Higher baseline TSH levels predict early hypothyroidism during cancer immunotherapy.

BACKGROUND AND PURPOSE: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that enhance the immune response against cancer cells. ICIs are generally well tolerated, although endocrine immune-related adverse events (irAEs) are common. We investigated the risk factors for thyroid irAEs in patients treated with ICIs. Moreover, we evaluated the clinical outcome of subjects who became hypothyroid compared to euthyroid patients. PATIENTS AND METHODS: We retrospectively analyzed a series of 195 consecutively subjects treated with ICIs for metastatic tumors at the University of Naples "Federico II" between January 2014 and March 2020. Only subjects tested for thyroid function before and during the treatment with ICIs were included. RESULTS: In the 96 patients treated with ICIs who were included [66 males, median age: 62 years (27-87)], thyroid irAEs occurred in 36 (37.5%), 16 (16.7%) a transient thyrotoxicosis, and 20 (20.8%) an hypothyroidism (in nine subjects hypothyroidism was preceded by a transient thyrotoxicosis). Only baseline TSH levels above 1.67 mIU/L and positive anti-thyroid antibodies (Ab-T) were associated with a higher risk of hypothyroidism. Patients with hypothyroidism during ICI treatment showed an improved 2-year PFS (HR = 0.82 CI 0.47-1.43; p = 0.0132) and OS (HR = 0.38 CI 95% 0.17-0.80; p = 0.011) compared to euthyroid patients. CONCLUSIONS: Baseline TSH levels above 1.67 mIU/L and presence of Ab-T are risk factors for the development of thyroid irAEs. Patients affected by thyroid irAEs showed a longer survival than patients who remained euthyroid.

Static patella tilt and axial engagement in knee extension are mainly influenced by knee torsion, the tibial tubercle-trochlear groove distance (TTTG), and trochlear dysplasia but not by femoral or tibial torsion.

PURPOSE: The aim of this study was to investigate the association of femoral (FT), tibial (TT), and knee torsion (KT) on the patella tilt (PT), the axial engagement index (AEI), and the tibial tuberosity-trochlear groove distance (TTTG). METHODS: Femoral torsion, tibial torsion, knee torsion, patella tilt, the axial engagement index, the TTTG, and trochlear dysplasia were retrospectively evaluated on 59 patients suffering from recurrent patella instability or anterior knee pain with 118 torsional lower limb magnetic resonance imaging studies. RESULTS: FT and TT did not show any significant associations with TTTG, PT, and AEI (n.s.). KT was significantly associated with a higher TTTG, higher PT, and lower AEI (all, p < 0.001). Higher grade trochlear dysplasia was associated with a higher PT and lower AEI (both, p < 0.001). The Dejour classification showed no significant association with FT, TT, KT, and TTTG (n.s.). All measurement parameters showed an excellent interrater agreement (ICC 0.89-0.97). CONCLUSIONS: Static patella tilt and patellofemoral axial engagement in knee extension are mainly influenced by knee torsion, TTTG, and trochlear dysplasia but not by femoral or tibial torsion. These findings help to understand the underlying reasons for the patella position in knee extensions in CT and MRI investigations in patients suffering from patella instability and patellofemoral pain syndrome. LEVEL OF EVIDENCE: III.

Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma.

