Georges Weryha

Bone metastases from differentiated thyroid carcinoma

The presence of distant metastases from differentiated thyroid carcinoma decreases the 10-year survival of patients by 50%. Bone metastases represent a frequent complication especially of follicular thyroid cancer and severely reduce the quality of life causing pain, fractures, and spinal cord compression. Diagnosis is established by correlating clinical suspicion with imaging. Imaging is essential to detect, localize, and assess the extension of the lesions and should be used in conjunction with clinical evidence. Bone metastases are typically associated with elevated markers of bone turnover, but these markers have not been evaluated in differentiated thyroid cancer. Skeletal and whole-body magnetic resonance imaging and fusion 2-deoxy-2-[18F]fluoro-D-glucose whole-body positron emission tomography/computed tomography (PET/CT) are the best anatomic and functional imaging techniques available in specialized centers. For well-differentiated lesions, iodine-PET scan combined (124)I-PET/CT is the newest imaging development and (131)I is the first line of treatment. Bisphosphonates reduce the complications rate and pain, alone or in combination with radioiodine, radionuclides, or external beam radiotherapy and should be employed. Surgery and novel minimally invasive consolidation techniques demand an appropriate patient selection for best results on a multimodal approach. Basic research on interactions between tumor cells and bone microenvironment are identifying potential novel targets for future more effective therapeutic interventions for less differentiated tumors.

Effects of denosumab on bone turnover markers in postmenopausal osteoporosis.

Denosumab, a fully human monoclonal antibody to RANKL, decreases bone remodeling, increases bone density, and reduces fracture risk. This study evaluates the time course and determinants of bone turnover marker (BTM) response during denosumab treatment, the percentage of denosumab‐treated women with BTMs below the premenopausal reference interval, and the correlations between changes in BTMs and bone mineral density (BMD). The BTM substudy of the Fracture REduction Evaulation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Trial included 160 women randomized to subcutaneous denosumab (60 mg) or placebo injections every 6 months for 3 years. Biochemical markers of bone resorption (serum C‐telopeptide of type I collagen [CTX] and tartrate‐resistant acid phosphatise [TRACP‐5b]) and bone formation (serum procollagen type I N‐terminal propeptide [PINP] and bone alkaline phosphatase [BALP]) were measured at baseline and at 1, 6, 12, 24, and 36 months. Decreases in CTX were more rapid and greater than decreases in PINP and BALP. One month after injection, CTX levels in all denosumab‐treated subjects decreased to levels below the premenopausal reference interval. CTX values at the end of the dosing period were influenced by baseline CTX values and the dosing interval. The percentage of subjects with CTX below the premenopausal reference interval before each subsequent injection decreased from 79% to 51% during the study. CTX and PINP remained below the premenopausal reference interval at all time points in 46% and 31% denosumab‐treated subjects, respectively. With denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase (r = −0.24 to −0.44). The BTM response pattern with denosumab is unique and should be appreciated by physicians to monitor this treatment effectively.

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

CONTEXT Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age ≤30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population. OBJECTIVE We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age ≤30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. DESIGN The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. PATIENTS AND SETTINGS One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study. RESULTS Twenty-one out of 174 (12%) patients had AIP (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (n=3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. CONCLUSION Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

Effect on osteoarthritis of spa therapy at Bourbonne-les-Bains

OBJECTIVES Several studies suggest a beneficial overall effect of spa therapy in chronic musculoskeletal diseases. The present open controlled study investigated the effects of spa therapy at Bourbonne-Les-Bains, France, in patients with hip or knee osteoarthritis or low back pain. PATIENTS AND METHODS In 1998, 102 men and women older than 50 years were included in the study. All had low back pain or lower limb osteoarthritis, and none had contraindications to spa therapy. Quality of life was assessed three times at intervals of 4 weeks, twice before and once immediately after 3 weeks of spa therapy, using the Duke Health Profile (five dimensions and five dysfunctions). RESULTS Mean age was 66.4 years, and 67% of the patients were women. Quality of life was markedly decreased as compared to the population at large (1996, CFES). The two pretreatment evaluations produced similar quality-of-life scores. Spa therapy was associated with significant improvements in overall quality of life (P=0.004), self-esteem (P=0.009), and pain (P=0.01). CONCLUSION These findings support those of other studies conducted in France and in other European countries. They indicate that patients report meaningful improvements in their quality of life after spa therapy.

Long term prognosis of patients with pediatric pheochromocytoma

A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention

Importance Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. Objective To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. Design, Setting, and Patients This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. Main Outcomes and Measures Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. Results Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). Conclusions and Relevance The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Trabecular Bone Score: Where are we now?

