F18-Choline PET/CT or MIBI SPECT/CT in the Surgical Management of Primary Hyperparathyroidism: A Diagnostic Randomized Clinical Trial.

Importance: Whether F18-choline (FCH) positron emission tomographic (PET)/computed tomographic (CT) scan can replace Tc99m-sestaMIBI (MIBI) single-photon emission (SPE)CT/CT as a first-line imaging technique for preoperative localization of parathyroid adenomas (PTA) in patients with primary hyperparathyroidism (PHPT) is unclear. Objective: To compare first-line FCH PET/CT vs MIBI SPECT/CT for optimal care in patients with PHPT needing parathyroidectomy and to compare the proportions of patients in whom the first-line imaging method resulted in successful minimally invasive parathyroidectomy (MIP) and normalization of calcemia 1 month after surgery. Design, Setting, and Participants: A French multicenter randomized open diagnostic intervention phase 3 trial was conducted. Patients were enrolled from November 2019 to May 2022 and participated up to 6 months after surgery. The study included adults with PHPT and an indication for surgical treatment. Patients with previous parathyroid surgery or multiple endocrine neoplasia type 1 (MEN1) were ineligible. Interventions: Patients were assigned in a 1:1 ratio to receive first-line FCH PET/CT (FCH1) or MIBI SPECT/CT (MIBI1). In the event of negative or inconclusive first-line imaging, they received second-line FCH PET/CT (FCH2) after MIBI1 or MIBI SPECT/CT (MIBI2) after FCH1. All patients underwent surgery under general anesthesia within 12 weeks following the last imaging. Clinical and biologic (serum calcemia and parathyroid hormone levels) assessments were performed 1 and 6 months after surgery. Main Outcomes and Measures: The primary outcome was a true-positive first-line imaging-guided MIP combined with uncorrected serum calcium levels of 2.55 mmol/l or less 1 month after surgery, corresponding to the local upper limit of normality. Results: Overall, 57 patients received FCH1 (n = 29) or MIBI1 (n = 28). The mean (SD) age of patients was 62.8 (12.5) years with 15 male (26%) and 42 female (74%) patients. Baseline patient characteristics were similar between groups. Normocalcemia at 1 month after positive first-line imaging-guided MIP was observed in 23 of 27 patients (85%) in the FCH1 group and 14 of 25 patients (56%) in the MIBI1 group. Sensitivity was 82% (95% CI, 62%-93%) and 63% (95% CI, 42%-80%) for FCH1 and MIBI1, respectively. Follow-up at 6 months with biochemical measures was available in 43 patients, confirming that all patients with normocalcemia at 1 month after surgery still had it at 6 months. No adverse events related to imaging and 4 adverse events related to surgery were reported. Conclusions: This randomized clinical trial found that first-line FCH PET/CT is a suitable and safe replacement for MIBI SPECT/CT. FCH PET/CT leads more patients with PHPT to correct imaging-guided MIP and normocalcemia than MIBI SPECT/CT thanks to its superior sensitivity. Trial Registration: ClinicalTrials.gov Identifier: NCT04040946.

Factors Associated with Survival in Anaplastic Thyroid Carcinoma: A Multicenter Study from the ENDOCAN-TUTHYREF Network.

