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Background: Accurately identifying cognitive changes in Mexican American (MA) adults using the Mini-Mental State Examination (MMSE) requires knowledge of population-based norms for the MMSE, a scale which has widespread use in research settings. Objective: To describe the distribution of MMSE scores in a large cohort of MA adults, assess the impact of MMSE requirements on their clinical trial eligibility, and explore which factors are most strongly associated with their MMSE scores. Methods: Visits between 2004–2021 in the Cameron County Hispanic Cohort were analyzed. Eligible participants were ≥18 years old and of Mexican descent. MMSE distributions before and after stratification by age and years of education (YOE) were assessed, as was the proportion of trial-aged (50–85– year-old) participants with MMSE

Prenatal alcohol exposure (PAE) has been shown to alter fetal blood flow in utero and is also associated with placental insufficiency and intrauterine growth restriction (IUGR), suggesting an underlying connection between perturbed circulation and pregnancy outcomes.Timed-pregnant C57/BL6NHsd mice, bred in-house, were exposed by gavage on gestational day 10 (GD10) to ethanol (3 g/kg) or purified water, as a control. Pulse-wave Doppler ultrasound measurements for umbilical arteries and ascending aorta were obtained post-gavage (GD12, GD14, GD18) on 2 fetuses/litter. RNA from the non-decidual (labyrinthine and junctional zone) portion of placentas was isolated and processed for RNA-seq and subsequent bioinformatic analyses, and the association between transcriptomic changes and fetal phenotypes assessed.Exposure to ethanol in pregnant mice on GD10 attenuates umbilical cord blood flow transiently during gestation, and is associated with indices of IUGR, specifically decreased fetal weight and morphometric indices of cranial growth. Moreover, RNA-seq of the fetal portion of the placenta demonstrated that this single exposure has lasting transcriptomic changes, including upregulation of Tet3, which is associated with spontaneous abortion. Weighted gene co-expression network analysis (WGCNA) identified erythrocyte differentiation and homeostasis as important pathways associated with improved umbilical cord blood flow as gestation progresses. WGCNA also identified sensory perception of chemical stimulus/odorant and receptor activity as important pathways associated with cranial growth.Our data suggest that PAE perturbs the expression of placental genes relevant for placental hematopoiesis and environmental sensing, resulting in transient impairment of umbilical cord blood flow and, subsequently, IUGR.

Many studies report an overlap of MRI and clinical findings between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), which in part is reflective of inclusion of subjects with variable disease duration and short periods of follow-up. To overcome these limitations, we examined the differences between RRMS and SPMS and the relationship between MRI measures and clinical outcomes 30 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis. Sixty-three patients were studied 30 years after their initial presentation with a clinically isolated syndrome; only 14% received a disease modifying treatment at any time point. Twenty-seven patients developed RRMS, 15 SPMS and 21 experienced no further neurological events; these groups were comparable in terms of age and disease duration. Clinical assessment included the Expanded Disability Status Scale, 9-Hole Peg Test and Timed 25-Foot Walk and the Brief International Cognitive Assessment For Multiple Sclerosis. All subjects underwent a comprehensive MRI protocol at 3 T measuring brain white and grey matter (lesions, volumes and magnetization transfer ratio) and cervical cord involvement. Linear regression models were used to estimate age- and gender-adjusted group differences between clinical phenotypes after 30 years, and stepwise selection to determine associations between a large sets of MRI predictor variables and physical and cognitive outcome measures. At the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS. Across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the Expanded Disability Status Scale; cortical lesions alone explained 43%. Grey matter volume, cortical lesions and gender explained 43% of the variance of Timed 25-Foot Walk. Reduced cortical magnetization transfer ratios emerged as the only significant explanatory variable for the symbol digit modality test and explained 52% of its variance. Cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogeneous disease duration, indicating that this should be the target of therapeutic interventions., Haider et al. followed a cohort of individuals for 30 years after their initial presentation with symptoms suggestive of multiple sclerosis. Cortical involvement was the main correlate of progressive disease and disability and therefore might provide a promising diagnostic and therapeutic target.

