Hypophosphatemia attenuates improvements in vitality after intravenous iron treatment in patients with inflammatory bowel disease.

PURPOSE: Iron deficiency anemia is common in people with inflammatory bowel disease (IBD), causing deterioration in quality of life, which can be reversed by treatment that increases iron stores and hemoglobin levels. The present post hoc analyses estimate health state utility values for patients with IBD after treatment with ferric derisomaltose or ferric carboxymaltose and evaluate the health domains driving the changes. METHODS: SF-36v2 responses were recorded at baseline and day 14, 35, 49, and 70 from 97 patients enrolled in the randomized, double-blind, PHOSPHARE-IBD trial (ClinicalTrials.gov ID: NCT03466983), in which patients with IBD across five European countries were randomly allocated to either ferric derisomaltose or ferric carboxymaltose. Changes in SF-36v2 scale scores and SF-6Dv2 health utility values were analyzed by mixed models. RESULTS: In both treatment arms, SF-6Dv2 utility values and all SF-36v2 scale scores, except Bodily Pain, improved significantly (p = < 0.0001). The improvement in SF-6Dv2 utility values showed no significant treatment group difference. The improvement in utility values was completely explained by improvement in Vitality scores. Vitality scores showed significantly larger improvement with ferric derisomaltose versus ferric carboxymaltose (p = 0.026). Patients with the smallest decrease in phosphate had significantly larger improvements in Vitality scores at each time point (p = < 0.05 for all comparisons) and overall (p = 0.0006). CONCLUSIONS: Utility values improved significantly with intravenous iron treatment. Improvement in utility values was primarily driven by Vitality scores, which showed significantly greater improvement in the ferric derisomaltose arm. Smaller decreases in phosphate were associated with significantly higher Vitality scores, suggesting that quality of life improvement is attenuated by hypophosphatemia. The utility values can inform future cost-utility analysis.

Myonuclear alterations associated with exercise are independent of age in humans.

Age-related decline in skeletal muscle structure and function can be mitigated by regular exercise. However, the precise mechanisms that govern this are not fully understood. The nucleus plays an active role in translating forces into biochemical signals (mechanotransduction), with the nuclear lamina protein lamin A regulating nuclear shape, nuclear mechanics and ultimately gene expression. Defective lamin A expression causes muscle pathologies and premature ageing syndromes, but the roles of nuclear structure and function in physiological ageing and in exercise adaptations remain obscure. Here, we isolated single muscle fibres and carried out detailed morphological and functional analyses on myonuclei from young and older exercise-trained individuals. Strikingly, myonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than those from untrained individuals. Complementary to this, exercise resulted in increased levels of lamin A and increased myonuclear stiffness in mice. We conclude that exercise is associated with myonuclear remodelling, independently of age, which may contribute to the preservative effects of exercise on muscle function throughout the lifespan. KEY POINTS: The nucleus plays an active role in translating forces into biochemical signals. Myonuclear aberrations in a group of muscular dystrophies called laminopathies suggest that the shape and mechanical properties of myonuclei are important for maintaining muscle function. Here, striking differences are presented in myonuclear shape and mechanics associated with exercise, in both young and old humans. Myonuclei from trained individuals were more spherical, less deformable and contained a thicker nuclear lamina than untrained individuals. It is concluded that exercise is associated with age-independent myonuclear remodelling, which may help to maintain muscle function throughout the lifespan.

Declining levels of serum chemokine (C-X-C motif) ligand 10 over time are associated with new onset of psoriatic arthritis in patients with psoriasis: a new biomarker?

