French Endocrine Society Guidance on endocrine side effects of immunotherapy.

The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPIs). However, the use of ICPI has a risk of side effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, and we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side effects in oncology using 'common terminology criteria for adverse events' (CTCAE) and the difficulties in applying this to endocrine side effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side effects (high-dose corticosteroids, contraindicated in ICPI for example) and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high-dose glucocorticoid intake.

Histologically Proven Bronchial Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort Study.

OBJECTIVE: To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death. br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis. METHODS: The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5-59.6] years by the Groupe d'étude des Tumeurs Endocrines was analyzed using time-to-event techniques. RESULTS: br-NETs were found in 51 patients (4.8%, [95% CI 3.6-6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28-66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02-5.14]). AC tended to have a worse prognosis than TC (p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (p = 10-4) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths. CONCLUSIONS: Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.

Clinical presentation of hyperthyroidism in a large representative sample of outpatients in France: relationships with age, aetiology and hormonal parameters.

OBJECTIVE: Signs and symptoms of thyrotoxicosis are not specific, and thyroid function tests are frequently prescribed to recognize such thyroid dysfunction. Ultrasensitive assays of thyroid-stimulating hormone (TSH) allow early diagnosis and identification of mild hyperthyroidism (generally designed as 'subclinical'). The aim of this study was to re-evaluate the clinical picture of thyrotoxicosis in the context of the current large utilization of ultrasensitive TSH assays. DESIGN: Prospective descriptive cohort. METHODS: Clinical presentation of 1572 patients with a recent (<3 months) diagnosis of thyrotoxicosis recruited by a large representative sample of 263 French endocrinologists was studied using two questionnaires (one at inclusion and the second after 3 months) concerning symptoms, hormonal evaluation and treatment. RESULTS: A total of 1240 (78·9%) patients were women, mean age 48 ± 17 years. Subclinical hyperthyroidism (SCHT) was present in 86 patients (10·4%). Symptoms of thyrotoxicosis were in decreasing frequency order: palpitations, weakness, heat-related signs and disturbed sleep. A total of 64·9% of patients had lost weight. Signs and symptoms were more frequent in Graves' disease, in young patients, and were partially related to biochemical severity. Symptoms were less frequent in elderly patients except for cardiac manifestations (atrial fibrillation). Most patients with SCHT had one or several signs or symptoms of thyrotoxicosis. CONCLUSION: This study confirms that elderly patients have less symptoms of thyrotoxicosis than younger subjects but are at increased risk of cardiac complications. Our results show that most patients with 'subclinical' HT have in fact signs or symptoms of thyrotoxicosis.

[Adrenocortical carcinomas: therapeutic advances in 2011]. / Corticosurrénalomes: actualités thérapeutiques.

Adrenocortical cancer (ACC) is a rare aggressive malignancy with a poor prognosis (5-year survival: 45 %). Their management requires multidisciplinary expertise. Complete resection by an expert surgeon is the only curative treatment. Very few adjuvant treatments are available and their efficacy is not fully proved. Adjuvant mitotane therapy increases the disease-free survival in the majority of patients after surgery but further studies are needed to determine patients in whom this treatment is the more beneficial. Blood concentrations of mitotane between 14 and 20mg/l are necessary to have a full efficiency but this therapeutic window may cause side effects difficult to control. When aggressive parameters are present, radiotherapy is proposed. In case of residual or unresectable disease, combination of chemotherapy and mitotane is conventionally proposed. FIRM-ACT study establishes that EDP (etoposide, doxorubicine et cisplatine) is the most effective chemotherapy for progressive ACC. The first results of treatment with tyrosine kinase inhibitors, in patients with progressive disease despite one or two lines of chemotherapy are disappointing but this may be partly explained by the interaction with mitotane which reduces the plasma concentrations of sunitinib in particular. Clinical trials are underway to assess the effectiveness of other targeted therapies, including treatments acting on the IGF-1 receptor.

Lymph node management in clinically node-negative patients with papillary thyroid carcinoma.