The total economic burden of cancer reflects direct and indirect costs, including productivity loss due to employment change, absenteeism, and presenteeism of patients and caregivers.This study estimated the magnitude of employment decrease, work absence (WA), short-term disability (STD), long-term disability (LTD), and associated indirect costs among employees newly diagnosed with metastatic versus non-metastatic cancer in the USA.IBMDuring the first year after diagnosis, compared to patients without metastases, significantly higher proportions of patients with metastases had employment decrease and STD or LTD claims (p0.001). The mean total number of days missing from work for patients with versus without metastases was 33.39 versus 14.91 (ratio = 2.40), 64.05 versus 27.15 (ratio = 2.36), and 105.93 versus 46.29 (ratio = 2.29) days within 3, 6, and 12 months after diagnosis, respectively. Estimates of indirect cost differences between the two groups ranged from $6,877 to $22,283 in the first year.Earlier detection of cancer may reduce productivity loss of patients and indirect costs by initiating treatment before cancer progresses to late stage.

Background We determined whether in vitro potency assays inform which placental mesenchymal stromal cell (PMSC) lines produce high rates of ambulation following in utero treatment of myelomeningocele in an ovine model. Methods PMSC lines were created following explant culture of three early-gestation human placentas. In vitro neuroprotection was assessed with a neuronal apoptosis model. In vivo, myelomeningocele defects were created in 28 fetuses and repaired with PMSCs at 3 × 105 cells/cm2 of scaffold from Line A (n = 6), Line B (n = 7) and Line C (n = 5) and compared to no PMSCs (n = 10). Ambulation was scored as ≥ 13 on the Sheep Locomotor Rating Scale. Results In vitro, Line A and B had higher neuroprotective capability than no PMSCs (1.7 and 1.8 respectively vs 1, p = 0.02, ANOVA). In vivo, Line A and B had higher large neuron densities than no PMSCs (25.2 and 27.9 respectively vs 4.8, p = 0.03, ANOVA). Line C did not have higher neuroprotection or larger neuron density than no PMSCs. In vivo, Line A and B had ambulation rates of 83% and 71%, respectively, compared to 60% with Line C and 20% with no PMSCs. Conclusion The in vitro neuroprotection assay will facilitate selection of optimal PMSC lines for clinical use. Level of evidence n/a. Type of study Basic science.

Misfolding and fibrillar aggregation of Aβ is a characteristic hallmark of Alzheimer's disease and primarily participates in neurodegenerative pathologies. There has been no breakthrough made in the therapeutic regime of Alzheimer's disease while the pharmacological interventions against Aβ are designed to sequester and clear Aβ burden from the neurological tissues. Based on the physiological relevance of Aβ, therapeutic approaches are required to inhibit and stabilize Aβ fibrillization, instead of cleaning it from the neurological system. In this context, we have designed a selenadiazole-based library of compounds against the fibrillization paradigm of Aβ. Compounds that completely inhibited the Aβ fibrillization appeared to stabilize Aβ at the monomeric stage as indicated by ThT assay, CD spectrophotometry, and TEM imaging. Partial inhibitors elongated the nucleation phase and allowed limited fibrillization of Aβ into smaller fragments with slightly higher β-sheets contents, while noninhibitors did not interfere in Aβ aggregation and resulted in mature fibrils with fibrillization kinetics similar to Aβ control. Molecular docking revealed the different binding positions of the compounds for three classes. Complete inhibitors alleviated Aβ toxicity to SH-SY5Y neuroblastoma cells and permeated across the blood-brain barrier in zebrafish larvae. The amino acid residues from Aβ peptide that interacted with the compounds from all three classes were overlapping and majorly lying in the amyloidogenic regions. However, compounds that stabilize Aβ monomers displayed higher association constants (Ka) and lower dissociation constants (Kd) in comparison to partial and noninhibitors, as corroborated by ITC. These results support further structure activity-based preclinical development of these selenadiazole compounds for potential anti-Alzheimer's therapy.