BACKGROUND: We previously found that serum levels of chemokine (C-X-C motif) ligand 10 (CXCL10) decreased after the onset of psoriatic arthritis (PsA). OBJECTIVES: We measured CXCL10 levels over time in patients with psoriasis who developed PsA to determine whether the drop in CXCL10 was specific to these patients and further assess its association with PsA development. METHODS: Prospectively followed patients with psoriasis without arthritis [cutaneous psoriasis (PsC)] were assessed yearly by rheumatologists for the presence of PsA. Patients with PsC who developed PsA (converters) were matched to those that did not develop PsA (nonconverters) based on psoriasis duration and the interval between follow-up visits. The duration between baseline and the first visit postconversion in converters was used to assign a pseudoconversion date in nonconverters. Linear mixed-effects models were used to model the expression of CXCL10 over time. RESULTS: CXCL10 significantly declined over time in converters prior to PsA development with a significant difference in the trend over time between converters (n = 29) and nonconverters (n = 52; P < 0·001). CXCL10 continued to decline after PsA onset in a subset of converters. There was a significant difference in the trend of CXCL10 levels between converters (n = 24) and nonconverters (n = 16; P = 0·01) preconversion/pseudoconversion. This difference remained postconversion (P = 0·006) and was not different from the preconversion period (P = 0·75). CONCLUSIONS: A large difference in CXCL10 was identified in patients with PsC that are destined to develop PsA over time. This exploratory analysis supports the association of CXCL10 with PsA development in patients with PsC and warrants further study of the predictive ability of this chemokine. What is already known about this topic? Chemokine (C-X-C motif) ligand 10 (CXCL10) is elevated in psoriatic affected tissues and serum and/or plasma. Patients with psoriasis that develop psoriatic arthritis (PsA) have elevated CXCL10 levels at baseline and these levels drop after arthritis onset. What does this study add? By monitoring levels of CXCL10 in serum over multiple visits in patients with psoriasis that develop PsA as well as those that do not develop PsA, an association was identified between CXCL10 and PsA development. What is the translational message? CXCL10 is a strong candidate for use by physicians for the detection of patients with psoriasis that are at risk of developing PsA. Linked Comment: Kirby and Fitzgerald. Br J Dermatol 2020; 183:805-806.

Broadband NIRS Cerebral Evaluation of the Hemodynamic and Oxidative State of Cytochrome-c-Oxidase Responses to +Gz Acceleration in Healthy Volunteers.

We used a miniature broadband NIRS system to monitor concentration changes in brain oxygenation (oxy- and deoxy- haemoglobin [HbO2], [HHb]) and oxidised cytochrome-c-oxidase ([oxCCO]) during a high +Gz acceleration, induced by a human centrifuge, on two healthy experienced volunteers (2 male, 34 and 37 years). We performed a sequence of several +Gz exposures that were terminated at the onset of visual symptoms (loss of peripheral vision). Systemic parameters were recorded (i.e. heart rate, blood pressure and arterial saturation), and brain tissue blood volume changes ([HbT] = [HbO2] + [HHb]) and oxygen delivery ([HbDiff] = [HbO2] - [HHb]) were calculated. Volunteer 1 demonstrated a decrease in [HbT] of -3.49 ± 0.02 µMol and [HbDiff] of -3.23 ± 0.44 µMol, and an increase of [oxCCO] of 0.42 ± 0.01µMol. Volunteer 2 demonstrated a decrease in [HbDiff] of -4.37 ± 0.23 µMol, and no significant change in [HbT] (0.53 ± 0.06 µMol) and [oxCCO] (0.09 ± 0.06 µMol). The variability of the brain metabolic response was related to the level of ischaemia, suggesting that suppression of metabolism was due to lack of glucose substrate delivery rather than oxygen availability.

The incidence and outcome of chondral tumours as incidental findings on investigation of shoulder pathology.

PURPOSE: The aim of this study is to describe outcomes of incidental chondral tumours in the shoulder referred to our Bone Tumour Unit (BTU). METHODS: Our hospital radiology database was searched using the filtered terms "enchondroma", "low-grade chondral tumour", "chondrosarcoma" with "humerus", "arm", "shoulder", "scapula" and "clavicle". Case note review of results assessed primary reasons for referral, radiological diagnosis, recommended management with subsequent reviews and outcomes, either in clinic or surveillance scan reports. RESULTS: Ninety-nine patients had full case note review, mean age 54.5 years (range 18-84 years). Mean follow-up was 41.7 months (range 1-265 months). Over 50% of patients were referred for shoulder pain. Three patients had high-grade chondrosarcoma. Forty-three patients had interval scans, none showing any changes. Thirty-five patients had surgery for their lesions with one recurrence. Forty-four patients had alternative diagnoses made on clinical and radiological examination. At most recent follow-up, 70% of these patients were asymptomatic after physiotherapy/surgical attention to their alternative diagnoses. CONCLUSIONS: Chondral lesions in the shoulder have low risk of malignant transformation and are rarely responsible for shoulder symptoms. We recommend patients be referred to a dedicated BTU for surveillance if there are any concerning features, but to proceed with management for any alternative diagnosis.

