adjusting for age, sex, and ethnic origin (95% CI 0.94-2.00, P = 0.097) compared with that of the lower quartiles. Male sex, older age, and North African origins were associated with a greater risk of mortality during follow-up time. CONCLUSIONS: This long-term cohort study may suggest a role for basal elevated insulin levels, mainly as a negative predictor in cancer prognosis.

Intensifying insulin therapy with insulin analog premixes: transitioning from basal insulin in type 2 diabetes.

Because of the progressive nature of type 2 diabetes, basal insulin alone may not be able to provide sufficient glycemic control over the long term, and thus insulin regimens will typically need to be intensified--especially for controlling postprandial glucose excursions. In patients with type 2 diabetes requiring more intensive intervention, insulin analog premix formulations can offer a simple, effective, and convenient option for tighter management of hyperglycemia in lieu of a traditional basal-bolus regimen.

Basal-state hyperinsulinemia in healthy normoglycemic adults is predictive of type 2 diabetes over a 24-year follow-up: a preliminary report.

OBJECTIVE We examined the predictive value of hyperinsulinemia in the basal state on the 24-year progression from normoglycemia to dysglycemia. RESEARCH DESIGN AND METHODS A sample of 515 normoglycemic men and women were studied again after 24 years for glycemic status. RESULTS Half of the participants developed dysglycemia: 11.1% progressed to impaired fasting glucose (IFG), 9.9% to impaired glucose tolerance (IGT), 4.5% to both IFG and IGT, and another 24.3% to type 2 diabetes. Elevated levels of overnight fasting (basal) insulin, triglycerides, BMI > or =27 kg/m(2), fasting blood glucose, blood pressure, North African or Yemenite background, and male sex each favored conversion to dysglycemia after 24 years. In multiple ordered logistic regression analysis, the most significant predictor of progression to dysglycemia was hyperinsulinemia (upper quintile), after adjusting for BMI, ethnic origin, sex, age, smoking, physical activity, blood pressure, and triglycerides. CONCLUSIONS Basal hyperinsulinemia in normoglycemic adults constitutes an independent risk factor for developing dysglycemia over 24 years.

Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?

Insulin resistance, recently recognized as a strong predictor of disease in adults, has become the leading element of the metabolic syndrome and renewed as a focus of research. The condition exists when insulin levels are higher than expected relative to the level of glucose. Thus, insulin resistance is by definition tethered to hyperinsulinemia. The rising prevalence of medical conditions where insulin resistance is common has energized research into the causes. Many causes and consequences have been identified, but the direct contributions of insulin itself in causing or sustaining insulin resistance have received little sustained attention. We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance. 1) Mice transfected with extra copies of the insulin gene produce basal and stimulated insulin levels that are two to four times elevated. The mice are of normal weight but show insulin resistance, hyperglycemia, and hypertriglyceridemia. 2) Somogyi described patients with unusually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded by studies including continuous glucose monitoring. 3) Rats and humans treated with escalating doses of insulin show both hyperinsulinemia and insulin resistance. 4) The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin. 5) Many patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) responsiveness to administered insulin. In summary, hyperinsulinemia is often both a result and a driver of insulin resistance.