Although health care providers are required to sustain care in difficult circumstances, some patients challenge this principle. Evoking compassion seems likely to be helpful in such situations. This research aimed to evaluate whether inducing compassion in health care providers might mitigate disengagement with patients who have challenging presenting features such as those with disgusting symptoms and/or are to blame for their own health problems.An online experimental study with clinical health care providers.Medical students (n = 219) and qualified health care professionals (n = 108) took part in an online experiment. Participants were randomized to view a slideshow of either neutral images (control) or compassion-inducing images (compassion condition) and were then presented with a series of patient vignettes where presenting problems systematically varied on patient responsibility and disgusting symptoms. Engagement was assessed by asking participants how caring they felt, how much they would want to help, how challenging it would be, and whether they would wear a mask.Participants reported less engagement with patients who were responsible for their illness and who presented with disgusting symptoms. Induced compassion offset disengagement and qualified health professionals were more caring and willing to help patients than medical students. The compassion induction eliminated some differences between experienced and trainee clinicians.This research demonstrates that disgust and patient responsibility impacts clinical engagement and that medical students are more impacted by such scenarios than qualified health providers. Inducing compassion may help to mitigate these differences, and further investigation into strategies that foster engagement with difficult patients is warranted. Statement of contribution What is already known on the subject? Health care providers are required to sustain care across all patients; however, some patients are more difficult to engage with than others. Clinical engagement appears to be impacted when patients present with disgusting symptoms and/or are to blame for their own health problems. What does this study add? This work reports on a vignette-based study that shows that disgusting symptoms and patient responsibility impact self-reported measures of clinical engagement in response to patient scenarios. Qualified health care providers are less likely to disengage in these situations than medical students. A very brief online induction of compassion has potential to mitigate differences between trained professionals and students.

Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple sclerosis (MS) patients. Methods: Litak® was offered to MS-patients irrespective of disease course. Litak® 10 mg was administered for 3–4 days during week 1. Based on lymphocyte count at week 4, patients received another 0–3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts. Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17–72) years and EDSS 0–8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data ( n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data ( n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months. Conclusions: Litak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.

In women with very active multiple sclerosis (MS), natalizumab can be continued during pregnancy to prevent rebound disease activity. Our aim was to evaluate changes in serum natalizumab trough concentrations during pregnancy. Blood samples of 3 patients were collected before, during, and after pregnancy. Natalizumab trough concentrations gradually decreased during pregnancy. The patient with the lowest trough concentrations during the third trimester was treated with extended interval dosing (EID). After delivery, natalizumab concentrations increased to similar levels as before pregnancy. All patients remained clinically and radiologically stable. MS neurologists should be aware of decreasing natalizumab concentrations during pregnancy, especially in patients with low initial trough concentrations and patients with EID.

Pulmonary thromboembolic events cause significant morbidity and mortality after severe trauma. Clinically, these lesions are believed to be emboli arising secondary to deep venous thrombosis (DVT) in the lower extremities. Recently, this notion has been challenged by clinical studies, showing that pulmonary clots arise after trauma in the absence of DVT. This suggests that pulmonary blood clots arise in situ via de novo thrombosis. In the present study, we characterize a murine weight-drop model of lateral blunt thoracic trauma. Our model demonstrates severe unilateral lung contusion injury with low (10%) mortality in the absence of extrapulmonary injury, after impact with a 50-g weight dropped from 45 cm height (657 J/m). At 24 h after injury, immunofluorescence and histological evidence revealed early pulmonary arterial thrombosis in the form of eccentric accumulation of fibrin and CD41 positive eosinophilic proteinaceous material, on both coup and contrecoup lung lobes of injured mice, indicating early thrombotic events both within and outside of the area of primary lung injury. Our model is ideal in that lateral impact enables greater impact energy to be applied to achieve significant lung contusion without significant mortality or extrapulmonary injury, and the model has additional translational value in creating thrombosis analogous to pulmonary embolism observed clinically after blunt thoracic trauma. To our knowledge, this is the first demonstration of de novo pulmonary thrombosis in a clinically translational model of blunt thoracic trauma, and supports challenges to current assumptions about the origin of pulmonary blood clots in the wake of severe traumatic injury.