Cardiorespiratory fitness not sedentary time or physical activity is associated with cardiometabolic risk in active older adults.

Sedentary time (ST) and moderate-to-vigorous physical activity (MVPA) are associated with cardiometabolic health. Cardiorespiratory fitness (CRF) is also implicated but often overlooked in health recommendations. This study assessed the relationships between ST, MVPA, CRF, and cardiometabolic health in highly active older individuals. 125 healthy amateur cyclists aged 55 to 79 years had their ST and MVPA levels assessed by actigraphy over a 7-day period. CRF was assessed using a maximal effort cycle ergometry test to determine VO2max with results normalized to both body mass and fat-free mass measured by DXA. Markers of cardiometabolic risk (blood glucose, triglycerides, cholesterol, HDL, LDL, Insulin, HOMA IR, blood pressure, and body fat) were assessed and used to determine cumulative cardiometabolic risk. Multiple linear regression was used to assess ST, MVPA, and CRF associations with cardiometabolic health with the relationship between activity levels and CRF determined. CRF was associated with training volume (P = .003), but not ST or MVPA. A high CRF was associated with lower cumulative cardiometabolic risk, body fat percentage, triglyceride, and HDL levels (P < .05 in all cases). MVPA was negatively associated with body fat percentage, while ST was not associated with any marker of cardiometabolic risk when adjusting for activity levels. An association between CRF and cardiometabolic risk even in a group of older individuals with high fitness levels highlights the importance that CRF may have in maintaining health.

The functional MICA-129 polymorphism is associated with skin but not joint manifestations of psoriatic disease independently of HLA-B and HLA-C.

A methionine/valine polymorphism at amino acid 129 of the major histocompatibility complex class I chain-related gene A (MICA-129) categorizes alleles into strong and weak binders of the natural killer (NK) and T-cell receptor NKG2D. We investigated whether MICA-129 is differentially associated with skin and joint manifestations of psoriatic disease (PsD) independently of human leukocyte antigen (HLA)-C and HLA-B in patients and controls from Toronto and St. John's. The MICA-129 methionine (Met) allele, particularly Met/Met homozygosity, was strongly associated with both cutaneous psoriasis (PsC) and psoriatic arthritis (PsA) independently of HLA-B and HLA-C in Toronto patients, and was also associated with PsA in St. John's patients, but with no additional effect of Met/Met homozygosity. No association remained after adjustment for HLA alleles in St. John's patients. MICA-129 was not associated with PsA when compared with PsC. We conclude that MICA-129 is a marker of skin manifestations of PsD that is independent of HLA class I in Toronto patients.

Evaluating the cost-effectiveness of laparoscopic adjustable gastric banding versus standard medical management in obese patients with type 2 diabetes in the UK.

AIM: To evaluate the cost-effectiveness of laparoscopic adjustable gastric banding (LAGB) versus standard medical management (SMM) in obese patients with type 2 diabetes from a UK healthcare payer perspective. METHODS: A validated computer model of diabetes was used to project outcomes reported from a randomized clinical trial of LAGB versus SMM in obese patients with type 2 diabetes. Two-year follow-up data from the trial were projected over a 40-year time horizon and cost-effectiveness was assessed from the perspective of the National Health Service. Future costs and clinical outcomes were discounted at 3.5% annually and all costs were reported in 2010 pounds sterling. A series of sensitivity analyses were performed. RESULTS: LAGB was associated with benefits in HbA1c, systolic blood pressure, body mass index and serum lipid concentrations, which led to significant increases in discounted life expectancy (an increase of 0.64 years) and quality-adjusted life expectancy (an increase of 0.92 quality-adjusted life years, QALYs) and reduced incidence of diabetes complications relative to SMM. Treatment costs in the LAGB arm increased by 4552 Great British Pounds (GBP), but this was partially offset by cost savings resulting from a reduction in the incidence of all modelled diabetes complications. The incremental cost-effectiveness ratio of GBP 3602 per QALY in the base case fell well below commonly quoted willingness-to-pay thresholds in the UK setting. CONCLUSIONS: On the basis of data from a recent randomized controlled trial, LAGB is likely to be considered cost-effective from the healthcare payer perspective when compared with SMM of obesity in patients with type 2 diabetes in the UK setting.

