Variation in treatment strategies of Swiss general practitioners for subclinical hypothyroidism in older adults.

QUESTIONS UNDER STUDY: As the best management of subclinical hypothyroidism is controversial, we aimed to assess variations in treatment strategies depending on different Swiss regions, physician and patient characteristics. METHODS: We performed a case-based survey among general practitioners (GPs) in different Swiss regions, which consisted of eight hypothetical cases presenting a female patient with subclinical hypothyroidism and nonspecific complaints differing by age, vitality status and thyroid-stimulating hormone (TSH) concentration. RESULTS: A total of 262 GPs participated in the survey. There was considerable variation in the levothyroxine starting dose chosen by GPs, ranging from 25 µg to 100 µg. Across the Swiss regions, GPs in the Bern region were significantly more inclined to treat, with a higher probability of initiating treatment (60%, p = 0.01) and higher mean starting doses (45 µg, p <0.01) compared with the French-speaking region (44%, 36 µg); the Zurich region had intermediate values (52%, 39 µg). We found no association between treatment rate and other physician characteristics. GPs were more reluctant to initiate treatment in 85-year-old than in 70-year-old women (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.63-0.94), and more likely to treat women with a TSH of 15 mU/l than those with a TSH of 6mU/l (OR 8.71, 95% CI 6.21-12.20). CONCLUSIONS: There are strong variations in treatment strategies for elderly patients with subclinical hypothyroidism across different Swiss regions, including use of higher starting doses than the recommended 25 µg in the Swiss guidelines, which recommend a starting dose of 25 µg. These variations likely reflect the current uncertainty about the benefits of treatment, which arise from the current lack of evidence from adequately powered clinical trials.

FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies.

The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca(2) (+) pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.

Ultrasound-guided fine-needle aspiration of thyroid nodules: assessment of the ideal number of punctures

OBJECTIVE: To determine the number of punctures in fine-needle aspiration biopsies required for a safe cytological analysis of thyroid nodules. MATERIALS AND METHODS: Cross-sectional study with focus on diagnosis. The study population included 94 patients. RESULTS: The mean age of the patients participating in the study was 52 years (standard-deviation = 13.7) and 90.4% of them were women. Considering each puncture as an independent event, the first puncture has showed conclusive results in 78.7% of cases, the second, in 81.6%, and the third, in 71.8% of cases. With a view to the increasing chance of a conclusive diagnosis at each new puncture, two punctures have showed conclusive results in 89.5% of cases, and three punctures, in 90.6% of cases with at least one conclusive result. CONCLUSION: Two punctures in fine-needle aspiration biopsies of thyroid nodules have lead to diagnosis in 89.5% of cases in the study sample, suggesting that there is no need for multiple punctures to safely obtain the diagnosis of thyroid nodules.

Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thyroid Cytopathology.

BACKGROUND: Recent discussions have focused on redefining noninvasive follicular variant of papillary thyroid carcinoma (NI-FVPTC) as a neoplasm rather than a carcinoma. This study assesses the potential impact of such a reclassification on the implied risk of malignancy (ROM) for the diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). METHODS: The study consisted of consecutive fine-needle aspiration biopsy (FNAB) cases collected between January 1, 2013 and June 30, 2014 from 5 academic institutions. Demographic information, cytology diagnoses, and surgical pathology follow-up were recorded. The ROM was calculated with and without NI-FVPTC and was presented as a range: all cases (ie, overall risk of malignancy [OROM]) versus those with surgical follow-up only. RESULTS: The FNAB cohort consisted of 6943 thyroid nodules representing 5179 women and 1409 men with an average age of 54 years (range, 9-94 years). The combined average ROM and OROM for the diagnostic categories of TBSRTC were as follows: nondiagnostic, 4.4% to 25.3%; benign, 0.9% to 9.3%; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 12.1% to 31.2%; follicular neoplasm (FN), 21.8% to 33.2%; suspicious for malignancy (SM), 62.1% to 82.6%; and malignant, 75.9% to 99.1%. The impact of reclassifying NI-FVPTC on the ROM and OROM was most pronounced and statistically significant in the 3 indeterminate categories: the AUS/FLUS category had a decrease of 5.2% to 13.6%, the FN category had a decrease of 9.9% to 15.1%, and the SM category had a decrease of 17.6% to 23.4% (P < .05), whereas the benign and malignant categories had decreases of 0.3% to 3.5% and 2.5% to 3.3%, respectfully. The trend of the effect on the ROM and OROM was similar for all 5 institutions. CONCLUSIONS: The results from this multi-institutional cohort indicate that the reclassification of NI-FVPTC will have a significant impact on the ROM for the 3 indeterminate categories of TBSRTC. Cancer Cytopathol 2016;124:181-187. © 2015 American Cancer Society.