STUDY QUESTION: What are the consequences of radioactive iodine (RAI) therapy for testicular function? SUMMARY ANSWER: A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities. WHAT IS KNOWN ALREADY: Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function. STUDY DESIGN, SIZE, DURATION: A longitudinal prospective multi-center study on testicular function performed in DTC patients before a single 131I ablative activity of 3.7 GBq (V0) and at 3 months (V3) and 13 months (V13) after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Forty male patients, aged 18-55 years, with DTC participated. Hormonal analysis included FSH, LH, testosterone and inhibin B serum levels at V0, V3 and V13. Furthermore, sperm parameters, DNA fragmentation and sperm chromosomal abnormalities were evaluated at each time points. The differences in all parameters, between V0-V3, V0-V13 and V3-V13, were analyzed, using a Wilcoxon test. MAIN RESULTS AND THE ROLE OF CHANCE: Prior to RAI administration, all patients had normal gonadal function. At V3, a statistically significant increase in FSH levels and a decrease in inhibin B levels were observed and sperm concentration, as well as the percentage of morphologically normal spermatozoa, were significantly decreased (P < 0.0001). These modifications were transient as both sperm concentration and normal morphology rate returned to baseline values at V13. However, at this later time point, FSH and inhibin B levels were still impacted by RAI administration but remained in the normal range. Although no DNA fragmentation was observed at V3 nor V13, our study revealed a statistically significant increase in the number of sperm chromosomal abnormalities both at V3 (P < 0.001) and V13 (P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Among the 40 patients included in the study, only 24 had all the parameters available at all visits. WIDER IMPLICATIONS OF THE FINDINGS: Prospective studies with longer term follow up would be helpful to determine whether the chromosome abnormalities persist. These studies would be required before sperm banking should be suggested for all patients. However, sperm preservation for DTC patients who require cumulative radioiodine activities higher than 3.7 GBq should be proposed. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Programme Hospitalier de Recherche Clinique, AP-HP (No. P040419). The authors report no conflict of interest in this work. TRIAL REGISTRATION NUMBER: NCT01150318.

Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma.

BACKGROUND: Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up. PATIENTS AND METHODS: EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported. RESULTS: Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis. CONCLUSION: The secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib. TRIAL REGISTRATION NUMBER: NCT00704730.

Are dietary reports in a case-control study on thyroid cancer biased by risk perception of Chernobyl fallout?

BACKGROUND: In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects' beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France. METHODS: The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi2 tests and differences in dietary reports were analyzed using a two-way ANOVA. RESULTS: In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects. CONCLUSION: We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions.

Screening in asymptomatic SDHx mutation carriers: added value of ¹8F-FDG PET/CT at initial diagnosis and 1-year follow-up.

PURPOSE: Specific recommendations on screening modalities for paraganglioma (PGL) and phaeochromocytoma (PCC) in asymptomatic SDHx mutation carriers (relatives) are still lacking. We evaluated the added value of (18)F-FDG PET/CT in comparison with morphological imaging at initial diagnosis and 1 year of follow-up in this population. METHODS: The study included 30 consecutive relatives with a proven SDHx mutation who were investigated by (18)F-FDG PET/CT, gadolinium-enhanced magnetic resonance angiography of the head and neck, thoracic/abdominal/pelvic (TAP) contrast-enhanced CT and/or TAP MRI. (123)I-MIBG scintigraphy was performed in 20 subjects and somatostatin receptor scintigraphy (SRS) in 20 subjects. The gold standard was based on pathology or a composite endpoint as defined by any other positive imaging method and persistent tumour on follow-up. Images were considered as false-positive when the lesions were not detected by another imaging method or not confirmed at 1 year. RESULTS: At initial work-up, an imaging abnormality was found in eight subjects (27%). The final diagnosis was true-positive in five subjects (two with abdominal PGL, one with PCC and two with neck PGL) and false-positives in the other three subjects (detected with (18)F-FDG PET/CT in two and TAP MRI in one). At 1 year, an imaging abnormality was found in three subjects of which one was an 8-mm carotid body PGL in a patient with SDHD mutaion and two were considered false-positive. The tumour detection rate was 100% for (18)F-FDG PET/CT and conventional imaging, 80% for SRS and 60% for (123)I-MIBG scintigraphy. Overall, disease was detected in 4% of the subjects at the 1-year follow-up. CONCLUSION: (18)F-FDG PET/CT demonstrated excellent sensitivity but intermediate specificity justifying combined modality imaging in these patients. Given the slow progression of the disease, if (18)F-FDG PET/CT and MRI are normal at baseline, the second imaging work-up should be delayed and an examination that does not expose the patient to radiation should be used.

Target therapies for radioiodine refractory advanced thyroid tumors.

