Local delivery of tacrolimus using electrospun poly-ϵ-caprolactone nanofibres suppresses the T-cell response to peripheral nerve allografts.

Objective.Repair of nerve gap injuries can be achieved through nerve autografting, but this approach is restricted by limited tissue supply and donor site morbidity. The use of living nerve allografts would provide an abundant tissue source, improving outcomes following peripheral nerve injury. Currently this approach is not used due to the requirement for systemic immunosuppression, to prevent donor-derived cells within the transplanted nerve causing an immune response, which is associated with severe adverse effects. The aim of this study was to develop a method for delivering immunosuppression locally, then to test its effectiveness in reducing the immune response to transplanted tissue in a rat model of nerve allograft repair.Approach.A coaxial electrospinning approach was used to produce poly-ϵ-caprolactone fibre sheets loaded with the immunosuppressant tacrolimus. The material was characterised in terms of structure and tacrolimus release, then testedin vivothrough implantation in a rat sciatic nerve allograft model with immunologically mismatched host and donor tissue.Main results.Following successful drug encapsulation, the fibre sheets showed nanofibrous structure and controlled release of tacrolimus over several weeks. Materials containing tacrolimus (and blank material controls) were implanted around the nerve graft at the time of allograft or autograft repair. The fibre sheets were well tolerated by the animals and tacrolimus release resulted in a significant reduction in lymphocyte infiltration at 3 weeks post-transplantation.Significance.These findings demonstrate proof of concept for a novel nanofibrous biomaterial-based targeted drug delivery strategy for immunosuppression in peripheral nerve allografting.

Myosteatosis evaluation using erector spinae and psoas muscles to predict adverse events during adjuvant chemotherapy for breast cancer.

BACKGROUND: Myosteatosis (intramuscular adiposity) is predictive of chemotherapy toxicity in women undergoing adjuvant chemotherapy for breast cancer (BC). We evaluated a novel, user-friendly and cost-effective technique utilizing a Picture Archiving and Communication Systems (PACS) tool that is readily available in the electronic medical record (EMR), using skeletal muscle density (SMD) to detect myosteatosis and then compared PACS results with those derived from widely used body composition software (SliceOMatic, QC, Canada). METHODS: Using retrospective data from a sample of women with early BC (Stage I-III) who had CT scan and received chemotherapy. Pearson correlation coefficients were used to compare SliceOMatic with PACS results. Associations of PACS results with chemotherapy-related adverse events were evaluated using multivariable (MV) log-binomial models adjusted for age, race, BMI, anthracycline-based therapy, and number of comorbidities. RESULTS: In 338 patients, mean age was 51, 32% were non-white, and 40% had obesity (BMI ≥ 30 kg/m2). Correlation of SMD using SliceOMatic whole muscle measurements with PACS psoas muscle was 0.76 (p < .0001) and with PACS erector spinae muscle 0.91 (p < .0001). Using PACS psoas muscle, myosteatosis was associated with any adverse event [RR 1.66, CI 1.22-2.26 (p < .0001)], dose reduction [RR 1.63, CI 1.01-2.65 (p = .05)], and early treatment discontinuation [RR 2.14, CI 1.10-4.14 (p = 0.03)]. Using PACS erector spinae muscle, myosteatosis was associated any adverse event [RR 1.59, CI 1.11-2.27 (p = 0.01)] and dose reduction [RR 1.91, CI 1.07-3.42 (p = .03)]. CONCLUSION AND RELEVANCE: Skeletal muscle density measures using PACS correlated strongly with SliceOMatic results and both are similarly predictive of chemotherapy-related adverse events.

Controlled local release of PPARγ agonists from biomaterials to treat peripheral nerve injury.

OBJECTIVE: Poor clinical outcomes following peripheral nerve injury (PNI) are partly attributable to the limited rate of neuronal regeneration. Despite numerous potential drug candidates demonstrating positive effects on nerve regeneration rate in preclinical models, no drugs are routinely used to improve restoration of function in clinical practice. A key challenge associated with clinical adoption of drug treatments in nerve injured patients is the requirement for sustained administration of doses associated with undesirable systemic sideeffects. Local controlled-release drug delivery systems could potentially address this challenge, particularly through the use of biomaterials that can be implanted at the repair site during the microsurgical repair procedure. APPROACH: In order to test this concept, this study used various biomaterials to deliver ibuprofen sodium or sulindac sulfide locally in a controlled manner in a rat sciatic nerve injury model. Following characterisation of release parameters in vitro, ethylene vinyl acetate tubes or polylactic-co-glycolic acid wraps, loaded with ibuprofen sodium or sulindac sulfide, were placed around directly-repaired nerve transection or nerve crush injuries in rats. MAIN RESULTS: Ibuprofen sodium, but not sulindac sulfide caused an increase in neurites in distal nerve segments and improvements in functional recovery in comparison to controls with no drug treatment. SIGNIFICANCE: This study showed for the first time that local delivery of ibuprofen sodium using biomaterials improves neurite growth and functional recovery following PNI and provides the basis for future development of drug-loaded biomaterials suitable for clinical translation.

