F. Illouz

Tyrosine kinase inhibitors and modifications of thyroid function tests: A review.

Tyrosine kinase inhibitors (TKI) belong to new molecular multi-targeted therapies that are approved for the treatment of haematological and solid tumours. They interact with a large variety of protein tyrosine kinases involved in oncogenesis. In 2005, the first case of hypothyroidism was described and since then, some data have been published and have confirmed that TKI can affect the thyroid function tests (TFT). This review analyses the present clinical and fundamental findings about the effects of TKI on the thyroid function. Various hypotheses have been proposed to explain the effect of TKI on the thyroid function but those are mainly based on clinical observations. Moreover, it appears that TKI could alter the thyroid hormone regulation by mechanisms that are specific to each molecule. The present propositions for the management of TKI-induced hypothyroidism suggest that we assess the TFT of the patients regularly before and during the treatment by TKI. Thus, a better approach of patients with TKI-induced hypothyroidism could improve their quality of life.

Relevance of Ki-67 and prognostic factors for recurrence/progression of gonadotropic adenomas after first surgery

OBJECTIVE Gonadotropin-secreting pituitary adenomas carry a high risk of local recurrence or progression (R/P) of remnant tumor after first surgery. The clinical characteristics and the long-term outcome of these silent adenomas, which show no signs of endocrine hyperfunction, differ from those of other types of pituitary adenomas. However, to date, no study has focused specifically on gonadotropic adenomas. MATERIALS AND METHODS To identify prognostic factors of R/P of remnants, we studied the postoperative outcome of 32 gonadotropic pituitary adenomas, defined on immunohistochemical staining, according to their clinical and radiological characteristics as well as the Ki-67 labeling index (LI). RESULTS The Ki-67 LI failed to provide independent information for the identification of patients at risk of progression of remnants or recurrence. Multivariate survival analysis (Cox regression) showed that neither invasiveness nor remnant tumors nor hyposomatotropism influenced tumor recurrence. The strongest predicting factors of R/P were the antero-posterior (AP) diameter in the sagittal plane (P = 0.014), and the age of the patient at surgery (P = 0.047), with younger patients being at greater risk. Hazard ratios were 2.11 for each 5 mm increase in AP diameter and 0.57 for every 10 years of age. CONCLUSION The two simple clinical criteria revealed by our study, the AP diameter of the tumor and the age of the patient, should be helpful in planning clinical management and radiological monitoring after first surgery of gonadotropic adenomas, while awaiting the identification of other pathological parameters.

Usefulness of repeated fine-needle cytology in the follow-up of non-operated thyroid nodules

OBJECTIVE The usefulness of repeated fine-needle cytology (FNC) in thyroid nodules with benign cytology remains unknown. We analyzed the relevance of repeated FNC to detect suspicious or malignant (S/M) cytologies and carcinomas. DESIGN A retrospective study (1983-2004) was conducted in our endocrinology department. METHODS We reviewed the reports of 895 adequate FNC performed in 298 patients (298 nodules) during a mean follow-up of 5 years. We compared the nodules with at least one suspicious or malignant FNC (S/M nodules) with nodules with repeatedly benign (RB) FNC (RB nodules). RESULTS Among the nodules with initial benign cytology, we found 35 nodules with one or more later suspicious or malignant results. The interval between the first FNC and the first S/M FNC was 2.9 years. The probability for a nodule to have a repeated benign FNC decreases with time and with the number of FNC. We did not find any clinical or ultrasonographic characteristics related to an S/M cytology. Seven cancers were detected by the second or the third FNC with S/M results. The proportion of cancers among S/M nodules was similar when S/M cytology appears during the first, the second, or the third FNC. CONCLUSIONS We suggest to repeat FNC up to three adequate samples in the follow-up of thyroid nodules so as not to miss the presence of malignant neoplasm.

Endocrine side-effects of anti-cancer drugs: thyroid effects of tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) are currently used by most oncologists. Among their side effects, thyroid dysfunctions are nowadays clearly observed. Whereas changes in thyroid function tests have been originally described with sunitinib, we now know that many TKIs can induce hypothyroidism and hyperthyroidism. In this study, the various molecules implicated in thyroid dysfunctions are analysed and the latest data on physiopathological mechanisms are approached in order to propose a strategy of thyroid monitoring of patients on TKI therapy.