A small but not irrelevant percentage of differentiated thyroid cancers become refractory to radioiodine treatment either because they lose the ability of taking up iodine over the time or because, despite a persistent uptaking ability, the effect of the radioiodine is lost in terms of tumor burden reduction. These patients receive only few and transient benefits from other conventional therapies and particularly from chemotherapy. In the last decade, several new drugs have been discovered as potentially useful and tested in clinical trials. They are mainly represented by protein kinase inhibitor molecules that should be proposed to advanced and progressive 131I refractory thyroid cancer patients by enrolling them in clinical trials or by the "off label" use of the drug.

[Use of SMS to ask mothers to come to vaccination sessions in Bobo-Dioulasso]. / Recours aux SMS pour convoquer les mères aux séances de vaccination à Bobo-Dioulasso.

Even though the expanded programme for immunization (EPI) coverage at national level is high in Burkina (95% of fully vaccinated children), mothers of children following EPI in Health Centres (HC) would benefit from being reminded of EPI sessions by sending SMS (short message service) to their own mobile phone, or through mobile phone of a family member living in the same compound. SMS could be sent through Computerized Immunization Registers (CIR), hosted by HC computers. 210 mothers of children aged 0 to 5 years were chosen at random and questioned if they owned a mobile phone, if they could read a SMS, or, if not, what language they would understand if a voice SMS was sent. They were also asked if a family member could receive, read and transmit the message, if mothers did not own a mobile phone. They were also asked if they are willing to give their telephone number to HC. 94% of mothers could be reached through written or voice SMS, sent to their own or family member's mobile phone. 100% of mothers would be willing to give their telephone number to their HC to improve their ability to come at the right time for vaccination sessions. SMS reminders, delivered through CIR, should improve EPI attendance and management of sessions in HC, especially in epidemic context.

[Positive impact of a video and TV documentary on attendance of women to catch-up collective vaccinations and reasons for non-attendance]. / Impact positif d'un documentaire vidéo-TV sur la vaccination antitétanique des femmes au Cambodge et causes de non-vaccination.

The impact of medical documentaries on attendance to immunization sessions is not documented in developing countries. The impact of a video and TV medical documentary on women's vaccination during a catch-up tetanus collective immunization was studied in Cambodia (2002-2004). A medical video documentary produced locally was publicly shown in 10 villages chosen at random among 63 villages to be covered by collective tetanus immunization. In each village where the video was shown, 33 women, older than age 11, were selected at random and questioned about their tetanus vaccination records, to assess if they attended the video and to evaluate their knowledge about tetanus. A second interview was conducted after the first collective vaccination to check their attendance and to record reasons for non-attendance. The same interview was conducted 10 months later, after the documentary was shown on a local TV channel and a second collective tetanus vaccination conducted. Data were collected from 323 (98%) women. Seventy-eight (24%) women saw the video documentary and only eight (2.4%) saw it on TV. Compared to farmers, shopkeepers saw significantly less the documentary (χ² of Yates: 5.77,P = 0.016; 95% CI: 0.10 < RR = 0.29 < 0.88) and no home keeper or civil servant attended it. Women of childbearing age with no school education were significantly more attracted by the video documentary (χ² of Yates: 5.99,P = 0.01; 95% CI: 1.10 < RR = 1.57 < 2.22) than other childbearing-aged women, although their final immunization coverage was not better. The documentary did not increase the knowledge that contamination for tetanus may come from earth and tools, but not from air and water, and that all ages are at-risk for tetanus, but it increased significantly the knowledge that vaccination can prevent the disease (χ² of Yates: 13.98;P = 0.0001; 95% CI: 1.28 < RR = 1.57 < 1.93). Women who saw the video documentary attended the first collective session more often than those who did not (χ² of Yates: 11.00; P = 0.0006; 95% CI: 1.23 < RR = 1.51 < 1.84)in spite of their better vaccination status before the immunization, and this was mostly significant for farmers and women more than 45 years of age. Women who saw the documentary either on video or on TV also attended more the second collective session, but not significantly (χ² of Yates: 1.23;P = 0.266; 95% CI: 0.91 < RR = 1.23 < 1.66). Forty-nine percent of women had not attended school and the video documentary was re-run twice after the first performance. Women older than 45 years (55%) completely escaped immunization significantly more often than women of childbearing age (35%) (χ² of Yates: 17.26;P = 0.00003, 95% CI: 1.53 < RR = 2.13 < 2.97), who did it more often than schoolgirls (2%) (χ² of Yates: 9.69;P = 0.002; 95% CI: 0.01 < RR = 0.09 < 0.65). The main reasons for not being vaccinated during catch-up collective tetanus vaccinations were a too short interval between doses according to the WHO schedule (25%), agricultural task (18%), leisure travel (8%), fear of injections (7%), and being completely vaccinated according to the WHO schedule (7%). Only 2% of women were not informed, showing that vaccination was well-publicized. This educational technique should be re-used in all villages during coming catch-up tetanus collective immunizations in Cambodia, mostly in urban contexts where coverage during these sessions is lower. Video is still the best method in rural context if some education is also provided to the audience. According to the WHO schedule, the interval between two catch-up tetanus sessions should be extended to over a year to be able to give booster shots to women who already received three or more tetanus doses. Vaccination of schoolgirls is significantly easier to achieve with the help of the teachers. Vaccinating women aged over 45 should be encouraged as they are at risk of tetanus even in developed Asian countries.