The association of body composition parameters and adverse events in women receiving chemotherapy for early breast cancer.

BACKGROUND: Body composition metrics as predictors of adverse events are a growing area of interest in oncology research. One barrier to the use of these metrics in clinical practice is the lack of standardized cut points for identifying patients with at-risk body composition profiles. We examined the association of chemotherapy adverse events with several body composition measures, using alternative cut points from published studies. METHODS: This is a retrospective study of women diagnosed with early breast cancer (EBC). Axial computerized tomography (CT) images from lumbar L3 segments were analyzed for the following body composition measures: myosteatosis (low Skeletal Muscle Density/SMD), sarcopenia (low Skeletal Muscle Index/SMI), and high Visceral Adipose Tissue (VAT). Adverse events during chemotherapy were dose reduction, early treatment discontinuation, and hospitalization. Log-binomial modeling was used to evaluate associations between body composition measures at different cut points with adverse events, adjusting for age, race, Body Mass Index/BMI, and comorbidities. Relative risks were reported as the measure of association. RESULTS: In a sample of 338 women, mean age was 51, 14% were age 65 or older, 32% were non-white, 40% had obesity (/BMI ≥ 30 kg/m2), and mean number of comorbidities was 1.56. In multivariable analysis (MV), all three SMD cut points for myosteatosis had significant associations with total number of adverse events, as well as different cut points having significant associations with either dose reduction, early treatment discontinuation or hospitalization. SMI and VAT were not significant in the MV analysis; however, in some models, age and total comorbidities were significant for adverse events. CONCLUSIONS: Among CT-derived measures of body composition, myosteatosis determined at any of three SMD cut points was associated with total and individual adverse events during chemotherapy for early breast cancer.

Association of body composition with function in women with early breast cancer.

BACKGROUND: Advances in breast cancer research are making treatment options increasingly effective and reducing mortality. Body composition is an example of a prognostic tool that can help personalize breast cancer treatments and further increase their effectiveness. In this study, we examine the association of several body composition measures with comorbidities, physical function, and quality of life. METHODS: This study is a cross-sectional analysis of 99 women with early breast cancer scheduled for chemotherapy. Univariate regression models were used to identify significant associations of body composition metrics with patient demographics, clinical characteristics, measures of physical function, and patient-reported outcomes (PRO)s. Multivariable modeling was used to evaluate associations adjusted for age. RESULTS: Median age was 58 (range 24-83), 27% were non-white, and, 47% were obese (≥ 30 kg/m2). Increasing age was associated with lower Skeletal Muscle Density (SMD) (p = 0.0001), lower Skeletal Muscle Gauge (SMG) (p = 0.0005), and higher Visceral Adipose Tissue (VAT) (p < 0.0001). In patients with a prolonged Timed Up and Go tests (> 14 s), mean VAT was 57.87 higher (p = 0.004), SMD 5.70 lower (p = 0.04), and SMG 325.4 lower (p = 0.02). For each point of higher performance on the Short Physical Performance Battery (SPPB), VAT decreased 12.24 (p = 0.002) and SMD rose 1.22 (p = 0.02). In multivariable analysis adjusting for age, the association of TUG > 14 with higher VAT remained significant (p = 0.02). CONCLUSIONS: Suboptimal body composition prior to treatment is associated poor physical function and may be an indicator of clinical importance.

Myosteatosis and prognosis in cancer: Systematic review and meta-analysis.

