Subclinical thyroid dysfunction and fracture risk: a meta-analysis.

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Fertility-preservation counselling and treatment for medical reasons: data from a multinational network of over 5000 women.

Fertility-preservation techniques for medical reasons are increasingly offered in national networks. Knowledge of the characteristics of counselled patients and techniques used are essential. The FertiPROTEKT network registry was analysed between 2007 and 2013, and included up to 85 university and non-university centres in Germany, Austria and Switzerland; 5159 women were counselled and 4060 women underwent fertility preservation. In 2013, fertility-preservation counselling for medical reasons increased significantly among nullipara and women aged between 21 and 35 years (n = 1043; P < 0.001). Frequency of GnRH applications slowly decreased, whereas tissue, oocytes and zygote cryopreservation increased. In 2013, women with breast cancer mainly opted for tissue freezing, whereas women with lymphoma opted for GnRH agonist. Women younger than 20 years predominantly opted for GnRH agonists and ovarian tissue cryopreservation; women aged between 20 and 40 years underwent a variety of techniques; and women over 40 years opted for GnRH agonists. The average number of aspirated oocytes per stimulation cycle decreased as age increased (< 30 years: 12.9; 31-35 years: 12.3; 36-46: 9.0; > 41 years: 5.7). For ovarian tissue cryopreservation, removal and cryopreservation of fewer than one ovary was preferred and carried out in 97% of cases in 2013.

Impact of Diabetic Status on Outcomes After Revascularization With Drug-Eluting Stents in Relation to Coronary Artery Disease Complexity: Patient-Level Pooled Analysis of 6081 Patients.

BACKGROUND Diabetes mellitus and angiographic coronary artery disease complexity are intertwined and unfavorably affect prognosis after percutaneous coronary interventions, but their relative impact on long-term outcomes after percutaneous coronary intervention with drug-eluting stents remains controversial. This study determined drug-eluting stents outcomes in relation to diabetic status and coronary artery disease complexity as assessed by the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score. METHODS AND RESULTS In a patient-level pooled analysis from 4 all-comers trials, 6081 patients were stratified according to diabetic status and according to the median SYNTAX score ≤11 or >11. The primary end point was major adverse cardiac events, a composite of cardiac death, myocardial infarction, and clinically indicated target lesion revascularization within 2 years. Diabetes mellitus was present in 1310 patients (22%), and new-generation drug-eluting stents were used in 4554 patients (75%). Major adverse cardiac events occurred in 173 diabetics (14.5%) and 436 nondiabetic patients (9.9%; P<0.001). In adjusted Cox regression analyses, SYNTAX score and diabetes mellitus were both associated with the primary end point (P<0.001 and P=0.028, respectively; P for interaction, 0.07). In multivariable analyses, diabetic versus nondiabetic patients had higher risks of major adverse cardiac events (hazard ratio, 1.25; 95% confidence interval, 1.03-1.53; P=0.026) and target lesion revascularization (hazard ratio, 1.54; 95% confidence interval, 1.18-2.01; P=0.002) but similar risks of cardiac death (hazard ratio, 1.41; 95% confidence interval, 0.96-2.07; P=0.08) and myocardial infarction (hazard ratio, 0.89; 95% confidence interval, 0.64-1.22; P=0.45), without significant interaction with SYNTAX score ≤11 or >11 for any of the end points. CONCLUSIONS In this population treated with predominantly new-generation drug-eluting stents, diabetic patients were at increased risk for repeat target-lesion revascularization consistently across the spectrum of disease complexity. The SYNTAX score was an independent predictor of 2-year outcomes but did not modify the respective effect of diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00297661, NCT00389220, NCT00617084, and NCT01443104.