Clinical Outcome, Hormonal Status, Gonadotrope Axis, and Testicular Function in 219 Adult Men Born With Classic 21-Hydroxylase Deficiency. A French National Survey.

CONTEXT Outcomes of congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) have been widely studied in children and women, but less so in men. OBJECTIVE The objective was to analyze data from a network of metropolitan French teaching hospitals on the clinical outcome of classic 21OHD in a large sample of congenital adrenal hyperplasia/21OHD-genotyped adult men, and particularly the impact of 21OHD on the gonadotrope axis, testicular function, and fertility. METHODS From April 2011 to June 2014, tertiary endocrinology departments provided data for 219 men with 21OHD (ages, 18-70 y; 73.6% salt wasters, 26.4% simple virilizers). Testicular sonography was performed in 164 men, and sperm analysis was performed in 71 men. RESULTS Mean final height was 7.8 cm lower than in a reference population. Obesity was more common, and mean blood pressure was lower than in the reference population. None of the patients were diabetic, and lipid status was generally normal. Blood electrolyte status was normal in the vast majority of men, despite markedly elevated ACTH and renin levels. Serum progesterone, 17-hydroxyprogesterone, and androstenedione levels were above normal in the vast majority of cases. Hormonal profiling variously showed a normal gonadotrope-testicular axis, gonadotropin deficiency, or primary testicular insufficiency. Testicular sonography revealed testicular adrenal rest tumors (TARTs) in 34% of 164 men. Serum inhibin B and FSH levels were significantly lower and higher, respectively, in patients with TARTs. Severe oligospermia or azoospermia was found in 42% of patients and was significantly more prevalent in men with TARTs (70%) than in men with normal testes (3.6%; P < .0001). Among men living with female partners, TARTs were significantly more prevalent in those who had not fathered children. CONCLUSION We report the spectrum of testicular/gonadotrope axis impairment in the largest cohort of 21OHD men studied to date. Our results suggest that French men with 21OHD managed in specialized centers frequently have impaired exocrine testicular function but that its reproductive implications are often overlooked.

Utilisation de la cabergoline dans la maladie de Cushing non contrôlée

La cabergoline est un agoniste dopaminergiques dont l’efficacite a ete demontree dans le traitement des prolactinomes mais son utilisation a egalement ete rapportee chez des patients presentant un hypercorticisme non controle par les traitements conventionnels. Nous decrivons l’utilisation de la cabergoline chez 3 patients porteurs d’une maladie de Cushing dont un qui presentait un adenome corticotrope silencieux recidivant. Ces 3 patients ont ete operes et un seul a ete traite par radiotherapie. Cependant, l’hypercortisolisme persistant a motive l’utilisation de cabergoline. Nous avons objective une regression ou une normalisation de l’hypercortisolisme, et pour un patient, il semble que la progression tumorale ait ete stoppee. Si la cabergoline a pu diminuer l’hypersecretion de cortisol ou inhiber la croissance des tumeurs corticotropes, il est encore difficile de savoir quels sont ses sites d’action.

False-positive Iodine-131 whole-body scan findings in patients with differentiated thyroid carcinoma: Report of 11 cases and review of the literature

BACKGROUND Iodine-131 (I-131) whole-body scan (WBS) plays an important role in the management of patients with differentiated thyroid carcinoma (DTC), to detect normal thyroid remnants and recurrent or metastatic disease. A focus of I-131 accumulation outside the thyroid bed and the areas of physiological uptake is strongly suggestive of a distant functioning metastasis. However, many false-positive I-131 WBS findings have been reported in the literature. PATIENT FINDINGS We describe a series of 11 personal cases of patients with DTC, collected from 1992 to 2011, in whom diagnostic or post-treatment WBS showed false-positive retention of I-131 in various locations. SUMMARY False-positive accumulations of I-131 on WBS may be classified according to the underlying pathophysiological mechanisms: external and internal contaminations by body secretions, ectopic normal thyroid and gastric tissues, inflammatory and infectious diseases, benign and malignant tumors, cysts and effusions of serous cavities, thymic uptake, and other non classified causes. CONCLUSIONS Clinicians must be aware of possible false-positive findings to avoid misinterpretations of the I-131 WBS, which could lead to inappropriate treatments.