AIMS: Systematic lymph node dissection in patients with papillary thyroid carcinoma (PTC) remains controversial. The objective of this study was to study the pattern of lymph node spread in patients with PTC clinically node-negative and then to propose a lymph node management strategy. METHODS: We retrospectively reviewed the records of patients who had undergone total thyroidectomy and a systematic central neck dissection (CND) and lateral neck dissection. Ninety patients with PTC without lymph nodes metastases (LNM) detected on preoperative palpation and ultrasonographic examination were included. RESULTS: Forty-one patients (45.5%) had LNM. Twenty-eight patients (31%) had a central and a lateral involvement. Thirteen patients (14.5%) had only a central involvement. All the patients without LNM in the central compartment were also free in the lateral compartment. There was no correlation between LNM status and TNM staging. The largest LNM in the central compartment was smaller than or equal to 5mm in 66% of the cases, and that could explain the lack of sensitivity of the preoperative ultrasonographic examination. CONCLUSION: CND could be considered at preoperative or intraoperative diagnosis of PTC whereas lateral neck dissection should be performed only in patients with preoperative suspected and/or intraoperatively proven LNM. Systematic CND allows an objective evaluation of lymph node status in this central cervical area where the LNM are particularly small and difficult to detect preoperatively.

[Pituitary carcinomas and aggressive adenomas: an overview and new therapeutic options]. / Carcinomes et adénomes hypophysaires agressifs : mise au point et nouvelles options thérapeutiques.

Pituitary carcinomas are a rare disease with an estimated prevalence around 0.2 % of the pituitary tumours. They are defined by the presence of intra or extra-cranial metastases but initially they can share the same features as aggressive pituitary adenomas. Indeed there are some indicators that help to differentiate adenomas and carcinomas such as histological findings and immunohistochemical characteristics. Usually in carcinomas, mitotic activity is higher, proliferative index Ki-67 is higher, p53 expression is positive and microvascular density is mostly increased. The majority of carcinomas are prolactin or ACTH-secreting tumors. Dopamine and somatostatin-receptor agonists are not as effective as for the treatment of adenomas. Carcinomas require often repeated surgery and radiotherapy fail to control the tumor. Conventional chemotherapy is poorly effective, but recent case reports with the alkylating agent temozolomide have provided better results at least in the short term. The effects of temozolomide are reversed by the enzyme MGMT and the treatment's response can be predicted by the study of MGMT's expression : tumours lacking MGMT are especially sensitive to temozolomide.

[Status of iodine nutrition in France: prevention of iodine deficiency in pregnant and lactating women]. / Apport iodé en France: prévention de la carence iodée au cours de la grossesse et l'allaitement.

Iodine intake varies with age and physiological status: in pregnant and lactating women, recommended iodine intake ranges from 200 to 250 mg/day. Recent epidemiological studies in France demonstrate the presence of moderate iodine deficiency in the majority of pregnant and lactating women. This iodine deficiency induces maternal thyroid hyperplasia and then development of goiter in women, as well as impaired thyroid parameters. Maternal hypothyroxinemia during the first trimester of pregnancy can be associated with abnormal cognitive development and intellectual outcomes in the newborn and the children. According to the recent World Health Organization recommendations for the prevention and control of iodine deficiency in pregnant and lactating women, systematic iodine supplementation is indicated in France: 100 microg/day for women of reproductive age and 200 microg/day in pregnant and lactating women in order to eradicate iodine deficiency during pregnancy and lactation, and prevent the maternal and fetal consequences.

Defective efficacy of retinoic acid treatment in patients with metastatic thyroid carcinoma.

Radioiodine (I-131) therapy is of proven efficacy for differentiated thyroid carcinoma. However, its efficacy relies on specific uptake mechanisms, which may be lost during the evolution of the disease. Attempts to increase the iodine uptake of such tumors have been made using retinoic acid because it exerts redifferentiating effects on thyrocytes. This study aims to assess the capability of the retinoic acid (RA) treatment to reinforce iodine 131-irradiation efficacy for metastatic and progressive multi-irradiated thyroid cancer. In this clinical prospective study, 11 patients (mean age +/- 1 SD = 61 +/- 12 years, sex ratio M/F = 5/6) with a progressive disease despite iterative surgery and iodine irradiations were treated with 13-cis-retinoic acid (1.5 mg/kg day) over 8 weeks prior to I-131 irradiation. The redifferentiating effect of RA was evaluated by serum thyroglobulin (Tg) monitoring during RA treatment and qualitative analysis of iodine uptake on the post-therapeutic whole body scan. The clinical usefulness of RA treatment was assessed by clinical follow-up, Tg monitoring, and tumor size. No serious event that could possibly be related to the treatment was reported. The mean follow up time was 24.2 +/- 12 months (range 3-46 months). Iodine uptake was only slightly improved in two patients. Nevertheless, the clinical benefits of RA seem to be very poor. Five patients died of a metastatic disease. Five others presented new clinical evidences of a progressive disease. In conclusion, this prospective study demonstrates the absence of efficacy of I-131 irradiation combined with RA for the treatment of patients with aggressive, rapidly growing metastatic thyroid cancer. Thus, patients with highly aggressive disease, rapidly growing in a short period from 2 to 6 months, should not be considered for RA therapy.