BACKGROUND: The evidence that body composition parameters influence multiple cancer outcomes is rapidly expanding. Excess adiposity deposits in muscle tissue, termed myosteatosis, can be detected in CT scans through variations in the density of muscle tissues (Hounsfield Units). Patients with similar muscle mass but different amounts of intramuscular adipose infiltration have increased chemotherapy toxicity, time to tumor progression and other adverse outcomes among different cancer types. Our review examines the impact of myosteatosis on overall survival (OS) in patients with cancer. METHODS: A systematic search of the literature was conducted on PubMed/ MEDLINE, Cochrane CENTRAL, and EMBASE. Meta-analysis was conducted using a random-effects model. Risk of bias was evaluated using the Newcastle-Ottawa Quality assessment for cohort studies, funnel plot (publication bias), and GRADE summary of findings tool from Cochrane. RESULTS: A total of 4880 articles were screened from which 40 articles selected, including 21,222 patients. The overall mean proportion of patients with myosteatosis was 48 % (range 11-85 %). Using skeletal muscle density (SMD), patients classified as having myosteatosis had 75 % greater mortality risk compared to non-myosteatosis patients (HR 1.75 95 % CI 1.60-1.92, 40 studies) (p < .00001) (i2 = 62 %). Specifically, myosteatosis was prognostic for worse OS in patients with gynecological, renal, periampullary/pancreatic, hepatocellular, gastroesophageal, and colorectal carcinoma, and lymphomas. CONCLUSION: Our analysis of the literature shows that cancer patients with myosteatosis have shorter survival. Our findings suggest that in oncological practice, muscle density assessment is valuable as a prognostic parameter.

Muscle composition and outcomes in patients with breast cancer: meta-analysis and systematic review.

PURPOSE: Breast cancer is the most common cancer and leading cause of cancer death in women. Body composition parameters, especially those related to muscle, have become a growing focus of cancer research. In this review, we summarize the literature on breast cancer and muscle parameters as well as combine their outcomes for overall survival (OS), time to tumor progression (TTP), and chemotherapy toxicity in a meta-analysis. METHODS: A systematic search of the literature for randomized controlled trials and observational studies was conducted on MEDLINE, Cochrane CENTRAL, and EMBASE through May 1, 2019. Two reviewers independently searched and selected. Meta-analysis was conducted using a random-effects model. The risk of bias was evaluated using the Newcastle-Ottawa quality assessment for cohorts and GRADE summary of findings tool from Cochrane. RESULTS: A total of 754 articles were screened from which 6 articles and one abstract were selected. Using skeletal muscle index (SMI), patients classified as sarcopenic had a 68% greater mortality risk compared to non-sarcopenic patients (HR 1.68 95% CI 1.09-2.59, 5 studies) (p = .02) (i2 = 70%). Low muscle density was not predictive of OS (HR 1.44 95% CI 0.77-2.68, 2 studies) (p = .25) (i2 = 87%). Patients with sarcopenia (56%) had more grade 3-5 toxicity compared to non-sarcopenic (25%) (RR 2.17 95% CI 1.4-3.34, 3 studies) (p = .0005) (i2 = 0%). TTP was nearly 71 days longer in advanced/metastatic patients classified as non-sarcopenic compared to patients with sarcopenia (MD - 70.75 95% CI - 122.32 to - 19.18) (p = .007) (i2 = 0%). CONCLUSION: Our synthesis of the literature shows that patients with sarcopenia have more severe chemotherapy toxicity as well as shorter OS and TTP, and that low muscle density is prognostic of OS for women with metastatic breast cancer. Our findings suggest that in clinical practice, body composition assessment is valuable as a prognostic parameter in breast cancer.

Thyroid diseases and bone health.

Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X-ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor α (TRα). Discovery of this rare condition recapitulated animal studies demonstrating that TRα mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post-menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength.

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts.

BACKGROUND: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear. OBJECTIVE: To investigate the association between subclinical thyroid dysfunction and bone loss. METHODS: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach. RESULTS: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = -0.18 (95% CI: -0.34, -0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = -0.14 (95% CI: -0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: -0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%ΔBMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site. CONCLUSION: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

Thyroid Stimulating Hormone Suppression in the Long-term Follow-up of Differentiated Thyroid Cancer.

Differentiated thyroid cancer is the most common form of thyroid cancer and its prognosis is favourable in most cases. Suppression of thyroid stimulating hormone (TSH) by supra-physiological thyroid hormone replacement has been the mainstay of long-term management for over 60 years. However, evidence for a beneficial outcome of TSH suppression is conflicting and intervention must be balanced against adverse effects, particularly affecting the cardiovascular system and skeleton. Here we discuss the role of TSH suppression in the long-term management of differentiated thyroid cancer in the context of risk stratification for disease recurrence and the latest clinical guidelines.

Weight gain during adjuvant endocrine treatment for early-stage breast cancer: What is the evidence?