A Preclinical Model for ERα-Positive Breast Cancer Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response.

Seventy-five percent of breast cancers are estrogen receptor α positive (ER(+)). Research on these tumors is hampered by lack of adequate in vivo models; cell line xenografts require non-physiological hormone supplements, and patient-derived xenografts (PDXs) are hard to establish. We show that the traditional grafting of ER(+) tumor cells into mammary fat pads induces TGFβ/SLUG signaling and basal differentiation when they require low SLUG levels to grow in vivo. Grafting into the milk ducts suppresses SLUG; ER(+) tumor cells develop, like their clinical counterparts, in the presence of physiological hormone levels. Intraductal ER(+) PDXs are retransplantable, predictive, and appear genomically stable. The model provides opportunities for translational research and the study of physiologically relevant hormone action in breast carcinogenesis.

Is there any association between Hashimoto’s thyroiditis and thyroid cancer? A retrospective data analysis

AbstractObjective:To evaluate the association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC).Materials and Methods:The patients were evaluated by ultrasonography-guided fine needle aspiration cytology. Typical cytopathological aspects and/or classical histopathological findings were taken into consideration in the diagnosis of HT, and only histopathological results were considered in the diagnosis of PTC.Results:Among 1,049 patients with multi- or uninodular goiter (903 women and 146 men), 173 (16.5%) had cytopathological features of thyroiditis. Thirty-three (67.4%) out of the 49 operated patients had PTC, 9 (27.3%) of them with histopathological features of HT. Five (31.3%) out of the 16 patients with non-malignant disease also had HT. In the groups with HT, PTC, and PCT+HT, the female prevalence rate was 100%, 91.6%, and 77.8%, respectively. Mean age was 41.5, 43.3, and 48.5 years, respectively. No association was observed between the two diseases in the present study where HT occurred in 31.1% of the benign cases and in 27.3% of malignant cases (p = 0.8).Conclusion:In spite of the absence of association between HT and PCT, the possibility of malignancy in HT should always be considered because of the coexistence of the two diseases already reported in the literature.

Added value of SPECT/CT in addition to whole-body scintigraphy augmented with prone lateral views in patients with well-differentiated thyroid carcinoma

Purpose: We aimed to determine the impact of SPECT/CT performed in addition to whole-­‐body scintigraphy augmented with prone lateral views in patients with well-­‐differentiated thyroid carcinoma. Methods and Materials: This retrospective study included 141 patients (87 female, 54 male, mean age 47 years) with well-­‐differentiated thyroid carcinoma (105 papillary, 31 follicular, 1 Hürthle cell and 4 poorly differentiated) treated with radioiodine therapy (1000-7400 MBq). Patients were referred for either first postsurgical therapy (n=76) or further treatment (n=65). Two nuclear medicine physicians interpreted the scans in consensus (first whole-­‐body scintigraphy with prone lateral view, then SPECT/CT) reporting abnormal iodine uptake in the thyroid bed, lymph nodes and distant metastasis. The corresponding ATA risk score was calculated for each patient before and after SPECT/CT, as well as change in disease extension Results: The analysis showed a difference between scintigraphy and SPECT/CT in n=17 lesions in 14 patients (9.9%): 12 were described as suspicious on scintigraphy and could be considered as benign on SPECT/CT (3 corresponded to local iodine uptake, 6 to lymph nodes metastases and 3 to distant metastases). The others 5 corresponded to metastases (4 lymph nodes and 1 distant) that were not seen on whole-­‐body scintigraphy augmented with prone lateral views. In 10 of 141 (7.1%) patients, we observed a change in ATA risk stratification, with a risk increase in 4 of them (2.8%). Conclusion: SPECT/CT allowed detecting 5 focal lesions missed on planar scintigraphy, and to precise benignity of 12 suspicious lesions on planar scintigraphy. Moreover, SPECT/CT improved the risk stratification in 10 patients with a significant change in the patient management