Purpose The purpose of this study is to determine the feasibility of fetal surgical repair of myelomeningocele (MMC) in a rodent model using human placental mesenchymal stromal cells (PMSCs) seeded onto extracellular matrix (ECM) and to characterize the resulting changes in spinal cord tissue. Methods Fetal rodents with retinoic acid (RA) induced MMC underwent surgical repair of the MMC defect using an ECM patch on embryonic age (EA) 19 and were collected via caesarean section on EA 21. Various seeding densities of PMSC-ECM and ECM only controls were evaluated. Cross-sectional compression (width/height) and apoptotic cell density of the lumbosacral spinal cord were analyzed. Results 67 dams treated with 40mg/kg of RA resulted in 352 pups with MMC defects. 121 pups underwent MMC repair, and 105 (86.8%) survived to term. Unrepaired MMC pups had significantly greater cord compression and apoptotic cell density compared to normal non-MMC pups. Pups treated with PMSC-ECM had significantly less cord compression and demonstrated a trend towards decreased apoptotic cell density compared to pups treated with ECM only. Conclusion Surgical repair of MMC with a PMSC-seeded ECM disc is feasible with a postoperative survival rate of 86.8%. Fetal rodents repaired with PMSC-ECM have significantly less cord deformity and decreased histological evidence of apoptosis compared to ECM only controls.

3070 Background: A multi-cancer early detection (MCED) test that uses targeted methylation-based cfDNA technology to detect cancer and predict cancer signal origin (CSO) has potential to efficiently identify malignancies for which effective screening modalities do not exist. A previous version of a blood-based MCED test demonstrated favorable classification and test characteristics. Samples from the ongoing PATHFINDER study were reanalyzed in a prespecified interim analysis to evaluate performance of a more recent version of the test with an updated classifier (eg, updated CSO localization, hematological signal threshold) that is planned for clinical implementation as a general multi-cancer screening tool. Methods: PATHFINDER (NCT04241796) is an interventional, prospective study in which results (cancer signal detected/not detected and predicted CSO) using a previous version of the MCED test are returned to investigators, and those with a signal detected undergo further diagnostic testing. In this prespecified interim analysis, samples from those enrolled as of October 6, 2020 were reanalyzed with the more recent version of the MCED test (these results were not returned to investigators). The positive predictive value (PPV) for cancer detection, overall CSO accuracy, and concordance between the two test versions were assessed. Results: A total of 4011/4047 (99%) participants (pts) were analyzable (mean [SD] age 63.9 [8.7] years, 62% female, 92% white, 24% with prior cancer history, 39% ever smoker [4% current], 6% with genetic cancer predisposition). Cancer signal was detected in 0.95% (38/4011). A total of 27/38 also had signal detected by the previous version of the MCED test, including 19 who reached diagnostic resolution (13 with cancer diagnosis and 6 without); 11/38 were discordant positives. Nine different cancer types were detected in the 13 pts (2 stage I, 3 stage II, 2 stage III, and 3 stage IV); 1 had no AJCC stage expected, 1 metastatic recurrence and 1 stage evaluation underway. A conservative minimal PPV assuming all discordant positives are false positives, was 43.3% (13/30, 95% CI 27.4-60.8%) based on 19 pts with diagnostic resolution and 11 discordant positives. High negative percent agreement (PA) 99.7% (99.5-99.8%) between the two test versions was observed. Positive PA of 43.5% (95% CI, 31.9-55.9%) was consistent with the more stringent threshold for hematologic signal in the recent MCED version, as most discrepant cases had hematologic CSO with the previous MCED test. Among 13 detected cancers, accuracy of the top CSO prediction was 92.3% (12/13, 95% CI 66.7-99.6%). Conclusions: In this prespecified interim analysis, the more recent version of the MCED test detected cancers with high PPV and high accuracy of CSO prediction, supporting readiness for use in clinical practice. Full enrollment cohort data will be available at the meeting. Clinical trial information: NCT04241796.