[Computerized temperature monitoring of the vaccine cold chain in a tropical climate, Chad]. / Surveillance informatisée de la chaîne du froid en milieu tropical (Tchad).

Because new EPI liquid vaccines are highly sensitive to freezing and overheating, close monitoring of the cold chain is mandatory. The new Testostore 171-1 electronic thermometer (Testo) provides more reliable monitoring of cold chain temperature than freezer indicators, vaccine vial monitors and color strips that only indicate if vaccines are out-of-date. The Testo thermometer uses a probe placed in refrigeration units to periodically measure and store temperature readings. Temperature curves are displayed via a USB connection on a laptop computer running special software (Comfort software light). Testo temperature data can easily be communicated to all management levels by e-mail. The first experience using the Testo system in Africa involved regional EPI supervision in Mondou, Logone Occidental, Chad. After a preliminary mission in Chad in 2006 showed the feasibility of using this method to manage the national cold chain at all levels, a nurse was appointed as EPI supervisor and given a refresher course in Chad's capital Ndjamena in March 2009. In April-May 2009, the supervisor was sent back to the Logone Occidental Region to monitor, by himself, refrigeration units making up the regional and district cold chain for vaccine storage in five health centers (rural and urban). Temperature curve readings were performed on site in the presence of the medical staff and results were compared to those recorded twice a day on conventional temperature charts using lamellar thermometers installed in refrigerators doors. Testo curves showed that liquid vaccine storage temperatures fell below freezing too frequently and that temperatures readings of door thermometers were often inaccurate. Testo readings also detected power outages in refrigeration units used in urban settings and flame extinctions in kerosene lamp refrigerators due to refrigerator breakdown or windy weather conditions before the rainy season. The main advantage of this monitoring method is to provide reliable data as a basis not only for detection of possible freezing of liquid vaccines but also for discussion of cold chain management and improvement with medical staff.

Consequences of atmospheric contamination by radioiodine: the Chernobyl and Fukushima accidents.