Most breast cancer (BC) tumors are early stage and hormone receptor positive, where treatment generally includes adjuvant endocrine treatment (ET). Oncology providers and women about to start ET want to know about side effects, including potential weight gain. The aim of this study was a literature review to identify the independent effect of ET on post-diagnosis weight gain. Weight gain is of concern with regard to potential associations with BC recurrence, mortality, and quality of life in survivorship. We conducted a targeted review of the literature. Thirty-eight studies met our inclusion criteria. Patient-reported weight gain ranged widely from 18 to 52 % of patients in Year 1 and from 7 to 55 % in Year 5. Some studies reported categories of weight change: lost weight (9-17 %), stable weight (47-64 %), and gained weight (27-36 %). Most studies comparing ET with placebo or tamoxifen with AI reported no significant difference between the two groups. Wide-ranging and inconsistent results point to the need for further research to clarify annual weight change (loss, gain, stability) from BC diagnosis through 5 years of ET and beyond. There is also a need to explore weight change by type of ET and to explore risk factors for weight gain in women on ET, including tumor type, sociodemographic characteristics, and health behaviors. More specific information is needed to identify high-risk BC patients who could be targeted for weight management interventions.

Risk factors for blood transfusion after shoulder arthroplasty.

AIMS: Currently, there is little information about the need for peri-operative blood transfusion in patients undergoing shoulder arthroplasty. The purpose of this study was to identify the rate of transfusion and its predisposing factors, and to establish a blood conservation strategy. METHODS: We identified all patients who had undergone shoulder arthroplasty at our hospital between 1 January 2011 and 31 December 2013. The rate of transfusion was determined from the patient's records. While there were exceptions, patients typically underwent transfusion if they had a level of haemoglobin of < 7.5 g/dl if asymptomatic, < 9.0 g/dl if they had a significant cardiac history or symptoms of dizziness or light headedness. Multivariable regression analysis was undertaken to identify predictors of transfusion. High- and low-risk cohorts for transfusion were identified from a receiver operating characteristic (ROC) curve. RESULTS: Of 1174 shoulder arthroplasties performed on 1081 patients, 53 cases (4.5%) required transfusion post-operatively. Predictors of blood transfusion were a lower pre-operative haematocrit (p < 0.001) and shoulder arthroplasty undertaken for post-traumatic arthritis (p < 0.001). ROC analysis identified pre-operative haematocrit of 39.6% as a 90% sensitivity cut-off for transfusion. In total 48 of the 436 (11%) shoulder arthroplasties with a pre-operative haematocrit < 39.6% needed transfusion compared with five of the 738 (0.70%) shoulder arthroplasties with a haematocrit above this level. DISCUSSION: We found that transfusion was needed less frequently than previously described for shoulder arthroplasty. Patients with a pre-operative haematocrit < 39.6% should be advised that there is an increased risk for blood transfusion, while those with a haematocrit above this level are unlikely to require transfusion. TAKE HOME MESSAGE: The rate of transfusion after shoulder arthroplasty is under 5%, and those with a pre-operative haematocrit greater than or equal to 39.6% have a very low likelihood (< 1%) of requiring a transfusion.

Quantitative X-ray microradiography for high-throughput phenotyping of osteoarthritis in mice.

OBJECTIVE: To investigate and validate digital X-ray microradiography as a novel, high-throughput and cost-effective screening approach to identify abnormal joint phenotypes in mice. METHOD: Digital X-ray microradiography was used to quantify the subchondral bone mineral content (BMC) in the medial tibial plateau. Accuracy and reproducibility of the method were determined in 22 samples from C57BL/6(B6Brd;B6Dnk;B6N-Tyr(c-Brd)) wild-type mice. The method was then validated in wild-type mice that had undergone surgical destabilisation of medial meniscus (DMM) and in a genetically modified mouse strain with an established increase in trabecular bone mass. RESULTS: The measurement of subchondral BMC by digital X-ray microradiography had a coefficient of variation of 3.6%. Digital X-ray microradiography was able to demonstrate significantly increased subchondral BMC in the medial tibial plateau of male mice 4 and 8 weeks after DMM surgery and in female mice 8 weeks after surgery. Furthermore, digital X-ray microradiography also detected the increase in subchondral BMC in a genetically modified mouse strain with high trabecular bone mass. CONCLUSION: Quantitation of subchondral BMC by digital X-ray microradiography is a rapid, sensitive and cost-effective method to identify abnormal joint phenotypes in mice of both genders at several ages.

Low bone mineral density is related to high physiological levels of free thyroxine in peri-menopausal women.