Sleep and Menopause. Hormone Therapy and Sleep Deprivation

This study evaluated the effect of menopause, hormone therapy (HT) and aging on sleep. Further, the mechanisms behind these effects were examined by studying the associations between sleep and the nocturnal profiles of sleep-related hormones. Crosssectional study protocols were used to evaluate sleep in normal conditions and during recovery from sleep deprivation. The effect of initiation of HT on sleep and sleeprelated hormones was studied in a prospective controlled trial. Young, premenopausal and postmenopausal women were studied, and the methods included polysomnography, 24-h blood sampling, questionnaires and cognitive tests of attention. Postmenopausal women were less satisfied with their sleep quality than premenopausal women, but this was not reflected in sleepiness or attention. The objective sleep quality was mainly similar in pre- and postmenopausal women, but differed from young women. The recovery mechanisms from sleep deprivation were relatively well-preserved after menopause. HT offered no advantage to sleep after sleep deprivation or under normal conditions. The decreased growth hormone (GH) and prolactin (PRL) levels after menopause were reversible with HT. Neither menopause nor HT had any effect on cortisol levels. In premenopausal women, HT had only minor effects on PRL and cortisol levels. The temporal link between GH and slow wave sleep (SWS) was weaker after menopause. PRL levels were temporally associated with sleep stages, and higher levels were seen during SWS and lower during rapid-eye-movement (REM) sleep. Sleep quality after menopause is better determined by age than by menopausal state. Although HT restores the decreased levels of GH and PRL after menopause, it offers no advantage to sleep quality under normal conditions or after sleep deprivation.

Highly functional binding surface for miniaturised solid-phase immunoassays. - A spot story -

Several bioaffinity assays are based on the detection of an analyte which is bound on a solid substrate via biochemical interaction. These so called solid phase assays are based on the adhesion of the primary binding partner on a solid surface, which then binds the analyte to be detected. In this thesis work a novel solid phase based assay technology, known as spot technology, was developed. The spot technology is based on combination of high-capacity solid phases, concentrated in a spot format, utilising modified streptavidin molecules and recombinant antibody fragments. The reduction of the solid phase binding surface to a size of a spot enabled denser binding of the target molecules, providing improved signal intensities and signal-to-background ratio when applied in different solid phase immunoassays. Streptavidin-biotin interactions are commonly utilised in numerous different bioaffinity assays and the ultimate nature of streptavidin to bind biotin is among the strongest non-covalent interaction reported between two biomolecules. In this study native core streptavidin was chemically modified to provide polymerised streptavidin molecules with altered adsorption properties. These streptavidin conjugates, when coated onto polystyrene surface, provided enhanced biotin binding capacity and surface stability when compared to a reference coating constructed with native streptavidin. Furthermore, the combination of chemically modified streptavidin, sitespecifically biotinylated antibody fragments and the spot coating technology provided highly dense solid phase coating with improved binding properties. The performance of the spot assay technology was further demonstrated in different immunoassay configurations. Human thyroid stimulating hormone (TSH) and human cardiac troponin I (cTnI) were used as model analytes to show the applicability of the highly sensitive spot-based solid-phase immunoassay for detection of very low levels of analytes. It was demonstrated that the spot technology provided an assay concept with enhanced sensitivity and short turn-around times, characteristics that are highly suitable for point-of-care applications.

Targeted ablation of gonadotropin dependent endocrine tumors in transgenic mice through their luteinizing hormone receptor (LHR)

Gonadal somatic cell and adrenocortical endocrine tumors are rare. The incidence of adrenocortical carcinomas is only 1-2/1000000 a year. However, they are aggressive, especially in adulthood and currently surgery is the only curative treatment. Cytotoxic agents are in use in advanced cancers, but side effects and multidrug resistance are often problems. Thus there is a need for novel curative treatment methods. In contrast, ovarian granulosa cell tumors and testicular Leydig cell tumors are usually benign, especially at a younger age. The aim of the present thesis was to study a novel targeted treatment method through luteinizing hormone/chorionic gonadotropin receptor (LHCGR) in a transgenic mouse tumor model. The cytotoxic agent was lytic peptide Hecate-CGbeta conjugate where 23 amino acid Hecate, a synthetic form of honeybee venom melittin, was conjugated to 15 amino acid fragment of human chorionic gonadotropin β subunit. Lytic peptides are known to act only on negatively charged cells, such as bacteria and cancer cells and hereby, due to hCGbeta fragment, the conjugate is able to bind directly to LHCGR bearing cancer cells, saving the healthy ones. The experiments were carried out in inhibin-alpha-Simian Virus 40-T-antigen transgenic mice that are known to express LHCGR-bearing gonadal tumors, namely Leydig and granulosa cell tumors by 100% penetrance. If the mice are gonadectomized prepubertally they form adrenocortical tumors instead. Transgenic and wild type mice were treated for three consecutive weeks with control vehicle, Hecate or Hecate-CGbeta conjugate. GnRH antagonist or estradiol was given to a group of mice with or without Hecate-CGbeta conjugate to analyze the additive role of gonadotropin blockage in adrenocortical tumor treatment efficacy. Hecate-CGbeta conjugate was able to diminish the gonadal and adrenal tumor size effectively in males. No treatment related side effects were found. Gonadotropin blockage through GnRH antagonist was the best treatment in female adrenal tumors. The mode of cell death by Hecate-CGbeta conjugate was proven to be through necrosis. LHCGR and GATA-4 were co-expressed in tumors, where the treatment down-regulated their expression simultaneously, suggesting their possible use as tumor markers. In conclusion, the present thesis showed that Hecate-CGbeta conjugate targets its action selectively through LHCGR and selectively kills the LHCGR bearing tumor cells. It works both in gonadal somatic and in ectopic LHCGR bearing adrenal tumors. These results establish a more general principle that receptors expressed ectopically in malignant cells can be exploited in targeted cytotoxic therapies without affecting the normal healthy cells.