Evaluating the cost-effectiveness of reduced mild hypoglycaemia in subjects with Type 1 diabetes treated with insulin detemir or NPH insulin in Denmark, Sweden, Finland and the Netherlands.

AIMS: To estimate short-term cost-effectiveness of insulin detemir vs. NPH insulin based on the incidence of mild hypoglycaemia in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands. METHODS: A model was developed to evaluate cost-effectiveness based on mild (self-treated) hypoglycaemia and pharmacy costs over 1 year. Published rates of mild hypoglycaemia were used for NPH insulin and insulin detemir. Effectiveness was calculated in terms of quality-adjusted life expectancy. Pharmacy costs were accounted using published prices and defined daily doses for both insulins. Costs were expressed in 2010 euros (€). RESULTS: Treatment with insulin detemir was associated with fewer mild hypoglycaemic events than NPH insulin (mean rates of 26.3 vs. 35.5 events per person-year), leading to an improvement in mean quality-adjusted life expectancy of approximately 0.019 (0.030) quality-adjusted life years (standard deviation). Annual costs were € 573.55 (110.42) vs. € 332.76 (62.18) in Denmark for insulin detemir and NPH insulin, respectively. These values were € 545.79 (106.54) vs. € 306.12 (57.78) in Sweden, € 720.10 (140.74) vs. € 408.73 (78.61) in Finland and € 584.01 (109.47) vs. € 359.60 (64.84) in the Netherlands. Incremental cost-effectiveness ratios were approximately € 12,644 (Denmark), € 12,612 (Sweden), € 16,568 (Finland) and € 12,216 (the Netherlands) per quality-adjusted life year gained for insulin detemir vs. NPH insulin. CONCLUSIONS: Insulin detemir is likely to be cost-effective vs. NPH insulin in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands. Increased pharmacy costs with insulin detemir should not be a barrier to therapy based on these findings.

Do fathead minnows, Pimephales promelas Rafinesque, alter their club cell investment in responses to variable risk of infection from Saprolegnia?

Fish in the Superorder Ostariophysi possess large epidermal club cells that release chemical cues warning nearby conspecifics of danger. Despite the long-held assumption that such club cells evolved under the selective force of predation, recent studies demonstrated that predation has no effect on club cell investment. Rather, club cells have an immune function and cell production may be stimulated by skin-penetrating pathogens and parasites. The current work investigates whether fathead minnows, Pimephales promelas, alter their club cell characteristics based on variation in infection risk. In a 2 × 3 design, we exposed minnows to infective cysts of two oomycete species (Saprolegnia ferax and S. parasitica) at three different concentrations (2, 20 or 200 cysts L(-1)). Club cell characteristics (number and size) were quantified 12 days after exposure. Saprolegnia parasitica is thought to be more pathogenic than S. ferax, hence we predicted greater club cell investment and a larger turnover rate of cells by minnows exposed to S. parasitica than S. ferax. We also predicted that minnows exposed to higher numbers of cysts should invest more in club cells and have a higher turnover rate of cells. We found no difference in club cell density or size between fish exposed to the two Saprolegnia species; however, fish exposed to high concentrations of pathogens had smaller club cells than those exposed to low concentrations, indicating a higher rate of turnover of cells in the epidermis.

Comparison of the minimally invasive and standard medial parapatellar approaches for primary total knee arthroplasty.

PURPOSE: The minimally invasive surgical (MIS) approach has been popularised as an alternative to the standard medial parapatellar approach (MPP) in total knee arthroplasty (TKA). Advocates of this technique suggest earlier functional recovery due to less injury to the surrounding tissues. Potential disadvantages however may include reduced overall exposure, component malalignment and damage to neurovascular structures. METHODS: A systematic review and meta-analysis of randomised and quasi-randomised trials were conducted to compare the MIS and MPP approaches in primary TKA. Methodological features were rated independently by two reviewers. RESULTS: Seventeen studies were included involving 733 patients with mean age of 69 (SD ± 2.8) in the MIS group and 692 patients with mean age of 68.6 (SD ± 3.1) in the MPP group. Using a MIS approach led to significant increase in flexion within the first week after a TKA (mean difference (MD) of 9.9° (95% confidence interval (CI) 8.2-11.6, P < 0.01)). However, this effect was not sustainable at further follow-ups of ≥ 3 months. MIS showed a significantly increased risk of developing intraoperative complications with a risk ratio (RR) of 7.6 (95% CI 3.5-16.3, P < 0.01). CONCLUSION: MIS results in superior function in the immediate postoperative period after a primary TKA but is also associated with increased rates of intraoperative complications, and therefore, a standard approach that allows adequate exposure and avoids tension to the wound edges would be more appropriate to prevent such complications. LEVEL OF EVIDENCE: Therapeutic study, Level I.