An unusual form of Riedel's thyroiditis: a case report and review of the literature.

We report the case of a 36-year old woman with a history of long-term fever associated with a biologic inflammatory syndrome that was not corrected by several courses of corticosteroid treatment. The only remarkable result during previous investigations was the presence of a positive Epstein-Barr virus (EBV) serology. Clinical examination revealed an heterogenous thyroid with a nodule on the right lobe. Serum thyrotropin (TSH) concentration was normal. The levels of antiperoxidase antibodies and thyrocalcitonin were normal. Ultrasound examination of the neck showed a 3-cm hypoechogenous nodule in the right lobe of the thyroid. A total thyroidectomy was performed. Histopathologic findings led to the diagnosis of Riedel's thyroiditis. We observed a dramatic improvement after surgery with absence of fever and normalization of inflammatory parameters. The role of EBV infection in the process of this unusual form of Riedel's thyroiditis is discussed.

One-year follow-up of patients with acromegaly treated with fixed or titrated doses of lanreotide Autogel.

OBJECTIVE: Somatostatin analogue treatment is first-line medical therapy for acromegaly. This study compared the efficacy and tolerability of titrated doses of the long-acting somatostatin analogue preparation lanreotide Autogel with fixed doses and with lanreotide prolonged release (PR) 30 mg microparticles. PATIENTS: Patients entering the initial study had received a diagnosis of active acromegaly within the previous 5 years. DESIGN: This open, comparative, multicentre study was a 1-year extension of a previous trial during which patients with acromegaly had switched from lanreotide PR 30 mg microparticles injected intramuscularly every 7, 10 or 14 days, for at least 3 months, to one of three fixed doses of lanreotide Autogel (120, 90, or 60 mg every 28 days, respectively). In this extension study, patients continued to receive 60, 90, or 120 mg of lanreotide Autogel by deep subcutaneous injection every 28 days for 1 year. Doses could be titrated at entry or after four or eight injections, according to the GH/IGF-I response (dose increased if GH > 2.5 micro g/l, or decreased if GH < 1 micro g/l with normal IGF-I). MEASUREMENTS: Mean +/- SEM GH and IGF-I concentrations were analysed and gallbladder echography performed at weeks 0, 16, 32, and 48. Acromegaly symptoms were recorded monthly and tolerance and side-effects were monitored throughout the study. RESULTS: In total, 130 patients entered this extension phase. After 1 year of treatment with titrated doses of lanreotide Autogel, mean GH (2.4 +/- 0.2 micro g/l) and IGF-I (287 +/- 12 micro g/l) concentrations were significantly lower than with lanreotide microparticles (GH, 2.8 +/- 0.2 micro g/l, P < 0.001; IGF-I, 332 +/- 15 micro g/l, P < 0.01) or with fixed-dose lanreotide Autogel (GH, 3.0 +/- 0.2 micro g/l, P < 0.001; IGF-I, 310 +/- 14 micro g/l, P = 0.02). GH hypersecretion was reduced to

Pituitary apoplexy and idiopathic thrombocytopenic purpura: a new case and review of the literature.

Pituitary apoplexy can occur as a complication of idiopathic thrombocytopenic purpura. We report here a new case of such association. A male patient aged 59 years, complaining of decreased libido for one year, was referred to the emergency department for purpura and severe thrombocytopenia (4000 platelets/mm3). 24 hours after the cutaneous rash the patient presented with clinical symptoms of bilateral cavernous sinus compression comprising ptosis, bilateral ophtalmoplegia and right supraorbital hypoesthesia. Cranial CT scan showed an enlarged sella and a pituitary mass with signs of intrapituitary haemorrhage. Hormonal evaluation showed hyperprolactinemia (50 ng/mL) and hypopituitarism, and the patient needed substitution with hydrocortisone and levothyroxine. Immunoglobulins and corticosteroids were given to the patient to treat thrombocytopenia, then worsening of neurological and ophtalmological symptoms led to pituitary surgery. Histopathological examination found necrotical pituitary tissue. Immunostaining with an anti-prolactin antibody was positive in several groups of cells. Neurological symptoms subsided and thrombocytopenia was corrected by treatment. In conclusion, we report a case of pituitary apoplexy due to severe thrombocytopenia occurring as a complication of a preexisting macroprolactinoma.