10550 Background: The COVID-19 pandemic imposes significant impact on daily activities with regard to public health orders and individual responses to the pandemic. Much of the direct or indirect impact is potentially in reductions in healthcare encounters for services such as preventive care. Here, we quantified changes in cancer screening rates to better understand the impact of the evolving COVID-19 implications and shifts in health-seeking behaviors. Methods: We conducted a retrospective analysis of cancer screening rates during March-June 2019 (pre-COVID-19) and March-June 2020 (post-COVID-19 restrictions), using Optum’s de-identified Clinformatics Data Mart Database which includes Medicare and commercially insured members. Members meeting age and/or sex criteria as detailed in the United States Preventive Services Task Force recommendations for breast, colorectal, lung, prostate, and cervical cancer screening represented the eligible membership for screening. Procedure and laboratory services were used to identify those who received cancer screening. Analyses were conducted cross-sectionally by cancer screening type. Results: Eligible cohorts were identified from insured members within March-June 2019 and 2020 (2019: 17,931,318; 2020: 17,521,411). The percent of eligible members screened in March-June 2019 was 19.3%, 9.4%, 16.7%, 0.4%, and 7.8% for breast, cervical, prostate, lung, and colorectal cancer, respectively. Changes in screening rates from 2019 to 2020 are summarized in Table, with the sharpest decline in April. The percent change from 2019 to 2020 during the combined March-June period for each cancer screening type was statistically significant (p

3010 Background: PATHFINDER (NCT04241796) is an interventional, prospective study evaluating implementation of a blood-based multi-cancer early detection (MCED) test that uses targeted methylation-based cfDNA analysis to detect multiple cancer types and simultaneously predict cancer signal origin (CSO). We present a prespecified interim analysis of PATHFINDER evaluating an MCED test in a clinical setting. Methods: Participants (pts; ≥50y) were enrolled into 2 risk cohorts: non-elevated and elevated (smoking history, prior cancer [ > 3y post treatment], or genetic predisposition). MCED test results (cancer signal detected/not detected) were returned to investigators; pts with a signal detected also received a CSO prediction and underwent further diagnostic testing by their medical team. The primary objective was to assess the extent of diagnostic testing needed to achieve diagnostic resolution (eg, time to resolution, number/type of tests). Secondary endpoints included positive predictive value (PPV) and a measure of test satisfaction (following diagnostic resolution [signal detected] and post test [signal not detected]). Results: PATHFINDER consented 6796 pts before closing accrual on 12/4/20; as of October 6, 2020, 4086 consented, 4047 enrolled, and 4033 analyzable pts were included in the interim analysis (62.4% female, 92.1% white). Two study-related adverse events (anxiety of mild severity) were reported. Cancer signal was detected in 1.5% (62/4033) of pts; 40/62 reached diagnostic resolution to date. Kaplan-Meier estimate of median time to resolution was 78 (95% CI, 54-151) days. Among 40 pts that reached diagnostic resolution, ≥1 imaging test was performed in 93% (37/40); ≥1 invasive procedure was performed in 72% (13/18) versus 18% (4/22) of pts with diagnostic resolution of cancer versus no cancer, respectively. Based on results to date, PPV was 45% (95% CI, 30.7-60.2%; 18/40). Of 18 cancer diagnoses, 11 were solid tumors (3 stage IV, 6 stages I-III, 1 metastatic recurrence, 1 missing stage), and 7 were hematologic malignancies (1 stage IV, 4 stages I-III, 2 without AJCC stage). Accuracy of the top CSO prediction in true positives was 82.4% (95% CI, 59.0-93.8%; 14/17). Most pts were satisfied with the test (43.7% extremely satisfied, 30.7% very satisfied, 14.6% satisfied). Signal detection rate and test satisfaction were similar in the 2 risk cohorts; PPV tended to be higher in the elevated risk cohort, as expected. Conclusions: An interim analysis of this return of results study demonstrated promising MCED test results. Of 40 pts achieving diagnostic resolution, nearly half had a diagnostic workup confirming cancer; CSO was predicted with high accuracy for detected cancers. Taken together with the rarity of adverse events and high test satisfaction, these results support the feasibility of clinical implementation. Full enrollment cohort data will be available at the meeting. Clinical trial information: NCT04241796.