Differential major histocompatibility complex class I chain-related A allele associations with skin and joint manifestations of psoriatic disease.

About 30% of patients with psoriasis have psoriatic arthritis (PsA), an inflammatory arthritis that can affect both axial and peripheral joints. Major histocompatibility complex class I chain-related A (MICA) alleles have previously been shown to be associated with PsA; however it is unclear whether there is a differential association of MICA alleles with skin and joint manifestations of PsA. Here, we describe a case-control study that aims to validate previously reported MICA allele associations with PsA and determine whether MICA alleles differentiate patients with PsA from those with psoriasis without PsA. Two hundred forty-nine unrelated Caucasian PsA patients, 243 psoriasis patients without arthritis, and 248 healthy controls were genotyped for 55 MICA alleles using PCR-SSP, and for human leucocyte antigen (HLA)-B and HLA-C alleles by PCR-SSO reverse line blot. Allele frequencies were calculated and logistic regressions were performed, adjusting for HLA-B and HLA-C alleles previously shown to be associated with psoriasis and/or PsA. Several MICA alleles were associated with psoriatic disease, PsA, and psoriasis compared with controls, and PsA compared with psoriasis in univariate analyses. Haplotype analysis showed evidence of strong linkage disequilibrium (LD) between PsA and psoriasis risk alleles of HLA-C, HLA-B, and MICA. After adjusting for significant HLA-B and HLA-C alleles in multivariate analyses, MICA*016 remained significantly associated with psoriasis [odds ratio (OR) = 5.5, P = 0.008]. MICA*00801 homozygosity was associated with susceptibility to PsA when compared with patients with psoriasis alone (OR = 2.26, P = 0.009). We conclude that most MICA allele associations with psoriasis and PsA are dependent on LD with HLA-B and HLA-C risk alleles. Independent of HLA, only MICA*016 influences the risk of developing psoriasis without arthritis, and homozygosity for MICA*00801 increases the risk of developing PsA in patients with psoriasis.

A humanized system for pharmacologic control of gene expression.

Gene therapy was originally conceived as a medical intervention to replace or correct defective genes in patients with inherited disorders. However, it may have much broader potential as an alternative delivery platform for protein therapeutics, such as cytokines, hormones, antibodies and novel engineered proteins. One key technical barrier to the widespread implementation of this form of therapy is the need for precise control over the level of protein production. A suitable system for pharmacologic control of therapeutic gene expression would permit precise titration of gene product dosage, intermittent or pulsatile treatment, and ready termination of therapy by withdrawal of the activating drug. We set out to design such a system with the following properties: (1) low baseline expression and high induction ratio; (2) positive control by an orally bioavailable small-molecule drug; (3) reduced potential for immune recognition through the exclusive use of human proteins; and (4) modularity to allow the independent optimization of each component using the tools of protein engineering. We report here the properties of this system and demonstrate its use to control circulating levels of human growth hormone in mice implanted with engineered human cells.

Point mutations cause the somatic diversification of IgM and IgG2a antiphosphorylcholine antibodies.

The genetic mechanism responsible for the somatic diversification of two mAbs was determined. The two PC-binding hybridomas were representative of events early and late in the immune response. The P28 cell line that produces an IgM antibody and thus represents events early in the immune response, was found to have 3 bp changes in its heavy chain variable (VH) region, with some changes in antibody affinity or specificity. The RP93 cell line that produces an IgG2a antibody and thus represents later events in the immune response, was found to have 9 bp changes in its VH region resulting in decreased affinity for PC and altered specificity. Oligonucleotides specific for linked base changes in the second hypervariable regions of both of these antibodies were used to look for previously undescribed V regions or other donor sequences that could have been responsible for these base changes. Since no donor sequences were found, we have concluded that somatic point mutation rather than gene conversion, V region replacement or the expression of an unidentified germline VH region gene is truly responsible for at least some of the somatic diversification of these antibodies.