PURPOSE: After the accidents of nuclear power plants at Chernobyl and at Fukushima, huge amounts of radioactive iodine were released into the atmosphere. METHODS: We reviewed data on the health consequences of these accidents with a focus on thyroid consequences. RESULTS: Among the 2 million children who were living in highly contaminated regions in Belarus, Ukraine and Russia, 7000 cases of thyroid cancer had occurred in 2005. This is the most significant radiation-induced consequence of the Chernobyl accident. The increased incidence of thyroid cancer observed in adult population who lived in these highly contaminated regions is at least in major part related to screening and it is not possible to individualize among these thyroid cancers those that are potentially caused by radiation exposure. For populations who lived outside these regions at the time of the accident, there is no detectable consequence of the radiation exposure on the thyroid gland. Among children who lived nearby the Fukushima power plant in 2011, there is currently no evidence of an increased incidence of thyroid cancer. Ultrasonography screening in these individuals detected a number of thyroid cancers that are probably not related to the accident. Because thyroid cancer is frequent, studies have been carried out to distinguish radiation-induced from their sporadic counterparts, and genomic signatures might be helpful. CONCLUSIONS: The consequences of the Chernobyl accident clearly demonstrate that populations living nearby a nuclear power plant should be protected in case of accident by sheltering, food restrictions and prophylaxis of thyroid irradiation by potassium iodine administration, if the predicted estimated dose to the thyroid gland of children might be >50 mGy. These countermeasures should be applied in priority to children, adolescents and pregnant women; they are safe and effective.

Endocrine pancreatic tumours: which are the most useful MRI sequences?

OBJECTIVES: To determine magnetic resonance imaging (MRI) signal and enhancement characteristics of endocrine pancreatic tumours (ETPs) and which MR sequences show them most consistently. METHODS: Fifty-five consecutive patients with 68 ETPs underwent 1.5-T abdominal MRI comprising T2-weighted, unenhanced T1-weighted and dynamic T1-weighted after injection of gadopentetate dimeglumine sequences. Twenty-one patients underwent diffusion-weighted imaging (DWI). Two radiologists identified the number, location, size, signal and enhancement patterns of ETPs, and determined a confidence scale indicating the presence of tumours on DWI. The results were compared with echo-endoscopy (endoscopic ultrasound) findings. RESULTS: The detection sensitivity was 95%, similar to that of echo-endoscopy. T2-weighted and T1-weighted sequences at the arterial phase had the highest contrast-to-noise ratio (CNR) median value. On DWI, the mean sensitivity was 65%. The mean apparent diffusion coefficient (ADC) value of ETP was significantly lower than in the normal parenchyma. CONCLUSION: In suspected ETP, MRI is a sensitive method, similar to echo-endoscopy and could be recommended as the first imaging technique. T2-weighted sequences and T1-weighted sequences in the arterial phase are the optimal pulse sequences. The quantitative assessment of ADC values is a promising tool for the characterisation of pancreatic lesions.

Locally unresectable differentiated thyroid cancer: outcomes and perspectives.

PURPOSE: Differentiated thyroid cancer (DTC) patients with an unresectable primary tumor cannot benefit from curative surgery, and radioiodine treatment for locoregional and distant disease is not possible with the thyroid gland still in place. Due to local invasion, these patients cannot be included in clinical trials, so that treatment options are limited. The aim of this study was to describe the characteristics and the prognosis of patients with these locally unresectable DTC. PATIENTS AND METHODS: A retrospective and multicentric analysis of consecutive cases of unresectable DTC diagnosed between 2000 and 2015 was performed. RESULTS: The study population consisted in 22 patients, 13 females (59%); median age: 77 years (range: 52-91). Thyroid tumors were papillary in six, follicular in seven, Hürthle cell in one and poorly differentiated in eight patients. Patients were treated with external beam radiation therapy (EBRT) (57%), locoregional therapy of distant metastases (41%), cytotoxic chemotherapy (38%) and tyrosine kinase inhibitors (TKIs) (33%). TKI treatment resulted in median disease control duration of 7 months with a grade 3-4 toxicity rate of 44%. Only one patient had a total thyroidectomy after neo-adjuvant EBRT. The 1, 3 and 5-year cumulative survival rate was 81%, 27.7% and 21.5%, respectively. The cause of death was DTC in 11 cases (local progression in 7), and to other causes in 7 cases; no patient died from treatment toxicity. CONCLUSIONS: Clinical trials and approved treatments are lacking for unresectable DTC. TKI treatment may allow prolonged disease control with acceptable toxicity.

Thermal-ablation of vertebral metastases prevents adverse events in patients with differentiated thyroid carcinoma.