Background The Berlin definition of Acute Respiratory Distress Syndrome (ARDS) has been applied to military burns resulting from combat-related trauma, but has not been widely studied among civilian burns. This study's purpose was to use the Berlin definition to determine the incidence of ARDS, and its associated respiratory morbidity, and mortality among civilian burn patients. Methods Retrospective study of burn patients mechanically ventilated for ≥48 h at an American Burn Association-verified burn center. The Berlin criteria identified patients with mild, moderate, and severe ARDS. Logistic regression was used to identify variables predictive of moderate to severe ARDS, and mortality. The outcome measures of interest were duration of mechanical ventilation and in-hospital mortality. Values are shown as the median (Q1–Q3). Results We included 162 subjects [24% female, age 48 (35–60), % total body surface area (TBSA) burn 28 (19–40), % body surface area (BSA) full thickness (FT) burn 13 (0–30), and 62% with inhalation injury]. The incidence of ARDS was 43%. Patients with ARDS had larger %TBSA burns [30.5 (23.1–47.0) vs. 24.8 (17.1–35), p = 0.007], larger FT burns [20.5(5.4–35.5) vs. 7 (0–22.1), p = 0.001], but had no significant difference in the incidence of inhalation injury (p = 0.216), compared to those without ARDS. The % FT burn predicted the development of moderate to severe ARDS [OR 1.034, 95%CI (1.013–1.055), p = 0.001]. ARDS developed in the 1st week after burn in 86% of cases. Worsening severity of ARDS was associated with increased days of mechanical ventilation in survivors (p = 0.001), a reduction in ventilator-free days/1st 30 days in all subjects (p = 0.004), and a strong indication of increased mortality (0% in mild ARDS vs. 50% in severe ARDS, unadjusted p = 0.02). Neither moderate ARDS nor severe ARDS were significant predictors of death. Conclusions ARDS is common among mechanically ventilated civilian burn patients, and develops early after burn. The extent of full thickness burn predicted development of moderate to severe ARDS. Increasing severity of ARDS based upon the Berlin definition was associated with a significantly greater duration of mechanical ventilation and a trend toward higher mortality.

Purpose The purpose of this study was to determine whether seeding density of placental mesenchymal stromal cells (PMSCs) on extracellular matrix (ECM) during in utero repair of myelomeningocele (MMC) affects motor function and neuronal preservation in the ovine model. Methods MMC defects were surgically created in 33 fetuses and repaired following randomization into four treatment groups: ECM only (n = 10), PMSC-ECM (42 K cells/cm2) (n = 8), PMSC-ECM (167 K cells/cm2) (n = 7), or PMSC-ECM (250–300 K cells/cm2) (n = 8). Motor function was evaluated using the Sheep Locomotor Rating Scale (SLR). Serial sections of the lumbar spinal cord were analyzed by measuring their cross-sectional areas which were then normalized to normal lambs. Large neurons (LN, diameter 30–70 μm) were counted manually and density calculated per mm2 gray matter. Results Lambs treated with PMSCs at any density had a higher median SLR score (15 [IQR 13.5–15]) than ECM alone (6.5 [IQR 4–12.75], p = 0.036). Cross-sectional areas of spinal cord and gray matter were highest in the PMSC-ECM (167 K/cm2) group (p = 0.002 and 0.006, respectively). LN density was highest in the greatest density PMSC-ECM (250–300 K/cm2) group (p = 0.045) which positively correlated with SLR score (r = 0.807, p Conclusions Fetal repair of myelomeningocele with high density PMSC-ECM resulted in increased large neuron density, which strongly correlated with improved motor function. Type of study Basic science. Level of evidence N/A