Background: Anaplastic thyroid carcinoma (ATC) is a rare and frequently fatal type of thyroid cancer. The degree of heterogeneity in survival rates for ATC is incompletely studied. This study evaluated the factors associated with overall survival (OS) of patients with ATC using multicenter real-world data from a national tertiary care center network in France. Methods: In this multicenter, retrospective cohort study, all patients with ATC diagnosed between 2010 and 2020 were identified from the national database of the French ENDOCAN-TUTHYREF network. Factors associated with OS were examined in multivariable analyses using Cox proportional hazards models. Results: The study included 360 patients. Of these, 220 (61%) were female and the median age was 72 years (interquartile range: 62-80). The percentages of patients with pure and mixed (synchronously-transformed) ATC (p-ATC and st-ATC) were 62.5% and 26.7%, respectively. The median OS was 6.8 months [confidence interval, CI: 5.5-8.1]: not reached for stage IVa, 11.4 months [8.2-17.8] for IVb, and 4.6 months [3.5-5.7] for IVc. Surgery, radiation therapy to the neck, chemotherapy, and best supportive care were administered to 69 (19.2%), 214 (59.4%), 254 (70.6%), and 66 (18.3%) patients, respectively. In a multivariable analysis, including stage IVb-IVc patients, significantly higher OS was observed in patients with Eastern Cooperative Oncology Group performance-status of 0-1 (hazard ratio [HR], 0.6; [CI, 0.4-0.9], p < 0.02), stage IVb [HR, 0.5; CI, 0.4-0.8, p < 0.001], and multimodal treatment (surgery and chemoradiotherapy) [HR, 0.07; CI, 0.04-0.1, p < 0.001]. Variables associated with significantly worse OS included: p-ATC (vs. st-ATC) [HR, 1.83; CI, 1.33-2.51, p = 0.001] and a neutrophil-to-lymphocyte ratio (NLR) >5.05 [HR, 2.05, CI, 1.39-3.05, p < 0.001]. Conclusions: Factors independently associated with improved OS in ATC included: European Cooperative Oncology Group performance status, disease stage, multimodality treatment, synchronously transformed ATC, and lower NLR. Long-term OS was observed in selected patients with ATC who underwent multimodal treatment.

Risk factors for hypothyroidism following hemithyroidectomy.

OBJECTIVE: Hypothyroidism is the most common complication of hemithyroidectomy for thyroid nodules. This retrospective cohort study investigated the prognostic factors for hypothyroidism following hemithyroidectomy. METHODS: We included patients who underwent hemithyroidectomy between 2016 and 2017, excluding those with history of preoperative hypothyroidism or malignancy on histopathological examination. The primary endpoint was development of hypothyroidism during follow-up (TSH≥2 above normal). RESULTS: Twenty-six of the 128 included patients (20%) developed postoperative hypothyroidism. The following independent prognostic factors were found: preoperative TSH level>1.5 mIU/L (OR 2.11; P=0.013), and remaining thyroid volume adjusted for body surface area<4.0mL/m2 (OR 1.77; P=0.015). Twenty-one patients (81%) had first TSH values above the upper limit of normal. Postoperatively, first TSH level correlated significantly with the preoperative value (R=0.5779, P<0.001). Levothyroxine was prescribed to 16% of patients, with a mean dose of 0.92µg/kg/day. CONCLUSION: Patients with TSH>1.5 mIU/or remaining thyroid volume adjusted for body surface area<4.0mL/m2 should have intensified clinical and biological follow-up in the first year after surgery.

Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer.

BACKGROUND: In patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, the postoperative administration of radioiodine (iodine-131) is controversial in the absence of demonstrated benefits. METHODS: In this prospective, randomized, phase 3 trial, we assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group). The primary objective was to assess whether no radioiodine therapy was noninferior to radioiodine therapy with respect to the absence of a composite end point that included functional, structural, and biologic abnormalities at 3 years. Noninferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary end points included prognostic factors for events and molecular characterization. RESULTS: Among 730 patients who could be evaluated 3 years after randomization, the percentage of patients without an event was 95.6% (95% confidence interval [CI], 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI, 93.3 to 97.7) in the radioiodine group, a difference of -0.3 percentage points (two-sided 90% CI, -2.7 to 2.2), a result that met the noninferiority criteria. Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment. Molecular alterations were similar in patients with or without an event. No treatment-related adverse events were reported. CONCLUSIONS: In patients with low-risk thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to an ablation strategy with radioiodine regarding the occurrence of functional, structural, and biologic events at 3 years. (Funded by the French National Cancer Institute; ESTIMABL2 ClinicalTrials.gov number, NCT01837745.).

