Predictors of Quality of Life Decline in Patients with Oligometastases treated with Stereotactic Ablative Radiotherapy: Analysis of the Population-Based SABR-5 Phase II Trial.

AIMS: Most patients experience stable quality of life (QoL) after stereotactic ablative radiotherapy (SABR) treatment for oligometastases. However, a subset of patients experience clinically relevant declines in QoL on post-treatment follow-up. This study aimed to identify risk factors for QoL decline. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases. Prospective QoL was measured using treatment site-specific tools at pre-treatment baseline and 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. The time to persistent QoL decline was calculated as the time from SABR to the first decline in QoL score meeting minimum clinically important difference with no improvement to baseline score on subsequent assessments. Univariable and multivariable logistic regression analyses were carried out to determine factors associated with QoL decline. RESULTS: One hundred and thirty-three patients were included with a median follow-up of 32 months (interquartile range 25-43). Thirty-five patients (26%) experienced a persistent decline in QoL. The median time until persistent QoL decline was not reached. The cumulative incidence of QoL decline at 2 and 3 years were 22% (95% confidence interval 14.0-29.6) and 40% (95% confidence interval 28.0-51.2), respectively. In multivariable analysis, disease progression (odds ratio 5.23, 95% confidence interval 1.59-17.47, P = 0.007) and adrenal metastases (odds ratio 9.70, 95% confidence interval 1.41-66.93, P = 0.021) were associated with a higher risk of QoL decline. Grade 3 or higher (odds ratio 3.88, 95% confidence interval 0.92-16.31, P = 0.064) and grade 2 or higher SABR-associated toxicity (odds ratio 2.24, 95% confidence interval 0.85-5.91, P = 0.10) were associated with an increased risk of QoL decline but did not reach statistical significance. CONCLUSIONS: Disease progression and adrenal lesion site were associated with persistent QoL decline following SABR. The development of grade 3 or higher toxicities was also associated with an increased risk, albeit not statistically significant. Further studies are needed, focusing on the QoL impact of metastasis-directed therapies.

Clinical and technical factors in endoscopic skull base surgery associated with reconstructive success.

BACKGROUND: In this study, we identified key discrete clinical and technical factors that may correlate with primary reconstructive success in endoscopic skull base surgery (ESBS). METHODS: ESBS cases with intraoperative cerebrospinal fluid (CSF) leaks at four tertiary academic rhinology programs were retrospectively reviewed. Logistic regression identified factors associated with surgical outcomes by defect subsite (anterior cranial fossa [ACF], suprasellar [SS], purely sellar, posterior cranial fossa [PCF]). RESULTS: Of 706 patients (50.4% female), 61.9% had pituitary adenomas, 73.4% had sellar or SS defects, and 20.5% had high-flow intraoperative CSF leaks. The postoperative CSF leak rate was 7.8%. Larger defect size predicted ACF postoperative leaks; use of rigid reconstruction and older age protected against sellar postoperative leaks; and use of dural sealants compared to fibrin glue protected against PCF postoperative leaks. SS postoperative leaks occurred less frequently with the use of dural onlay. Body-mass index, intraoperative CSF leak flow rate, and the use of lumbar drain were not significantly associated with postoperative CSF leak. Meningitis was associated with larger tumors in ACF defects, nondissolvable nasal packing in SS defects, and high-flow intraoperative leaks in PCF defects. Sinus infections were more common in sellar defects with synthetic grafts and nondissolvable nasal packing. CONCLUSIONS: Depending on defect subsite, reconstructive success following ESBS may be influenced by factors, such as age, defect size, and the use of rigid reconstruction, dural onlay, and tissue sealants.

Prospective Longitudinal Assessment of Quality of Life After Stereotactic Ablative Radiotherapy for Oligometastases: Analysis of the Population-based SABR-5 Phase II Trial.