Molecular prognosticators of complex karyotype soft tissue sarcoma outcome: a tissue microarray-based study.

BACKGROUND: Molecular markers are currently being utilized as sensitive prognosticators of cancer patient outcome. We sought to identify prognostic biomarkers for complex karyotype soft tissue sarcoma (STS). MATERIALS AND METHODS: A large (n = 205) clinically annotated tissue microarray (TMA) was constructed and immunostained for several tumor-related markers. Staining was scored via an automated Ariol image analysis system; data were statistically analyzed to evaluate the correlation of clinicopathological and molecular variables with overall survival (OS) and local recurrence. RESULTS: Multivariable analysis identified older age [hazard ratio (HR) 1.62, P < 0.0001], nonextremity location (HR 2.95, P = 0.001), high tumor grade (HR 2.5, P = 0.02), and increased matrix metalloproteinase (MMP) 2 expression (HR 1.74, P = 0.04) as predictors for poor OS. Similarly, older age (HR 1.51, P = 0.008), nonextremity location (HR 4.09, P = 0.001), and increased MMP2 expression (HR 6.28, P = 0.006) were all found to correlate with shorter local recurrence-free interval. High nuclear p53 expression was associated with shorter STS local recurrence-free interval, with a trend toward significance. CONCLUSIONS: Data presented indicate that a clinically annotated TMA can be utilized to identify STS-related prognostic markers. Specifically, MMP2 and nuclear p53 should be further evaluated for their potential inclusion in complex karyotype STS staging systems.

Postoperative nomogram for survival of patients with retroperitoneal sarcoma treated with curative intent.

BACKGROUND: Current American Joint Committee on Cancer retroperitoneal sarcoma (RPS) staging is not representative of patients with RPS specifically and has limited discriminative power. Our objective was to develop a RPS disease-specific nomogram capable of stratifying patients based on probability of overall survival (OS) after resection. PATIENTS AND METHODS: In all, 1118 RPS patients were evaluated at our institution (1996-2006). Patients with resectable, nonmetastatic disease were selected (n = 343) and baseline, treatment and outcome variables were retrieved. A nomogram was created and its performance was evaluated by calculating its discrimination (concordance index) and calibration and by subsequent internal validation. RESULTS: Median follow-up and OS were 50 and 59 months, respectively. Independent predictors of OS were included in the nomogram: age (> or = 65), tumor size (> or = 15 cm), type of presentation (primary versus recurrent), multifocality, completeness of resection and histology. The concordance index was 0.73 [95% confidence interval (CI) 0.71-0.75] and the calibration was excellent, with all observed outcomes within the 95% CI of each predicted survival probability. CONCLUSIONS: A RPS-specific postoperative nomogram was developed. It improves RPS staging by allowing a more dynamic and robust disease-specific risk stratification. This prognostic tool can help in patient counseling and for selection of high-risk patients that may benefit from adjuvant therapies or inclusion into clinical trials.

A cost-utility analysis of SIR-Spheres Y-90 resin microspheres versus best supportive care in the treatment of unresectable metastatic colorectal cancer refractory to chemotherapy in the UK.

BACKGROUND: Limited treatment options are available in chemotherapy-refractory or -intolerant metastatic colorectal cancer (mCRC). The objective of the present analysis was to evaluate the cost-utility of SIR-Spheres Y-90 resin microspheres relative to best supportive care (BSC) in the treatment of chemotherapy refractory mCRC from the perspective of the UK national healthcare payer. METHODS: A cost-utility model was developed in Microsoft Excel to simulate transitions from progression-free survival to post-progression survival and death in patients with mCRC. Unit costs were captured in 2019 pounds sterling (GBP) based on the literature, formulary listings, and National Health Service (NHS) England reference costs. Future costs and effects were discounted at 3.5% per annum. A series of one-way sensitivity analyses, and probabilistic sensitivity analysis (PSA) were conducted. RESULTS: The base case analysis showed that SIR-Spheres Y-90 resin microspheres would result in an increase in discounted quality-adjusted life years gained from 0.69 quality-adjusted life years (QALYs) to 1.50 QALYs, with an associated increase in cost from GBP 15,268 to GBP 34,168 yielding an incremental cost-utility ratio of GBP 23,435 per QALY. PSA showed that there would be a 56% likelihood that SIR-Spheres Y-90 resin microspheres would be cost-effective relative to BSC at a willingness-to-pay threshold of GBP 30,000 per QALY gained. CONCLUSIONS: This cost-utility analysis showed that, relative to BSC, SIR-Spheres Y-90 resin microspheres would be a cost-effective treatment option for patients with mCRC in the UK setting from the national healthcare payer perspective.