Prevention of exercise-induced hypoglycemia in 12 patients with type 1 diabetes running the Paris Marathon using continuous glucose monitoring: A prospective, single-center observational study.

OBJECTIVE: To investigate the glycemic balance before, during and after the 2016 Paris Marathon using a real-time continuous glucose monitoring (RT-CGM) system in patients with type 1 diabetes mellitus in a prospective single-center observational study. METHODS: Inclusion criteria were as follows: type 1 diabetes mellitus; age ≥18 years; HbA1c < 9%. Participants performed two 2h-preparatory races (PR) before the Marathon and were monitored with RT-CGM 24h before, during and 72h after each race. Hypoglycemic events were prevented via carbohydrate intake / insulin dose adjustments. The primary outcome was area under the curve (AUC) < 70 and > 200 mg/dl and percentage of time spent in euglycemia, hypoglycemia, and hyperglycemia during the races. RESULTS: Twelve patients (2F/10M; median HbA1c=6.8%) were included and completed the study. Median AUC < 70 and time spent in hypoglycemia (< 70 mg/dl) during the PRs and Marathon were equal to 0. However, no hypoglycemic episodes occurred during Marathon, while two patients experienced hypoglycemia during PR1 and PR2. There was a significant increase in AUC > 200 mg/dl during races between PR2 and Marathon (P = 0.009) although the median time spent > 200mg/dl was not statistically different in Marathon versus PR2 (48.4% versus 18.4%; P = 0.09). Median time spent in euglycemia (70-200 mg/dl) was lower in Marathon versus PR2 (51.6 versus 58%; P = 0.03). CONCLUSION: Our study proposes a medical support protocol for extreme endurance physical activity in patients with type 1 diabetes mellitus. Our results suggest that RT-CGM, coupled with adjustments in carbohydrate intake and insulin doses, appears to be effective to prevent hypoglycemia during and after exercise.

Thyroid dysfunction induced by immune checkpoint inhibitors is associated with a better progression-free survival and overall survival in non-small cell lung cancer: an original cohort study.

BACKGROUND: The objective of this study was to investigate the association between the onset of TD and treatment efficacy in NSCLC patients who initiated anti-PD-1 blockade (Nivolumab®) and to assess the impact of TD severity and subtype on nivolumab efficacy. MATERIALS AND METHODS: This study was performed at a referral oncology center between July 20, 2015 and June 30, 2018. Patients with histologically confirmed stage IIIB/IV NSCLC in progression after one or two lines of treatment and who initiated Nivolumab were included. Thyroid function (TSH ± fT4, fT3) was monitored and patients were classified according to TD status [TD(+) versus TD(-)], severity [moderate thyroid dysfunction: TSH level between 0.1 and 0.4 or 4.0 and 10 mIU/L and severe thyroid dysfunction: TSH ≤ 0.1 or ≥ 10mUI/L) and subtype (isolated hypothyroidism, isolated hyperthyroidism and hyperthyroidism then hypothyroidism)]. Clinical endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: Among 194 eligible patients, 134 patients (median age, 63 yo; 70.1% male) were included. Forty (29.9%) patients were classified in TD(+) and had a longer OS of 29.8 months (95% CI 18.8-NR) versus 8.1 months (95% CI 5.5-11.5) in TD(-) group (p < 0.001). PFS was also longer (8.7 months (95% CI 5.3-15.1) in TD(+) versus 1.7 months (95% CI 1.6-1.9) in TD(-) group (p < 0.001). In Cox proportional hazards analysis, TD remained an independent predictive factor of OS/PFS. Severity and subtype of TD were not correlated with OS/PFS. CONCLUSIONS: This study suggested that TD induced by Nivolumab appears to be an independent predictive factor of survival, irrespective of TD severity and subtype.

Limited efficacy of lenvatinib in heavily pretreated anaplastic thyroid cancer: a French overview.