AIMS: To evaluate longitudinal patient-reported quality of life (QoL) in patients treated with stereotactic ablative radiotherapy (SABR) for oligometastases. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases, conducted in six regional cancer centres in British Columbia, Canada from 2016 to 2020. Prospective QoL was measured using treatment site-specific QoL questionnaires at pre-treatment baseline and at 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. Patients with bone metastases were assessed with the Brief Pain Inventory (BPI). Patients with liver, adrenal and abdominopelvic lymph node metastases were assessed with the Functional Assessment of Chronic Illness Therapy-Abdominal Discomfort (FACIT-AD). Patients with lung and intrathoracic lymph node metastases were assessed with the Prospective Outcomes and Support Initiative (POSI) lung questionnaire. The two one-sided test procedure was used to assess equivalence between the worst QoL score and the baseline score of individual patients. The mean QoL at all time points was used to determine the trajectory of QoL response after SABR. The proportion of patients with 'stable', 'improved' or 'worsened' QoL was determined for all time points based on standard minimal clinically important differences (MCID; BPI worst pain = 2, BPI functional interference score [FIS] = 0.5, FACIT-AD Trial Outcome Index [TOI] = 8, POSI = 3). RESULTS: All enrolled patients with baseline QoL assessment and at least one follow-up assessment were analysed (n = 133). On equivalence testing, the patients' worst QoL scores were clinically different from baseline scores and met MCID (BPI worst pain mean difference: 1.8, 90% confidence interval 1.19 to 2.42]; BPI FIS mean difference: 1.68, 90% confidence interval 1.15 to 2.21; FACIT-AD TOI mean difference: -8.76, 90% confidence interval -11.29 to -6.24; POSI mean difference: -4.61, 90% confidence interval -6.09 to -3.14). However, the mean FIS transiently worsened at 9, 18 and 21 months but eventually returned to stable levels. The mean FACIT and POSI scores also worsened at 36 months, albeit with a limited number of responses (n = 4 and 8, respectively). Most patients reported stable QoL at all time points (range: BPI worst pain 71-82%, BPI FIS 45-78%, FACIT-AD TOI 50-100%, POSI 25-73%). Clinically significant stability, worsening and improvement were seen in 70%/13%/18% of patients at 3 months, 53%/28%/19% at 18 months and 63%/25%/13% at 36 months. CONCLUSIONS: Transient decreases in QoL that met MCID were seen between patients' worst QoL scores and baseline scores. However, most patients experienced stable QoL relative to pre-treatment levels on long-term follow-up. Further studies are needed to characterise patients at greatest risk for decreased QoL.

Evolution of Radiographic Changes of a Vascularized Pedicled Nasoseptal Flap after Endonasal Endoscopic Skull Base Surgery.

BACKGROUND AND PURPOSE: There is active research involving the radiographic appearance of the skull base following reconstruction. The purpose of this study was to describe the radiographic appearance of the vascularized pedicle nasoseptal flap after endoscopic skull base surgery across time. MATERIALS AND METHODS: We performed chart and imaging review of all patients with intraoperative nasoseptal flap placement during endoscopic skull base surgery at a tertiary academic skull base surgery program between July 2018 and March 2021. All patients underwent immediate and delayed (>3 months) postoperative MR imaging. Primary outcome variables included flap and pedicle enhancement, flap thickness, and flap adherence to the skull base. RESULTS: Sixty-eight patients were included. Flap (P = .003) enhancement significantly increased with time. Mean nasoseptal flap thickness on immediate and delayed postoperative scans was 3.8 and 3.9 mm, respectively (P = .181). The nasoseptal flap adhered entirely to the skull base in 37 (54.4%) and 67 (98.5%) patients on immediate and delayed imaging, respectively (P < .001). CONCLUSIONS: Our findings demonstrate heterogeneity of the nasoseptal flap appearance after skull base reconstruction. While it is important for surgeons and radiologists to evaluate variations in flap appearance, the absence of enhancement and lack of adherence to the skull base on immediate postoperative imaging do not appear to predict reconstructive success and healing, with many flaps "self-adjusting" with time.

The Effect of Breast Cancer Subtype on Symptom Improvement Following Palliative Radiotherapy for Bone Metastases.