PURPOSE: To evaluate a strategy that used thermal-ablation of vertebral metastases (VM) to prevent vertebral related events (VRE) in patients with differentiated thyroid cancer (DTC). METHODS: This single center study retrospectively reviewed records and post-operative imaging of all DTC patients treated with thermal-ablation for asymptomatic VMs. Rate of local tumor control at first post-operative imaging, 12 and 24 months after thermal-ablation and rate of VREs at 12 and 24 months among the treated VMs were reported. New VMs that occurred during the follow-up and were not considered for additional thermal-ablation were moniroted and VREs were reported. RESULTS: Thermal-ablation was used to achieve local control of 41 VMs in 28 patients. Median post-treatment follow-up was 22 months [range: 12-80] and the mean delay for first post-operative imaging was 2 months [range: 0.6-7.5]. Local control at first post-operative imaging, 12 and 24 months was achieved in 87.8%, 82.9% and 75.6%, respectively. Among the treated VMs the rates of VRE was 7.3% at 2 years, significantly lower if local control was achieved at first post-operative imaging than if it was not (0% vs 30%, p = 0.011, OR = 0.184 [95%CI = 0.094-0.360]). After thermal-ablation procedures, 19 news VMs occurred in 11 patients (39.2%) with a median interval of 8 months [range 1-26] and remained untreated. Among these untreated VMs, the rate of VREs at 2 years was significantly higher compared to the treated VMs: (36.8% vs. 7.3%, p = 0.008, OR = 0.135, [95%CI = 0.030-0.607]). CONCLUSION: local tumor control of VMs using thermal-ablation decreases the risk of VREs in DTC patients.

Notch signaling is involved in expression of thyrocyte differentiation markers and is down-regulated in thyroid tumors.

CONTEXT: Notch genes encode receptors for a signaling pathway that regulates cell growth and differentiation in various contexts, but the role of Notch signaling in thyroid follicular cells has never been fully published. OBJECTIVE: The objective of the study was to characterize the expression of Notch pathway components in thyroid follicular cells and Notch signaling activities in normal and transformed thyrocytes. DESIGN/SETTING AND PATIENTS: Expression of Notch pathway components and key markers of thyrocyte differentiation was analyzed in murine and human thyroid tissues (normal and tumoral) by quantitative RT-PCR and immunohistochemistry. The effects of Notch overexpression in human thyroid cancer cells and FTRL-5 cells were explored with analysis of gene expression, proliferation assays, and experiments involving transfection of a luciferase reporter construct containing human NIS promoter regions. RESULTS: Notch receptors are expressed during the development of murine thyrocytes, and their expression levels parallel those of thyroid differentiation markers. Notch signaling characterized also normal adult thyrocytes and is regulated by TSH. Notch pathway components are variably expressed in human normal thyroid tissue and thyroid tumors, but expression levels are clearly reduced in undifferentiated tumors. Overexpression of Notch-1 in thyroid cancer cells restores differentiation, reduces cell growth rates, and stimulates NIS expression via a direct action on the NIS promoter. CONCLUSION: Notch signaling is involved in the determination of thyroid cell fate and is a direct regulator of thyroid-specific gene expression. Its deregulation may contribute to the loss of differentiation associated with thyroid tumorigenesis.

Prediction and diagnosis of bone metastases in well-differentiated gastro-entero-pancreatic endocrine cancer: a prospective comparison of whole body magnetic resonance imaging and somatostatin receptor scintigraphy.