Anaplastic thyroid cancer (ATC) is a rare lethal disease. Lenvatinib is an off-label therapeutic option for ATC in most countries, except in Japan. The aim of this multicenter retrospective survey was to analyze the efficacy and the toxicity profile of off-label lenvatinib treatment in all adults advanced ATC patients, in France. Of the 23 patients analysed (14 males; mean age 64 years), 15 were pure ATC and 8 were mixed tumors (i.e. with a differentiated or poorly differentiated component). Prior treatments included neck external beam irradiation in 74%, at least one line of chemotherapy in 22 cases, two lines of chemotherapy in 11 patients, other TKI in 4 cases. A central RECIST assessment was performed. Since lenvatinib initiation, median PFS was 2.7 months (95% CI; 1.9-3.5) and median OS was 3.1 months (95% CI; 0.6-5.5). OS was significantly longer in case of mixed tumors compared with pure ATC (6.3 vs 2.7 months, P = 0.026). Best tumor response was partial response in two cases and stable disease in seven. Clinical improvement was achieved in seven patients. Lethal adverse events occurred in three patients, consisting in haemoptysis in two cases and pneumothorax in one case. Among long-surviving ATC patients (>6 months), four underwent biopsy of distant metastasis, revealing poorly differentiated histology; three of them had initial mixed ATC histology. Efficacy of lenvatinib appears limited, although pure vs mixed ATC disclose differences in disease aggressiveness and treatment response. Long-surviving ATC patients might benefit from biopsy of persistent disease, searching for histological transition or molecular target.

Diagnostic Value of FDG PET-CT Quantitative Parameters and Deauville-Like 5 Point-Scale in Predicting Malignancy of Focal Thyroid Incidentaloma.

Objective: To evaluate the diagnostic value of FDG PET-CT metabolic parameters and Deauville-like 5 point-scale to predict malignancy in a population of patients presenting focal thyroid incidentaloma (fTI). Design: This retrospective study included 41 fTI, classified according to cytological and histological data as benign (BL) or malignant lesion (ML). FDG PET-CT semi-quantitative parameters (SUVmax, SUVmean, SUVpeak, MTV, TLG), tumor to liver SUVmean ratio (TLRmax and TLRmean), tumor to blood-pool SUVmean ratio (TBRmax and TBRmean) were calculated. Each fTI was also classified on a Deauville-like 5-point scale (DS) currently used in lymphoma. Comparison between BL and ML was performed for each parameter and a ROC analysis was conducted. Results: All quantitative PET metabolic parameters (SUV parameters, volume based parameters and SUV ratio) were higher in ML compared with BL, yet no significant difference was reported. fTI (uptake) malignancy rate according to DS grades 2, 3, 4, and 5 was, respectively, 25% (1 of 4), 28.6% (2 of 7), 8.3% (1 of 12), and 33.3% (6 of 18) with no significant difference between ML and BL groups. Results of ROC analysis showed that mean TBR had the highest AUC in our cohort (0.66 95%CI [0.41; 0.91]) with a cut-off value of 2.2. Specificity of MTV and TLG was 100% (cut-off values: MTV 9.6 ml, TLG 22.9 g) and their sensitivity was 30 and 40%, respectively. Conclusion: Our study did not highlight any FDG PET/CT parameter predictor of fTI malignancy.

Comparison between preprandial vs. postprandial insulin aspart in patients with type 1 diabetes on insulin pump and real-time continuous glucose monitoring.