AIM: To assess the relationship between breast cancer subtypes and patient-reported outcomes (PRO) following palliative radiotherapy for bone metastases. MATERIALS AND METHODS: Prospectively collected PRO for all breast cancer patients treated with palliative, bone metastasis-directed radiotherapy from 2013 to 2016 in the province of British Columbia were analysed. The PRO questionnaire scored pain severity, level of function and symptom frustration at baseline and at 3-4 weeks following palliative radiotherapy using a 12-point scale. The primary outcome was the rate of overall response (any improvement in score); the secondary outcome was the rate of complete improvement in PRO (final PRO score of 0). Multivariate logistic analysis was used to compare response rates between molecular subgroup approximations of luminal A (LumA), luminal B (LumB), HER2-enriched (HER2) and triple negative (TN), as defined by grade and immunohistochemical staining. RESULTS: There were 376 patients who underwent 464 courses of palliative radiation for bone metastases. Subtypes included: 243 LumA, 146 LumB, 46 HER2 and 29 TN. There were 216 multifraction radiotherapy courses (median dose 20 Gy) and 248 single-fraction radiotherapy courses (median dose 8 Gy). The overall response rate was 85% and the complete response rate was 25%. In comparison with LumA breast cancers, TN breast cancers were associated with a lower rate of overall response (69% versus 86%, P = 0.021) and a lower rate of complete response (10% versus 28.8%, P = 0.045) on multivariate analyses. CONCLUSION: Patients with TN breast cancer have lower rates of pain, function and symptom frustration improvement following palliative radiation for bone metastases.

Whole Brain Radiotherapy Versus Stereotactic Radiosurgery in Poor-Prognosis Patients with One to 10 Brain Metastases: A Randomised Feasibility Study.

AIMS: A significant proportion of patients with brain metastases have a poor prognosis, with a life expectancy of 3-6 months. To determine the optimal radiotherapeutic strategy for brain metastases in this population, we conducted a randomised feasibility study of whole brain radiotherapy (WBRT) versus stereotactic radiosurgery (SRS). MATERIALS AND METHODS: Patients with a life expectancy of 3-6 months and between one and 10 brain metastases with a diameter ≤4 cm were enrolled at six Canadian cancer centres. Patients were randomly assigned (1:1) to receive either WBRT (20 Gy in five fractions) or SRS (15 Gy in one fraction). The primary end point was the rate of accrual per month. Secondary feasibility and clinical end points included the ratio of accrued subjects to screened subjects. This trial is registered with ClinicalTrials.gov (number NCT02220491). RESULTS: In total, 210 patients were screened to enrol 22 patients into the trial; 20 patients were randomised between the two arms. Two patients did not receive treatment because one patient died and another patient withdrew consent after being enrolled. Patients were accrued between January 2015 and November 2017; the accrual rate was 0.63 patients/month. The most common reasons for exclusion were anticipated median survival outside the required range (n = 40), baseline Karnofsky Performance Score below 70 (n = 28) and more than 10 brain metastases (n = 28). The median follow-up was 7.0 months and the median survival was 7.0 months for all patients in the trial. The median intracranial progression-free survival was 1.8 months in the SRS arm and 9.2 months in the WBRT arm. There were five grade 3+ toxicities in the SRS arm and one grade 3+ toxicity in the WBRT arm; no grade 5 toxicities were observed. The cumulative rates of retreatment were 40% in the SRS arm and 40% in the WBRT arm. CONCLUSIONS: A randomised trial evaluating WBRT versus SRS in patients with one to 10 metastases and a poor prognosis is feasible. A slower than expected accrual rate and difficulties with accurate prognostication were identified as issues in this feasibility study. A larger phase III randomised trial is planned to determine the optimal treatment in this patient population.

Etoposide phosphate for pediatric orthopedic malignancies after intravenous etoposide hypersensitivity.

BACKGROUND: Hypersensitivity reactions to etoposide have been reported and patients have been safely transitioned to etoposide phosphate for continued therapy. However, the safety and efficacy of substituting etoposide phosphate for etoposide has not been well established in pediatric orthopedic malignancies. The aim of this study is to determine whether etoposide phosphate can be substituted for etoposide in pediatric orthopedic malignancies. METHODS: A chart review of pediatric patients who developed hypersensitivity reactions to etoposide while being treated for orthopedic malignancies was performed at a large academic medical center. Three patients were identified, two with Ewing sarcoma and one with an osteosarcoma. All three patients experienced hypersensitivity reactions to their first doses of etoposide and were switched to etoposide phosphate for further therapy. RESULTS: After premedication, all three patients tolerated full doses of etoposide phosphate without a graded dose challenge or desensitization. Two of the patients were premedicated with diphenhydramine alone, while the third received diphenhydramine and dexamethasone. CONCLUSIONS: Etoposide phosphate is a potentially safe alternative for pediatric patients with orthopedic malignancies who experience etoposide hypersensitivity. However, caution is needed as there are cases of etoposide phosphate hypersensitivity.