An elevated level of TSH might be predictive of differentiated thyroid cancer.

Suppression therapy of thyreostimulin (TSH) using thyroid hormones improves survival of subjects operated for differentiated thyroid cancer. The TSH level might be different depending on the type of nodule. The objective of this study was to compare retrospectively the TSH level between two groups of subjects who underwent total thyroidectomy for a nodule, matched on sex, ethnicity, age and biological method of TSH measurement, one whose final histology was benign and one malignant. There was no significant difference between the two groups in terms of age, sex, family history of thyroid disease or thyroid autoimmunity. The subjects, whose final histology was malignant, had a mean TSH level significantly higher than subjects with benign disease (1.55 mU/l versus 0.96 mU/l, P=0.003). Cancer risk was greater when the TSH was in the upper tertile of normal range. There was no correlation between the risk of thyroid cancer and age, sex, family history of thyroid disease, or menopausal status. The relative risk of having thyroid carcinoma was higher when the margins of nodules were blurred or in the presence of microcalcifications. These data confirm a trend toward baseline values of TSH higher in subjects with a thyroid-differentiated cancer. However, we could not define a preoperative threshold that would reliably determine the malignant or benign nature of the nodule.

Long-Delayed Localization of a Cardiac Functional Paraganglioma With SDHC Mutation

TO THE EDITOR: The evidence supporting the effectiveness of early screening of African Americans at average risk for colorectal cancer (CRC) is scarce. It is surprising that the American College of Physicians’ (ACP) guidance statement (1) recommends CRC screening in this group at age 40 years when there is no evidence that such a strategy is effective. A recent article from Gupta and colleagues (2) reported that increasing colonoscopy participation by 5% and 10% among African Americans aged 50 years or older detected 53% and 57% of CRC, respectively, and early screening of African Americans at age 45 years detected 52% of CRC. You and colleagues (3) further demonstrate that early-onset CRC was more prevalent among nonwhite patients who were either uninsured or insured by Medicaid (3). The results of these 2 studies have several implications that feed into the wider debate on social determinants of health and access to health care by the underserved, who are often disproportionately African American. First, simply implementing race-specific, early-age CRC screening policy for African Americans is unlikely to significantly increase early detection rates. Second, factors leading to reduced colonoscopy participation among African Americans need to be identified and appropriately addressed. African Americans are a diverse group of self-identified Americans with varying amounts of African genetic admixture. Classifying this group as having aboveaverage risk for CRC presupposes that race, as a proxy of ancestral African genomic identification, predicts CRC disease clusters in the African American population. If that is the case, biological markers that make African Americans more likely to develop CRC earlier should be identifiable and would lend credence to the argument for earlier screening. Furthermore, there should be a corresponding clustering of CRC in ancestral populations in Africa; however, this is not the case, because the available evidence shows that the incidence of CRC in Africa is low (4). Therefore, the observed increased incidence of CRC among African Americans is probably related to environmental, lifestyle, and socioeconomic factors rather than biological or genetic factors (4). While the medical community eagerly awaits the outcome of ongoing studies on the effectiveness of initiating early CRC screening in African Americans, strategies to improve access to CRC screening and colonoscopy participation among African Americans aged 50 years or older should be actively pursued in addition to timely case detection of symptomatic young adults and sustained advocacy on healthier lifestyle choices.

Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists

Two types of immune checkpoint inhibitors, both antibodies that target cytotoxic T‐lymphocyte antigen‐4 and those that target programmed cell death‐protein 1, have been approved for use in melanoma, non‐small‐cell lung cancer, and renal cell carcinoma as first‐line or second‐line therapy. Their adverse events are primarily regarded as immune‐related adverse events. We felt it was important to pinpoint and discuss certain preconceptions or misconceptions regarding thyroid dysfunction, hypophysitis, and diabetes induced by immune checkpoint inhibitors. We have identified areas of uncertainty and unmet requirements, including essential interaction between endocrinologists and oncologists. Five issues have been identified for discussion: (1) diagnosis of endocrine toxicity, (2) assessment of toxicity severity, (3) treatment of toxicity, (4) withdrawal or continuation of immunotherapy, (5) preventive action.