BACKGROUND: The objective was to compare glycemic control between preprandial and postprandial bolus administration (15 min before [PRE] or immediately after the meal [POST]) in patients with type 1 diabetes using insulin pump and real-time continuous glucose monitoring. METHODS: Between September 2015 and February 2016, a single-centre, open randomized, 2-way crossover study of patients on bolus insulin aspart administration was conducted during two 14-day periods and according to 2 administration regimen schedules (PRE/POST or POST/PRE). Inclusion criteria were as follows: patients with type 1 diabetes, ≥18 and ≤ 65 years old, treated with insulin aspart using a Medtronic® insulin pump and trained on functional insulin therapy. Patients were randomly assigned to either regimen schedule. At the beginning of each period, each patient was provided with a standardized high fat meal. Primary outcome was the area under the curve for interstitial glucose above 140 mg/dL per minute (AUC > 140 mg/dL/min) during each period. Secondary outcomes were time spent in hypo/eu/hyperglycemia, glycemic variability indices, and AUC during 4 hours after high fat meal calculated with continuous glucose monitoring data. RESULTS: Twenty-two patients were included. Mean AUC > 140 mg/dL/min was statistically higher in patients on POST (43.70 mg/dL/min; 95%CI: 34.08 to 53.31) versus PRE insulin aspart regimen (37.24 mg/dL/min 95%CI: 27.63 to 46.85) (P = 0.03). Mean interstitial glycemia and glycemic variability indices were also increased (P < 0.05) on POST regimen. The mean AUC 4 hours after the high fat meal was higher on POST regimen but not statistically different (P = 0.06). CONCLUSIONS: In our study, postprandial administration of insulin aspart appears to mildly increase glycemic excursion and glycemic variability.

Malignancy rate of focal thyroid incidentaloma detected by FDG PET-CT: results of a prospective cohort study.

OBJECTIVE: To evaluate the malignancy rate of focal thyroid incidentaloma (fTI) in a population of patients undergoing a 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) for a non-thyroid purpose. DESIGN: We conducted a prospective cohort study from January 2013 to November 2014. All consecutive patients referred for a FDG PET-CT were prospectively screened. Patients with known neoplastic thyroid disease were excluded from the analysis. All patients presenting one or more fTI and who accepted to benefit from a complementary thyroid ultrasonography (US) were included and managed according to the French endocrine society consensus. Prevalence of fTI in our population and malignancy rate was assessed. RESULTS: During the inclusion period, 10,171 patients were referred for a FDG PET-CT in our center. Fifty-three patients presenting a known thyroid disease were excluded. Among the remaining 10,118 patients, 127 (1.3%) with 131 fTI were individualized. US could not be performed in 37 patients. The remaining 90 patients (92 fTI) were explored by US ± fine-needle aspiration biopsy (FNAB). US results demonstrated a nodule aspect in 80 cases of which 60 benefited from FNAB. Nineteen of 92 fTI underwent surgery with 10 malignant lesions among the 60 patients performing both US and FNAB. CONCLUSION: The prevalence of fTI discovered on FDG PET-CT in our population was 1.3% with 10 malignant lesions among the 60 patients performing both US and FNAB.

Results of the prolonged use of subcutaneous continuous infusion of hydrocortisone in a man with congenital adrenal hyperplasia.

This is a case report study of a young man with Congenital Adrenal Hyperplasia (CAH) who has been treated during 2 years by a subcutaneous continuous infusion hydrocortisone (SCIH) to optimize his treatment. Hydrocortisone was delivered via an insulin infusion device. We also studied the evolution of testicular adrenal rest tumors (TARTs) and the quality of life through SF36 survey. Four rates were determined, with a total of 47 mg per day. Biochemical parameters were normalized at 2 months. The SF36 questionnaire showed a progress of well-being. The weight decreased to 106 kg, that is, -5 kg (height: 1.71 m). Unfortunatly, there was no change of the TARTs. Two episodes of dermohypodermitis, with abscess at the infusion site, were observed. This case demonstrates the feasibility of prolonged SCIH therapy in patients with CAH, reporting positive effects on quality of life and on BMI.

Metabolic syndrome: a major risk factor for atherosclerosis in HIV-infected patients (SHIVA study).