Cerebral Ketones Detected by 3T MR Spectroscopy in Patients with High-Grade Glioma on an Atkins-Based Diet.

BACKGROUND AND PURPOSE: Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks. MATERIALS AND METHODS: Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients. RESULTS: At baseline, the ketone bodies acetone and ß-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and ß-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not ß-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and ß-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks. CONCLUSIONS: This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.

Psoas and Paraspinous Muscle Measurements on Computed Tomography Predict Mortality in European Americans with Type 2 Diabetes Mellitus.

BACKGROUND: Appendicular skeletal muscle mass index and muscle attenuation (density) are negatively associated with mortality in European-derived populations. OBJECTIVES: The present analyses assessed association between axial skeletal muscle density and muscle index with mortality in European Americans with type 2 diabetes mellitus (T2D). DESIGN: Single-center observational study. SETTING: Diabetes Heart Study. PARTICIPANTS: 839 European Americans with T2D. METHODS: Computed tomography-measured psoas and paraspinous muscle mass index (cross sectional area/height2) and radiographic density (Hounsfield Units) were assessed in all participants. A Cox proportional hazards model was computed. The fully-adjusted model included covariates age, sex, body mass index, smoking, alcohol use, diabetes duration, insulin use, hormone replacement therapy (women), prevalent cardiovascular disease (CVD), hypertension, and coronary artery calcified atherosclerotic plaque mass score. Deaths were recorded in the National Death Index data through December 31, 2015. RESULTS: Participants included 428 women and 411 men with median (25th, 75th quartile) age 62.8 (56.1, 69.1) years and diabetes duration 8.0 (5.0, 14.0) years. After 11.9 (9.4, 13.3) years of follow-up, 314 (37.4%) of participants were deceased. In the fully-adjusted model, psoas muscle density (hazard ratio [HR] 0.81, p<0.001), psoas muscle index (HR 0.82, p=0.008), and paraspinous muscle density (HR 0.85, p=0.003) were inversely associated with mortality. Paraspinous muscle index was not significantly associated with mortality (HR 0.90, p=0.08). Results did not differ significantly between men and women. CONCLUSIONS: In addition to established risk factors for mortality and CVD, higher psoas muscle index, psoas muscle density, and paraspinous muscle density were significantly associated with lower all-cause mortality in European Americans with T2D.

Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses.

BACKGROUND: The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy. OBJECTIVE: We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC). METHODS: We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID. RESULTS: We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG+ B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria. CONCLUSIONS: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.

Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations.

BACKGROUND: In the present study, we examined the pattern of metastatic spread in patients with advanced non-small-cell lung cancer (nsclc) and the effect of EGFR mutations. METHODS: Patients were identified from a provincial cancer registry, and individual medical records were reviewed. Patients were included if they had stage iv nsclc and underwent diagnostic EGFR mutation testing. Patients were divided into EGFR mutation-positive (EGFR+) and EGFR wild type (wt) cohorts. The primary endpoint was the cumulative incidence for each metastatic site: lung, bone, brain, liver, adrenal glands, distant nodes, and other. Cumulative incidence curves were estimated using a competing-risks method. The secondary outcome was survival. RESULTS: Of the 543 identified patients, 121 (22.3%) tested as EGFR+, and 422 (77.7%) tested as EGFR wt. The incidence of brain (39.2% vs. 28.2%, p = 0.038) and lung (61.2% vs. 51.0%, p = 0.048) metastasis was higher in the EGFR+ cohort than in the EGFR wt cohort. In the EGFR+ cohort, a higher incidence of liver metastasis was associated with the exon 21 mutation subtype than with the exon 19 deletion subtype [23% vs. 7%, p < 0.01; hazard ratio (hr): 3.47]. Median survival was significantly longer for the EGFR+ cohort than for the EGFR wt cohort (22.4 months vs. 7.9 months, p < 0.001). In multivariable analysis, brain (hr: 1.73), liver (hr: 1.69), and bone (hr: 1.89) metastases were associated with worse survival. CONCLUSIONS: Rates of lung and brain metastases are higher in EGFR mutation carriers, even when adjusted for differences in survival. Brain, liver, and bone metastases are independent negative prognostic factors for survival.