OBJECTIVE: To determine whether thyroid hormone (free thyroxine (fT4)) rather than TSH is directly related to bone mineral density (BMD). DESIGN: Cross-sectional population cohort study of peri-menopausal women. METHODS: Of a sample of 6846 peri-menopausal Dutch women who participated in an osteoporosis-screening programme, a cohort of 2584 was randomly selected for the assessment of thyroid function (TSH, fT4 and thyroid peroxidase antibodies (TPO-Abs)). TPO-Ab-positive women, with a previous history of thyroid dysfunction, overt thyroid disease, subclinical hypothyroidism, osteoporosis or bilateral oophorectomy and those receiving thyroid hormone or hormone replacement therapy were excluded. Of 1477 eligible women, 1426 had TSH and fT4 within the reference range and 51 had low or undetectable serum TSH. BMD was measured at the lumbar spine and low BMD was defined as <0.937 g/cm(2). RESULTS: The mean BMD in the 51 women with low or undetectable serum TSH was 0.984 g/cm(2) compared with 1.001 g/cm(2) in the remaining 1426 (t=0.94, P=0.35); 33% of women with low or undetectable serum TSH had low BMD compared with 34% in 1426 euthyroid women. High fT4 but not low TSH in euthyroid women was related to low BMD by multiple logistic regression corrected for age, BMI and smoking (OR, 1.30; 95% CI, 1.02-1.69). CONCLUSIONS: Higher fT4 levels within the normal reference range but not low or undetectable serum TSH were independently related to decreased BMD at lumbar spine in peri-menopausal women.

2012 European thyroid association guidelines for genetic testing and its clinical consequences in medullary thyroid cancer.

Twenty-five percent of medullary thyroid cancers (MTC) are familial and inherited as an autosomal dominant trait. Three different phenotypes can be distinguished: multiple endocrine neoplasia (MEN) types 2A and 2B, in which the MTC is associated with other endocrine neoplasias, and familial MTC (FMTC), which occurs in isolation. The discovery that germline RET oncogene activating mutations are associated with 95-98% of MEN 2/FMTC syndromes and the availability of genotyping to identify mutations in affected patients and their relatives has revolutionized the diagnostic and therapeutic strategies available for the management of these patients. All patients with MTC, both those with a positive familial history and those apparently sporadic, should be submitted to RET genetic screening. Once an RET mutation has been confirmed in an index patient, first-degree relatives should be screened rapidly to identify the 50% who inherited the mutation and are therefore at risk for development of MTC. Relatives in whom no RET mutation is identified can be reassured and discharged from further follow-up, whereas RET-positive subjects (i.e. gene carriers) must be investigated and a therapeutic strategy initiated. These guideline recommendations are derived from the most recent studies identifying phenotype-genotype correlations following the discovery of causative RET gene mutations in MEN 2 eighteen years ago. Three major points will be discussed: (a) identification of patients and relatives who should have genetic screening for RET mutations, (b) management of asymptomatic gene carriers, and (c) ethics.

Bilateral pisotriquetral loose bodies.

Case reports detailing diagnosis and effective treatment of pisotriquetral loose bodies are scarce. This article describes an even rarer case of bilateral pisotriquetral joint loose bodies, explores the relative diagnostic roles of magnetic resonance imaging versus computed tomography, and outlines effective strategies used for the management of this condition drawn from the literature and our own experience.

Thyroid hormones and bone development.

Thyroid hormones are critical determinants of postnatal skeletal development. Thyroid hormone deficiency or excess in children results in severe abnormalities of linear growth and bone maturation. These clinical observations have been recapitulated in mutant mice and these models have facilitated studies of the mechanisms of thyroid hormone action in the developing skeleton. In this review, we consider in detail the direct and indirect effects of thyroid hormone on bone and the molecular mechanisms involved.

Extrathyroidal expression of TSH receptor.

The TSH receptor expressed on the cell surface of thyroid follicular cells plays a pivotal role in the regulation of thyroid status and growth of the thyroid gland. In recent years it has become evident that the TSH receptor is also expressed widely in a variety of extrathyroidal tissues including: anterior pituitary; hypothalamus; ovary; testis; skin; kidney; immune system; bone marrow and peripheral blood cells; white and brown adipose tissue; orbital preadipocyte fibroblasts and bone. A large body of evidence is emerging to describe the functional roles of the TSH receptor at these various sites but their physiological importance in many cases remains a subject of controversy and much interest. Current understanding of the actions of the TSH receptor in extrathyroidal tissues and their possible physiological implications is discussed.