OBJECTIVE: Metabolic syndrome (MetS) is directly related to a high incidence of cardiovascular disease in the general population. The association is more doubtful among HIV-infected patients, although MetS has an elevated prevalence in this population. We explored the impact of MetS on early atherosclerosis markers. RESEARCH DESIGN AND METHODS: All HIV-infected outpatients followed at the Brest University Hospital were included in this cross-sectional hospital-based study (SHIVA study, France) (n=154). The MetS status (NCEP ATPIII definition, at least three of these five criteria: fasting glucose, triglycerides, HDL-C, waist circumference and hypertension.) of each patient was analyzed (Mann-Whitney test) according to carotid intima-media thickness, number of plaques, and a combined cardiovascular score. RESULTS: After exclusion of 6 patients treated with statins or insulin or both, MetS status was available for 140 (90.9%) patients and positive for 10 (7.1%). MetS status was due predominantly to blood glucose and triglyceride levels and was strongly correlated with all atherosclerosis markers (p < or = 0.01). CONCLUSION: The MetS prevalence in this population is low for a group with HIV infection, even after inclusion of the statin-treated patients (11.4%), but remains higher than among the general population. MetS in this population is probably a heterogeneous cluster of side effects of antiretroviral therapy (high triglycerides, lower HDL-C, and hypertension) and direct effects of HIV (glucose disturbances). Because it is strongly linked to the presence of plaque and intimal thickness, it is a pertinent criterion for deciding about cardiovascular prevention.

Management of ACTH-secreting supradiaphragmatic adenomas.

Supradiaphragmatic adrenocorticotropic hormone (ACTH) secreting pituitary adenomas are exceptionally encountered (14 cases previously described) and raise issues concerning their nosology and management. If surgery is the treatment of choice, the nature of surgical approach (craniotomy, transsphenoidal approach) remains controversial. To illustrate this issue, we presented two cases of supradiaphragmatic ACTH secreting pituitary adenomas successfully excised via a subfrontal approach. Both patients were female (20 and 41 years) and had a typical Cushing's syndrome. MRI revealed, in both cases, a suprasellar mass in contact with the pars tuberalis of the pituitary. In the first case, the patient underwent initially a transsphenoidal approach with negative exploration and subsequent partial hypophysectomy. One year later, the patient was operated on again via a subfrontal approach, allowing excision of a supradiaphragmatic adenoma and a complete cure of Cushing's disease. In the second case, the patient underwent initially a subfrontal approach and was definitely cured. In both cases, the diaphragma sellae was found to be intact and the pituitary stalk could be preserved. Postoperative MRI demonstrated a clearly visible intact pituitary stalk in conjunction with normal aspect of the pituitary. Supradiaphragmatic pituitary adenomas are most likely adenomas of the pituitary stalk with extra-axial development. Surgery remains the treatment of choice. Should the superior approach be preferred, the transsphenoidal-transtuberculum sellae approach may represent a viable alternative when performed by a well-trained surgical team. Surgery may be difficult, and drawbacks are non negligible, particularly in elderly patients. In these cases, stereotactic radiosurgery should receive more consideration.

Effects of the route of oestrogen administration on IGF-1 and IGFBP-3 in healthy postmenopausal women: results from a randomized placebo-controlled study.

OBJECTIVE: Oestrogens can modulate the action or secretion of GH. Previous studies in postmenopausal women have shown a differential effect between transdermal 17beta-oestradiol and oral ethynyl-oestradiol on GH and IGF-1 concentrations. This secondary analysis, based on a large randomized trial, aimed to estimate the effect of the route of administration of 17beta-oestradiol in combined hormone replacement therapy with progesterone on IGF-1 and IGFBP-3 levels. DESIGN: IGF-1 and IGFBP-3 were evaluated in a randomized study of 196 healthy postmenopausal women who were randomly allocated to receive on a continuous basis either 1 mg of 17beta-oestradiol orally combined with a daily intake of 100 mg progesterone (group 1; n = 63), or 50 microg of 17beta-oestradiol transdermally combined with a daily intake of 100 mg progesterone (group 2; n = 68), or triple dummy placebo (group 3; n = 65) over a 6-month period. IGF1 and IGFBP-3 levels were available for 133 women. RESULTS: Oral oestrogen significantly decreased IGF-1 levels compared to placebo (P = 0.04) and transdermal oestrogen (P = 0.004), whereas transdermal oestrogen had no effect on IGF-1 levels compared to placebo (P = 0.56). As regards IGFBP-3, no significant difference was detected between the three groups. CONCLUSIONS: Our data indicate that the route of oestrogen administration can influence IGF-1 levels. IGF-1 concentrations decreased significantly with oral oestrogen, whereas no significant change was observed with transdermal oestrogen at 6 months. The clinical relevance of these differential effects remains to be determined, particularly with regard to the risk for cardiovascular diseases.