Acetylation is essential for nuclear heme oxygenase-1-enhanced tumor growth and invasiveness.

Overexpression of heme oxygenase-1 (HO-1), an endoplasmic reticulum-anchored enzyme, is observed in many cancers. HO-1 nuclear translocation has been shown to correlate with progression of several cancers. We recently reported that HO-1 is susceptible to intramembrane proteolysis and translocates to the nucleus to promote cancer growth and invasiveness without depending on its enzymatic activity. In the present study, we show that the HO-1 lacking C-terminal transmembrane segment (t-HO-1) was susceptible to acetylation by p300 and CREB-binding protein (CBP) histone acetyltransferase in the nucleus. Mass spectrometry analysis of HO-1 isolated from human embryonic kidney cells 293T (HEK293T) cells overexpressing CBP and t-HO-1 revealed two acetylation sites located at K243 and K256. Mutation of both lysine residues to arginine (R) abolished t-HO-1-enhanced tumor cell growth, migration and invasion. However, mutation of the lysine residues to glutamine (Q), a mimic of acetylated lysine, had no significant effect on t-HO-1-mediated tumorigenicity. Mechanistic studies demonstrated that transcriptional factor JunD interacted with wild-type (WT) t-HO-1 and mutant carrying K243/256Q but not K243/256 R mutation. Moreover, JunD-induced AP-1 transcriptional activity was significantly enhanced by coexpression with WT and acetylation-mimic but not acetylation-defective t-HO-1. Consistent with the in vitro observations, the implication of K243/256 acetylation in t-HO-1-enhanced tumorigenicity was also demonstrated in xenograft models. Immunohistochemistry performed with a specific antibody against acetyl-HO-1 showed the positive acetyl-HO-1 nuclear staining in human lung cancer tissues but not in the corresponding non-tumor tissues, supporting its clinical significance. Collectively, our findings highlight the importance of nuclear HO-1 post-translational modification in the induction of cancer progression.

miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERK pathway.

Epithelial ovarian cancer is the most lethal gynecological cancer mainly due to late diagnosis, easy spreading and rapid development of chemoresistance. Cancer stem cells are considered to be one of the main mechanisms for chemoresistance, as well as metastasis and recurrent disease. To explore the stemness characteristics of ovarian cancer stem cells, we successfully enriched ovarian cancer stem-like cells from an established ovarian cancer cell line (SKOV-I6) and a fresh ovarian tumor-derived cell line (OVS1). These ovarian cancer stem-like cells possess important cancer stemness characteristics including sphere-forming and self-renewing abilities, expressing important ovarian cancer stem cell and epithelial-mesenchymal transition markers, as well as increased drug resistance and potent tumorigenicity. Microarray analysis of OVS1-derived sphere cells revealed increased expression of amphiregulin (AREG) and decreased expression of its conserved regulatory microRNA, miR-34c-5p, when compared with the OVS1 parental cells. Overexpression of AREG and decreased miR-34c-5p expression in SKOV-I6 and OVS1 sphere cells were confirmed by quantitative real-time PCR analysis. Luciferase reporter assay and mutant analysis confirmed that AREG is a direct target of miR-34c-5p. Furthermore, AREG-mediated increase of sphere formation, drug resistance toward docetaxel and carboplatin, as well as tumorigenicity of SKOV-I6 and OVS1 cells could be abrogated by miR-34c-5p. We further demonstrated that miR-34c-5p inhibited ovarian cancer stemness through downregulation of the AREG-EGFR-ERK pathway. Overexpression of AREG was found to be correlated with advanced ovarian cancer stages and poor prognosis. Taken together, our data suggest that AREG promotes ovarian cancer stemness and drug resistance via the AREG-EGFR-ERK pathway and this is inhibited by miR-34c-5p. Targeting AREG, miR-34c-5p could be a potential strategy for anti-cancer-stem cell therapy in ovarian cancer.

A systematic approach to predicting the risk of unicompartmental knee arthroplasty revision.