PURPOSE: Our purpose was to compare the sensitivity of whole body (WB) magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS) for the diagnosis of bone metastases (BMs) in patients with well-differentiated gastro-entero-pancreatic endocrine cancer (WD-GEP-EC) and to determine predictive factors of BM. PATIENTS AND METHODS: WB-MRI and SRS were prospectively performed in 79 patients with bronchial (11), thymic (five), gastric (two), duodeno-pancreatic (24), ileal (26), colic (one), or unknown primary (10) WD-GEP-EC. RESULTS: A total of 36 patients (46%) had 333 BMs involving 119 skeletal segments. WB-MRI and SRS were equally sensitive for detecting patients with BM (86 vs. 81%; P = 0.56), with 33% of the patients diagnosed with only one procedure. WB-MRI detected more BMs than SRS (80 vs. 57%; P = 0.017). Compared with SRS, WB-MRI detected more spine BMs (96 vs. 45%; P < 0.001) and tended to detect more pelvic and lower limb BMs (P = 0.054 and P = 0.06, respectively). Compared with WB-MRI, SRS detected more skull BMs (100 vs. 0%; P < 0.001) and tended to detect more rib BMs (P = 0.08). Sternal and upper-limb BMs were equally detected with WB-MRI and SRS (P = 0.32 and P = 0.46, respectively). Bone staging with SRS and spine MRI rather than WB-MRI would have detected 92% of the patients with BMs and 83% of all BMs. The extent of liver involvement and bronchial-thymic primary tumors were independent predictive factors for BM. CONCLUSIONS: We recommend bone staging with SRS and spine MRI in all patients with bronchial-thymic or unknown primary WD-GEP-EC. In case of duodeno-pancreatic or ileal primary, bone imaging may be restricted to patients with liver metastases.

[Serological study carried out in Cambodia during a tetanus vaccination in adults]. / Résultats d'une enquê te sérologique réalisée au Cambodge lors d'une vaccination antit ténique des adultes.

In 1997, the Ministry of Health tested the feasibility and serological activity of a two-dose vaccine at one year interval within a catch-up tetanus immunization programme in a rural population. In the district of Angkor Thom in the Siem Reap province (15,000 inhabitants), a team of nurses and administrative clerks travelling by motorcycle, conducted between February 1998 and February 1999 an EPI and tetanus immunization of the whole population gathered in meeting points. In 132 childbearing age female volunteers, 49 following a two-dose schedule at one year interval, and 70 following a WHO three-dose schedule, with two doses at one month interval and a booster dose one year later tetanus antibodies have been measured before vaccination, one year after the first dose or the two first doses, and six months after the second or third dose of vaccine. 129 male volunteers of the same age were also recruited in the serological study following only the two-dose schedule. The titration was done first with monoantigen ELISA, then with mouse seroneutralisation, the reference method for measuring tetanus seroprotection. Only 148 (57%) volunteers completely attended the serological study Compared to seroneutralisation, sensitivity for seroprotection with ELISA was 89% (CI95%: 85%-94%) and specificity 84% (CI95%: 81%-89%). The coverage of the general population vaccinated with two doses, in both sexes and in all age-groups, increased on average from 5% to 70%. The three-dose schedule gave significantly more protection than the two-dose schedule in women tested with seroneutralisation. On a first sample in those with no protective antibodies and testifying they had not been vaccinated before, 51% of these volunteers after one dose and 93% after two doses acquired protective antibodies. On first sample, 52% of female volunteers had protective antibodies in seroneutralisation, against 11.7% in men. 14% of subjects tested in ELISA and 6.8% tested in seroneutralisation showed in a second sample a decrease in titres, although they had received a tetanus vaccine. For unprotected volunteers on first sample and testifying they had not been vaccinated before, neither age nor past chronic cutaneous lesions or cows living around their houses, two possible sources of contact with CI. tetani, increased significantly seroconversion. Only female volunteers were significantly more seroconverting (81%) compared to men of same age (51%) (RR: 1.60, CI95%: I. 17-2.18) suggesting a memory bias in women supposed to be vaccinated by EPI. 30% of volunteers in ELISA and 14% in seroneutralisation showed spontaneous protecting antibodies in the first sample without having any document or memory of a past tetanus vaccination. Tested by seroneutralisation, no relation was to be found for having spontaneous antibodies with past chronic cutaneous lesions and cows living around their houses. Only the eldest (35-45 y.o.) female volunteers showed significantly more spontaneous antibodies (RR: 3.83, CIs%: 1.74-8.2) than men in the same age-group. A memory bias may be found also in this female age-group. Good serological response should encourage implementation of a catch-up tetanus vaccination in this country considering the large number of unprotected adults, mainly male adults. Due to problems with notification and recalling past vaccinations, only a prospective study in an unimmunized large cohort, studying all possible factors of tetanus toxin neutralisation, could confirm the existence and cause of spontaneous antibodies. Excluding vaccination in at-risk population for such a study would be however ethically unacceptable.