[Therapeutic strategies in somatotroph adenomas with extrasellar extension: role of the medical approach, a consensus study of the French Acromegaly Registry]. / Stratégies thérapeutiques dans les adénomes somatotropes avec extension extrasellaire. Place du traitement médical. Etude consensus du Répetoire français de l'Acromégalie.

UNLABELLED: From the first 198 patient files included into the French Acromegaly Registry, we analyzed 68 patients harboring a somatotroph adenoma with extrasellar extension, after exclusion of those treated by stereotactic or conventional radiotherapy. In these patients (including 37 women), aged 21-77 yr. (45.7 +/- 13.3), GH concentrations ranged from 2-260 microg/L (38.6 +/- 44.3), and IGF I from 86-967% of age-matched upper limit of normal (303 +/- 164). Maximal diameter of the adenoma at MRI was 11-36.5 mm (20.4 +/- 6.5), with cavernous sinus involvement in 68% of cases. Three subgroups were defined: 20 patients treated by long-acting somatostatin analogs only (group M), for a mean duration of 3 yr. (extremes 1-7 yr.), 48 patients initially treated by transsphenoidal surgery (group C), of whom 21 were secondarily treated by long-acting somatostatin analogs (group CM) for a mean duration of 1.2 yr. (extremes 0.2-2 yr.). All 3 groups were not statistically different in terms of tumor mass and initial levels of GH and IGF-1. Patients from group M were significantly older than those of the other groups (p<0.05). RESULTS: 46% of patients from group C after surgery vs. 45% of patients from group M had a mean GH below 2.5 microg/L. Biochemical remission (GH<2.5 microg/L and normal IGF1 normal) was obtained in 31% of cases in group C, vs. 25% in group M. In this group, a decrease of the largest tumor diameter was observed in 10 patients (71.5%), ranging from 10-25% in 7 (50%) and exceeded 50% in 3 (21.5%). In group CM, the biochemical remission rate (42%) and final GH or IGF1 values were not significantly different from group M. In conclusion, these data suggest that surgery or long-acting somatostatin analogs have a comparable efficacy in terms of remission rates in somatotroph macroadenomas with extrasellar extensions.

Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in the management of acromegaly.

Lanreotide Autogel is a new long-acting aqueous preparation of lanreotide for the treatment of acromegaly and is administered by deep sc injection from a small volume, prefilled syringe. The aim of this study was to evaluate the efficacy and safety of this new long-acting formulation in a large population of acromegalic patients previously responsive to lanreotide 30 mg, im (sustained release microparticle formulation). Lanreotide Autogel was administered by deep sc injection every 28 d to 107 patients (54 males and 53 females; mean age, 54 +/- 1.2 yr). All patients had been treated with lanreotide (30 mg) for at least 3 months before study entry and had a mean GH level less than 10 ng/ml after at least 4 subsequent im injections every 14 d (48%), 10 d (32%), or 7 d (20%). Treatment was switched from lanreotide 30 mg injected every 14, 10, or 7 d to 60, 90, or 120 mg lanreotide Autogel, respectively, every 28 d. After three fixed dose injections of lanreotide Autogel, mean lanreotide levels were similar to those obtained at steady state with lanreotide 30 mg. During lanreotide Autogel treatment, the control of acromegalic symptoms was comparable with that previously achieved during lanreotide 30 mg treatment. After 3 injections of lanreotide Autogel, mean GH (2.87 +/- 0.22 ng/ml) and IGF-I (317 +/- 15 ng/ml) values were comparable with those recorded at the end of lanreotide 30 mg treatment (GH, 2.82 +/- 0.19 ng/ml; IGF-I, 323 +/- 16 ng/ml). GH levels below 2.5 ng/ml and age-/sex-normalized IGF-I were achieved in 33% and 39% of patients during lanreotide 30 mg and lanreotide Autogel treatment, respectively. Diarrhea, abdominal pain, and nausea were reported by 38%, 22%, and 18% of patients during lanreotide 30 mg treatment and by 29%, 17%, and 9% of patients, respectively, during lanreotide Autogel treatment. In conclusion, this clinical study shows that lanreotide Autogel is at least as efficacious and well tolerated as lanreotide 30 mg. This new long-acting lanreotide formulation, lanreotide Autogel, which is administered from a small volume, prefilled syringe by deep sc injection, is therefore likely to improve the acceptability of medical treatment for patients requiring long-term somatostatin analog therapy.