OBJECTIVE: Unicompartmental knee arthroplasty (UKA) revision is usually due to the degenerative degree of knee articular osteochondral tissue in the untreated compartment. However, it is difficult to simulate the biomechanical behavior on this tissue accurately. This study presents and validates a reliable system to predict which osteoarthritis (OA) patients may suffer revision as a result of biomechanical reasons after having UKA. DESIGN: We collected all revision cases available (n = 11) and randomly selected 67 UKA cases to keep the revision prevalence of almost 14%. All these 78 cases have been followed at least 2 years. An elastic model is designed to characterize the biomechanical behavior of the articular osteochondral tissue for each patient. After calculated the force on the tissue, finite element method (FEM) is applied to calculating the strain of each tissue node. Kernel Ridge Regression (KRR) method is used to model the relationship between the strain information and the risk of revision. Therefore, the risk of UKA revision can be predicted by this integrated model. RESULTS: Leave-one-out (LOO) cross-validation (CV) is implemented to assess the prediction accuracy. As a result, the mean prediction accuracy is 93.58% for all these cases, demonstrating the high value of this model as a decision-making assistant for surgical plaining of knee OA. CONCLUSIONS: The results of this study demonstrated that this integrated model can predict the risk of UKA revision with theoretically high accuracy. It combines bio-mechanical and statistical learning approach to create a surgical planning tool which may support clinical decision in the future.

Effects of a One-Year Physical Activity Program on Serum C-Terminal Agrin Fragment (CAF) Concentrations among Mobility-Limited Older Adults.

OBJECTIVES: C-terminal Agrin Fragment (CAF) has been proposed as a potential circulating biomarker for predicting changes in physical function among older adults. To determine the effect of a one-year PA intervention on changes in CAF concentrations and to evaluate baseline and longitudinal associations between CAF concentrations and indices of physical function. DESIGN: Ancillary study to the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P), a multi-site randomized clinical trial designed to evaluate the effects of chronic exercise on the physical function of older adults at risk for mobility disability. SETTING: Four academic research centers within the U.S. PARTICIPANTS: Three hundred thirty three older adults aged 70 to 89 with mild to moderate impairments in physical function. INTERVENTION: A 12-month intervention of either structured physical activity (PA) or health education promoting successful aging (SA). MEASUREMENTS: Serum CAF concentrations and objectives measures of physical function - i.e. gait speed and performance on the Short Physical Performance Battery (SPPB). RESULTS: The group*time interaction was not significant for serum CAF concentrations (p=0.265), indicating that the PA intervention did not significantly reduce serum CAF levels compared to SA. Baseline gait speed was significantly correlated with baseline CAF level (r = -0.151, p= 0.006), however the association between CAF and SPPB was not significant. Additionally, neither baseline nor the change in CAF concentrations strongly predicted the change in either performance measure following the PA intervention. CONCLUSION: In summary, the present study shows that a one-year structured PA program did not reduce serum CAF levels among mobility-limited older adults. However, further study is needed to definitively determine the utility of CAF as a biomarker of physical function.

The association between vitamin K status and knee osteoarthritis features in older adults: the Health, Aging and Body Composition Study.

BACKGROUND: Vitamin K-dependent (VKD) proteins, including the mineralization inhibitor matrix-gla protein (MGP), are found in joint tissues including cartilage and bone. Previous studies suggest low vitamin K status is associated with higher osteoarthritis (OA) prevalence and incidence. OBJECTIVE: To clarify what joint tissues vitamin K is relevant to in OA, we investigated the cross-sectional and longitudinal association between vitamin K status and knee OA structural features measured using magnetic resonance imaging (MRI). METHODS: Plasma phylloquinone (PK, vitamin K1) and dephosphorylated-uncarboxylated MGP ((dp)ucMGP) were measured in 791 older community-dwelling adults who had bilateral knee MRIs (mean ± SD age = 74 ± 3 y; 67% female). The adjusted odds ratios (and 95% confidence intervals) [OR (95%CI)] for presence and progression of knee OA features according to vitamin K status were calculated using marginal models with generalized estimating equations (GEEs), adjusted for age, sex, body mass index (BMI), triglycerides and other pertinent confounders. RESULTS: Longitudinally, participants with very low plasma PK (<0.2 nM) were more likely to have articular cartilage and meniscus damage progression after 3 years [OR (95% CIs): 1.7(1.0-3.0), 2.6(1.3-5.2) respectively] compared to sufficient PK (≥ 1.0 nM). Higher plasma (dp)ucMGP (reflective of lower vitamin K status) was associated with higher odds of meniscus damage, osteophytes, bone marrow lesions, and subarticular cysts cross-sectionally [ORs (95% CIs) comparing highest to lowest quartile: 1.6(1.1-2.3); 1.7(1.1-2.5); 1.9(1.3-2.8); 1.5(1.0-2.1), respectively]. CONCLUSION: Community-dwelling men and women with very low plasma PK were more likely to have progression of articular cartilage and meniscus damage. Plasma (dp)ucMGP was associated with presence of knee OA features but not progression. Future studies are needed to clarify mechanisms underlying vitamin Ks role in OA.