Premature atherosclerosis in HIV positive patients and cumulated time of exposure to antiretroviral therapy (SHIVA study).

BACKGROUND: With the advent of antiretroviral therapy regimens in HIV positive patients, it is crucial to consider their long-term benefits to risk ratios. The responsibility of treatment in premature atherosclerosis is not clear. Thus, the aim of this study is to evaluate the impact of exposure to reverse transcriptase inhibitors (nucleosidic and non-nucleosidic) and to protease inhibitors on the cardiovascular status of an entire hospital based cohort of patients. METHODS: 154 patients were included. Using a linear analysis, we sought an association between the cumulative time of exposure to these three classes of antiretroviral drugs and the carotid intima-media thickness measured by ultrasonography and a cardiovascular composite score. RESULTS: The study confirms premature atherosclerosis, which not only correlates with the usual risk factors, such as triglyceride level, but also with protease inhibitor exposure, especially that of lopinavir. Nevertheless as regards current drug exposure, the clinical impact was low: five clinical complications of atherosclerosis and only one out of 35 scintigraphic and ECG exercise tests warranted a coronary angiography which was negative. CONCLUSION: These data should not lead to the rejection of protease inhibitors but should strengthen the prevention of cardiovascular diseases as an integral part of the management of HIV patients.

Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.

OBJECTIVE: Activated protein C (APC) resistance not related to the factor V Leiden mutation is a risk factor for venous thrombosis. Oral estrogen replacement therapy (ERT) has been reported to induce APC resistance. Little is known about the effect of transdermal estrogen. METHODS AND RESULTS: We enrolled 196 postmenopausal women who were randomly allocated to receive either 1 mg 17beta-estradiol orally (n=63) or 50 microg 17beta-estradiol transdermally per day (n=68), both associated with 100 mg progesterone daily or placebo (n=65) for 6 months. An activated partial thromboplastin time (APTT)-based test and the effect of APC on thrombin potential (ETP) were used. Oral ERT induced an ETP-based APC resistance compared with both placebo (P=0.006) and transdermal ERT (P<0.001), but there was no significant effect of transdermal ERT compared with placebo (P=0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1+2 plasma levels were significantly higher after 6 months of treatment in women allocated to oral ERT compared with those on placebo and transdermal ERT and were positively and significantly correlated with changes in ETP-based APC sensitivity ratio. CONCLUSIONS: Our data show that oral, unlike transdermal, estrogen induces APC resistance and activates blood coagulation. These results emphasize the importance of the route of estrogen administration.

Hodgkin's disease masquerading as fibrous thyroiditis: potential role of cytokines in in vivo and in vitro studies.

Hodgkin's disease appearing as, or associated with, fibrous thyroiditis has only been described rarely. We report the observation of a patient presenting with a goitre, fibrosis of the thyroid and adjacent structures, and hypothyroidism. The histological examination was compatible with fibrosclerotic thyroiditis. This diagnosis was reviewed 6 months later when the biopsy of a supraclavicular nodule that had subsequently appeared led to the diagnosis of a nodular-sclerosis type of Hodgkin's disease. The plasmatic levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) were very high compared to the levels in healthy subjects (12 and 40 IU/l vs. 0.05 and 2.0 IU/l, respectively). These cytokine levels decreased when the initial illness was treated, and their normalization was associated with the disappearance of the cervical and thyroidal fibroses. A parallel in vitro study of these cytokines and of TNF-alpha receptors and IL-13 was performed. The results suggest a possible cause-and-effect relationship between IL-6 and IL-13 produced locally by the tumoral tissue and the development of cervical fibrosis.