Comparação da sobrevivência e dos fatores prognósticos em pacientes com adenocarcinoma gástrico T2 e T3

OBJETIVO: Comparar a sobrevivência e os fatores prognósticos, após o tratamento cirúrgico de pacientes com adenocarcinoma gástrico que compromete a camada muscular própria (T2), e de pacientes cujo tumor invade a subserosa (T3). MÉTODOS: Estudo retrospectivo de 122 pacientes com câncer gástrico invadindo a muscular própria e subserosa, submetidos ao tratamento cirúrgico no período de janeiro de 1997 a dezembro de 2008 e acompanhados até dezembro de 2010. Foram analisadas variáveis demográficas, cirúrgicas e anatomopatológicas. RESULTADOS: Dos 122 pacientes, 22 (18%) foram excluídos da análise final porque apresentaram: margem positiva, mortalidade pós-operatória, segundo tumor primário e menos de 15 linfonodos na peça cirúrgica. Entre os 100 pacientes incluídos, 75 apresentavam tumores com invasão da muscular própria (T2) e 25 com invasão da subserosa (T3). A sobrevivência global foi 83,8%, sendo 90,6% no T2 e 52,1% no T3. Na análise univariada apresentaram significância: metástase linfonodal (p=0,02), tamanho do tumor (p=0,000), estadiamento patológico do tumor (p=0,000), estadiamento patológico linfonodal (p=0,000) e estadiamento por grupos da classificação TNM-UICC/AJCC, 2010 (p=0,000) Na análise multivariada, os fatores prognósticos independentes foram o tamanho do tumor e o estadiamento patológico linfonodal (pN). CONCLUSÃO: O comprometimento linfonodal e o tamanho do tumor são fatores prognósticos independentes nos tumores com invasão da muscular própria e nos tumores com invasão da subserosa. O T2 apresenta menor tamanho, menor taxa de linfonodos metastáticos e consequentemente, melhor prognóstico que o T3.

Evolution in the profile of thyroid cancer cases treated in an oncology reference service: what changed in the last 20 years

Objective: To evaluate the characteristics of thyroid carcinoma cases treated at a reference hospital for cancer between 2008 and 2010.Methods: we studied 807 cases and analyzed the following clinicopathologic variables: symptoms, risk factors, diagnostic tests, staging, histological type, treatment performed and complications.Results: Females were more affected, with 660 cases (82%). The average age at diagnosis was 44.5 years. Prior exposure to ionizing radiation was reported by 22 (3%) patients, a family history of thyroid cancer by 89 (11%), and 289 (36%) individuals reported other types of cancer in the family. The fine needle aspiration biopsy was the main parameter for surgical indication and was suggestive of carcinoma in 463 patients (57%). Papillary carcinoma was the most common histological type, with 780 cases (96.6%). There were 728 (90%) total thyroidectomies, 43 (5.3%) reoperations or partial thyroidectomies followed by totalization, 23 (2.8%) extended thyroidectomies and only 13 (1.6%) partial thyroidectomies (lobectomy with isthmectomy). Neck dissection associated with thyroidectomy was done in 158 patients (19.5%). We observed a predominance of tumors classified as T1 in 602 (74.6%) patients. Transient hypocalcemia was the most frequent complication.Conclusion: The results show that the worldwide increase in the incidence of thyroid cancer has changed the profile of patients seen at a referral service. In addition, there were changes in the type of surgical treatment used, with increased use of total thyroidectomy in relation to partial and subtotal ones, and decreased use of elective neck dissections.

Importance of bone assessment and prevention of osteoporotic fracture in patients with prostate cancer in the gonadotropic hormone analogues use

The antiandrogenic therapy (ADT) for prostate cancer represents an additional risk factor for the development of osteoporosis and fragility fractures. Still, bone health of patients on ADT is often not evaluated. After literature research we found that simple preventive measures can prevent bone loss in these patients, resulting in more cost-effective solutions to the public health system and family when compared to the treatment of fractures.