The Trabecular Bone Score is a rather new index obtained at the lumbar spine at the same time as a real bone mineral density. It was developed to reflect bone microarchitecture. It was proposed to be easily used in everyday practice as a surrogate of bone strength. Our aim was to review 1. technical points such as correlations between Trabecular Bone Score and bone microarchitectural parameters, Trabecular Bone Score and bone strength, the effects of dual-energy X-ray absorptiometry image spatial resolution, age, macroarchitecture, body mass index, and osteoarthritis, on Trabecular Bone Score, and 2. evidences to use Trabecular Bone Score for separating individuals with fragility fractures from controls, predicting fragility fractures, and for longitudinally monitoring changes related to treatments. Correlations between Trabecular Bone Score and bone microarchitectural parameters vary widely across bone sites, microarchitectural parameters, and study designs. In vivo, the Trabecular Bone Score explains little of the variance in trabecular microarchitectural parameters. We emphasize that it is a texture parameter. The Trabecular Bone Score is reduced in patients with fragility fracture. Several retrospective and prospective studies have shown its discriminative ability regarding the fracture risk. When combining the areal Bone mineral Density and Trabecular Bone Score, the Trabecular Bone Score remains a predictor of fracture but not the areal Bone Mineral Density. However in prospective studies, the best predictor of fracture remains hip areal bone mineral density. Due to the lack of evidence, we recommend not to use Trabecular Bone Score for following patients treated by anti-osteoporotic drugs.

Prise en charge de l’hyperparathyroïdie primaire asymptomatique: Consensus d’experts de la SFE

Son incidence en forte augmentation, est un phenomene recent lie au developpement depuis les annees 70 des dosages biochimiques automatises multiples. Les donnees chiffrees epidemiologiques qui ont tout d’abord « explose » auraient tendance actuellement a se stabiliser. L’etude epidemiologique realisee a Rochester nous donne les chiffres suivants : incidence annuelle de l’hyperparathyroidie primaire 14,6/100000 entre 1965 et 1974, augmentant a 67/100000 entre 1974 et 1982 pour se stabiliser a 20,8/100000 entre 1983 et 1992. C’est ce dernier chiffre qui est habituellement retenu pour estimer l’incidence annuelle de cette pathologie, sachant qu’il n’y a pas d’etude francaise et que ce chiffre est a Rochester plutot revu a la baisse actuellement (derniere evaluation seulement 4/100000). A cote de cette incidence globale dans la population generale, il faut souligner la rarete de cette affection chez l’enfant et l’adulte jeune et sa large predominance chez les femmes surtout apres 50 ans.

Tissue factor pathway inhibitor: a new link among arterial stiffness, pulse pressure, and coagulation in postmenopausal women.

Objective—To investigate in women older than 60 whether aortic stiffness or pulse pressure (PP) is associated with selected procoagulant or anticoagulant factors and to examine whether pulsatile stretch influences these factors in human vascular smooth muscle cells (VSMCs) in vitro. Methods and Results—Aortic pulse wave velocity (PWV) and carotid PP were studied in 123 apparently healthy postmenopausal women. PWV, PP, von Willebrand factor, and free tissue factor pathway inhibitor (TFPI), but not mean arterial pressure, increased with age. Free TFPI and PWV were positively correlated, even after adjustment for age and PP and other confounding parameters. In vitro, 5% or 10% pulsatile stretch (at 1 Hz) enhanced TFPI synthesis and secretion by VSMCs in a time-independent manner (1 to 48 hours) without changes in protein level of smooth muscle myosin heavy chain. Application of 5% static stretch had no effect. Conclusion—In postmenopausal women, free TFPI increases as vascular wall function deteriorates and PP increases. These findings are supported by the increase in TFPI synthesized by VSMCs in response to cyclic stress in vitro. They suggest that VSMCs require pulsatility to interfere with the coagulation process and highlight the relevance of plasma free TFPI levels to cardiovascular diseases.

Usefulness of bone density measurement in fallers.

The objective of this systematic literature review is to discuss the latest French recommendation issued in 2012 that a fall within the past year should lead to bone mineral density (BMD) measurement using dual-energy X-ray absorptiometry (DXA). This recommendation rests on four facts. First, osteoporosis and fall risk are the two leading risk factors for nonvertebral fractures in postmenopausal women. Second, BMD measurement using DXA supplies significant information on the fracture risk independently from the fall risk. Thus, when a fall occurs, the fracture risk increases as BMD decreases. Third, osteoporosis drugs have been proven effective in preventing fractures only in populations with osteoporosis defined based on BMD criteria. Finally, the prevalence of osteoporosis is high in patients who fall and increases in the presence of markers for frailty (e.g., recurrent falls, sarcopenia [low muscle mass and strength], limited mobility, and weight loss), which are risk factors for both osteoporosis and falls. Nevertheless, life expectancy should be taken into account when assessing the appropriateness of DXA in fallers, as osteoporosis treatments require at least 12months to decrease the fracture risk. Another relevant factor is the availability of DXA, which may be limited due to geographic factors, patient dependency, or severe cognitive impairments, for instance. Studies are needed to better determine how the fall risk and frailty should be incorporated into the fracture risk evaluation based on BMD and the FRAX® tool.