[Evaluation of an immunoassay for calcitonin]. / Evaluation d'une methode de dosage de la calcitonine par chimio luminescence dans le suivi des cancers medullaires de la thyroïde.

INTRODUCTION: The calcitonin is the most specific and the most sensitive marker of medullary thyroid carcinoma (MTC) both for screening and postoperative follow-up of the patients. Its measurement is made either remotely , or after stimulation of pentagastrin secretion which the answer is amplified at the carrier of CMT. The aim of this study was to estimate a chimioluminescent method by comparing it with an immunoradiological method, manual, used as reference. Correlation study was done. MATERIALS AND METHODS: Two hundred and sixty three serums (263) were tested among which 64 resulting of healthy subjects and 199 resulting of patients affected) by medullary thyroid carcinoma. Statistical analysis of results was made by a study of correlation with the software OriginLab version 7.0. The manual technique used as reference method is radioimmunological (Elsa hCT, international Cisbio, Gif on Yvette, France). It was compared with a chimioluminescent technique (Nichols Advantage, Nichols Institute Diagnostics, CA, the USA). RESULTS: The coefficients of correlation obtained between both tests were: r = 0.76 (exactness study), r = 0.91 (after stimulation), r = 0.95 and 0.79 (staged samples), r = 0.99 (M TC patients). CONCLUSIONS: Both techniques correlate strictly and significantly. The correlation coefficients we obtained show us that Nichols Advantage Calcitonin is completely reliable and sensitive for the measurement of the hCT in the follow-up of the CMT.

Challenges of cold chain quality for routine EPI in south-west Burkina-Faso: An assessment using automated temperature recording devices.

BACKGROUND: Abnormal temperatures are a major issue for vaccines within the Expanded Program of Immunization in tropical climates. Prolonged exposure to temperatures outside the standard +2 °C/+8 °C range can impact vaccine potency. METHODS: The current study used automatic temperature recording devices (Testostore 171-1©) to monitor cold chain in remote areas of Western Burkina Faso. A series of 25 randomly selected health centers representing 33% of the existing 176 EPI facilities in Western Burkina Faso were prospectively assessed for eight months in 2015. Automatic measurements were compared to routine temperature loggers and vaccine vial monitors (VVM). RESULTS: The median age for all refrigerators was 9 years with 10/25 (42%) older than 10 years. Adverse temperatures were recorded in 20/24 (83%) refrigerators and ranged from -18.5 °C to +34.2 °C with 12,958/128,905 (10%) abnormal hourly records below +2 °C and 7357/128,905 (5.7%) above +8 °C. Time of day significantly affected the rate of temperature excursions, with higher rates from 00 am to 06 am (p < 0.001) for low temperatures and 10-12 am (p < 0.001) and 13-16 pm (p < 0.001) for high temperatures. Abnormal temperatures lasted from 1 h to 24 h below +2 °C and 13-24 h above +8 °C. Standard manual registers reported only 182/2761 (7%) inadequate temperatures and VVM color change detected only 133/2465 (5%) disruptions. Reliability of the refrigerators ranged from 48% to 98.7% with a median of 70%. Risk factors for excursions were old age of the refrigerators, the months of April and May, hours of high activity during the day, and health staff-associated factors such as inappropriate actions or insufficient knowledge. CONCLUSION: Important cold chain reliability issues reported in the current study in Western Burkina Faso raise concern about vaccine potency. In the absence of systematic renewal of the cold chain infrastructure or improved staff training and monitoring, antibody response assessment is recommended to study levels of effective immunization coverage.