Signal peptide peptidase-mediated nuclear localization of heme oxygenase-1 promotes cancer cell proliferation and invasion independent of its enzymatic activity.

Heme oxygenase-1 (HO-1) is a heme-degrading enzyme anchored in the endoplasmic reticulum by a carboxyl-terminal transmembrane segment (TMS). HO-1 is highly expressed in various cancers and its nuclear localization is associated with the progression of some cancers. Nevertheless, the mechanism underlying HO-1 nuclear translocation and its pathological significance remain elusive. Here we show that the signal peptide peptidase (SPP) catalyzes the intramembrane cleavage of HO-1. Coexpression of HO-1 with wild-type SPP, but not a dominant-negative SPP, promoted the nuclear localization of HO-1 in cells. Mass spectrometry analysis of cytosolic HO-1 isolated from HeLa cells overexpressing HO-1 and SPP revealed two adjacent intramembrane cleavage sites located after S275 and F276 within the TMS. Mutations of S275F276 to A275L276 significantly hindered SPP-mediated HO-1 cleavage and nuclear localization. Nuclear HO-1 was detected in A549 and DU145 cancer cell lines expressing high levels of endogenous HO-1 and SPP. SPP knockdown or inhibition significantly reduced nuclear HO-1 localization in A549 and DU145 cells. The positive nuclear HO-1 stain was also evident in lung cancer tissues expressing high levels of HO-1 and SPP. Overexpression of a truncated HO-1 (t-HO-1) lacking the TMS in HeLa and H1299 cells promoted cell proliferation and migration/invasion. The effect of t-HO-1 was not affected by a mutation in the catalytic site. However, blockade of t-HO-1 nuclear localization abolished t-HO-1-mediated effect. The tumorigenic effect of t-HO-1 was also demonstrated in the mouse model. These findings disclose that SPP-mediated intramembrane cleavage of HO-1 promotes HO-1 nuclear localization and cancer progression independent of HO-1 enzymatic activity.

The impact of sarcopenia on a physical activity intervention: the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P).

OBJECTIVE: To determine if sarcopenia modulates the response to a physical activity intervention in functionally limited older adults. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Three academic centers. PARTICIPANTS: Elders aged 70 to 89 years at risk for mobility disability who underwent dual-energy x-ray absorptiometry (DXA) for body composition at enrollment and follow-up at twelve months (N = 177). INTERVENTION: Subjects participated in a physical activity program (PA) featuring aerobic, strength, balance, and flexibility training, or a successful aging (SA) educational program about healthy aging. MEASUREMENTS: Sarcopenia as determined by measuring appendicular lean mass and adjusting for height and total body fat mass (residuals method), Short Physical Performance Battery score (SPPB), and gait speed determined on 400 meter course. RESULTS: At twelve months, sarcopenic and non-sarcopenic subjects in PA tended to have higher mean SPPB scores (8.7±0.5 and 8.7±0.2 points) compared to sarcopenic and non-sarcopenic subjects in SA (8.3±0.5 and 8.4±0.2 points, p = 0.24 and 0.10), although the differences were not statistically significant. At twelve months, faster mean gait speeds were observed in PA: 0.93±0.4 and 0.95±0.03 meters/second in sarcopenic and non-sarcopenic PA subjects, and 0.89±0.4 and 0.91±0.03 meters/second in sarcopenic and non-sarcopenic SA subjects (p = 0.98 and 0.26), although not statistically significant. There was no difference between the sarcopenic and non-sarcopenic groups in intervention adherence or number of adverse events. CONCLUSION: These data suggest that older adults with sarcopenia, who represent a vulnerable segment of the elder population, are capable of improvements in physical performance after a physical activity intervention.