Surgical Outcome and Oncological Survival of Osteofibrous Dysplasia-Like and Classic Adamantinomas: An International Multicenter Study of 318 Cases.

BACKGROUND: Osteofibrous dysplasia-like adamantinoma (OFD-AD) and classic adamantinoma (AD) are rare, neoplastic diseases with only limited data supporting current treatment protocols. We believe that our retrospective multicenter cohort study is the largest analysis of patients with adamantinoma to date. The primary purpose of this study was to describe the disease characteristics and evaluate the oncological outcomes. The secondary purpose was to identify risk factors for local recurrence after surgical treatment and propose treatment guidelines. METHODS: Three hundred and eighteen confirmed cases of OFD-AD and AD for which primary treatment was carried out between 1985 and 2015 were submitted by 22 tertiary bone tumor centers. Proposed clinical risk factors for local recurrence such as size, type, and margins were analyzed using univariable and multivariate Cox regression analysis. RESULTS: Of the 318 cases, 128 were OFD-AD and 190 were AD. The mean age at diagnosis was 17 years (median, 14.5 years) for OFD-AD and 32 years (median, 28 years) for AD; 53% of the patients were female. The mean tumor size in the OFD-AD and AD groups combined was 7.8 cm, measured histologically. Sixteen percent of the patients sustained a pathological fracture prior to treatment. Local recurrence was recorded in 22% of the OFD-AD cases and 24% of the AD cases. None of the recurrences in the OFD-AD group progressed to AD. Metastatic disease was found in 18% of the AD cases and fatal disease, in 11% of the AD cases. No metastatic or fatal disease was reported in the OFD-AD group. Multivariate Cox regression analysis demonstrated that uncontaminated resection margins (hazard ratio [HR] = 0.164, 95% confidence interval [CI] = 0.092 to 0.290, p < 0.001), pathological fracture (HR = 1.968, 95% CI = 1.076 to 3.600, p = 0.028), and sex (female versus male: HR = 0.535, 95% CI = 0.300 to 0.952, p = 0.033) impacted the risk of local recurrence. CONCLUSIONS: OFD-AD and AD are parts of a disease spectrum but should be regarded as different entities. Our results support reclassification of OFD-AD into the intermediate locally aggressive category, based on the local recurrence rate of 22% and absence of metastases. In our study, metastatic disease was restricted to the AD group (an 18% rate). We advocate wide resection with uncontaminated margins including bone and involved periosteum for both OFD-AD and AD. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Outcome of locally recurrent and metastatic angiosarcoma.

BACKGROUND: Angiosarcoma (AS) is a rare soft tissue sarcoma with an enhanced propensity for local and systemic failure. The outcome of locally recurrent and metastatic AS treated at a single institution was evaluated. METHODS: Medical records of AS patients treated for local recurrence and distant metastasis (1993-2008) were retrospectively reviewed. Univariable and multivariable analyses were performed to identify prognosticators. RESULTS: Forty-four patients were treated for locally recurrent AS; the majority (59%) were 5 cm as the only independent adverse prognosticator of recurrent AS-specific survival [hazard ratio (HR): 3.26, P = 0.04]. Ninety-nine patients were treated for metastatic AS; 73% had multiple metastatic sites; the lung was the most common site (36%). Chemotherapy, mainly doxorubicin- and/or paclitaxel-based regimens, were administered to 95 patients (96%). Radiotherapy was utilized in 25% cases; 16% of patients underwent curative-intent surgery. Median DSS was 10 months (95% CI: 7.9-12 months). Isolated lymph node metastasis versus hematogenic spread was the only statistically significant favorable prognostic factor identified (HR: 0.29, P = 0.01). CONCLUSION: Locally recurrent AS is often treatable; complete resection can potentially prolong survival. In contrast, metastatic patients have a grave prognosis; however, patients with isolated lymphatic spread and possibly those treated with taxol-based chemotherapeutic regimens have a favorable outcome.