The management of rectal cancer with lateral lymph node involvement is distinctly different between Japan and Western countries. In Japan, total mesorectal excision (TME) surgery followed by autonomic nerve-preserving lateral pelvic lymph node dissection (LPND) is the standard surgical treatment, whereas in Western countries, patients are subjected to neoadjuvant cheomoradiotherapy followed by TME surgery. The present study aims to explore the current practice and role of LPND in rectal cancer.

Guidelines for preventing and treating patients with coronary artery disease have traditionally focused on reducing low-density lipoprotein cholesterol (LDL-C). Current treatments are effective; however, previous studies have identified a significant proportion of patients that are not achieving the recommended lipid levels. New guidelines were introduced November 2013. The objective of this study was to examine recent practice patterns and factors related to initiating treatment for hypercholesterolemia, which provides a comparative baseline to the introduction of new guidelines.We conducted a retrospective cohort analysis utilizing laboratory results of lipid profiles and medical claims from January 2007 to September 2011 to identify patients with elevated LDL-C and diagnoses of hypercholesterolemia without prior pharmacotherapy. Pharmacotherapy dispensed, treatment modifications, LDL-C-goal attainment, and potential drug intolerance were evaluated.Overall, among newly treated patients, 70.9% achieved the recommended LDL-C level within the first year of treatment; however, only 19.4% of those with coronary heart disease (CHD) or CHD risk equivalents achieved the more aggressive LDL-C goal of70 mg/dL (1.8 mmol/L). LDL-C goals were generally achieved with the use of statins; however, a majority of patients underwent treatment modification(s) (e.g., discontinuation or restart). More than half of the patients diagnosed with elevated LDL-C did not initiate pharmacotherapy.Data was unavailable for inpatient hospitalizations, family history of cardiovascular diseases, body weight, and height, and likely under-reporting of smoking within claims data.Newly treated patients with elevated LDL-C results generally achieved the recommended and risk-specific LDL-C goal with the use of lipid-altering drugs; however, there still exists a notable population of patients with CHD or CHD risk equivalents who were not treated to goal and a significant number of patients who do not receive lipid-lowering pharmacotherapy. New therapies and prescribing practices are warranted to adequately address these two patient populations.

BackgroundAfrican-born individuals in the U.S. are disproportionately affected by HIV yet have low HIV testing rates. We conducted a mixed methods study to assess the uptake and feasibility of a novel strategy for integrating HIV testing into residential health fairs among African-born individuals in Seattle, WA.MethodsFrom April to May 2018, we held six health fairs at three apartment complexes with high numbers of African-born residents. Fairs included free point-of-care screening for glucose, cholesterol, body mass index, blood pressure, and HIV, as well as social services and health education. The health fairs were hosted in apartment complex common areas with HIV testing conducted in private rooms. Health fair participants completed a series of questionnaires to evaluate demographics, access to health services, and HIV testing history. We conducted 18 key informant interviews (KIIs) with health fair participants and community leaders to identify barriers to HIV testing among African-born individuals.ResultsOf the 111 adults who accessed at least one service at a health fair, 92 completed questionnaires. Fifty-five (61%) were female, 48 (52%) were born in Africa, and 55 (63%) had health insurance. Half of African-born participants accepted HIV testing; all tested negative. The most common reasons for declining testing were lack of perceived risk for HIV and knowledge of HIV status. We identified a high prevalence of non-communicable diseases (NCDs) among health fair participants; among those tested, 77% (55/71) were overweight/obese, 39% (31/79) had blood pressure > 140/90 mmHg, and 30% (22/73) had total cholesterol > 200 mg/dL. KIIs identified community stigma and misinformation as major barriers to HIV testing among African-born individuals.ConclusionsResidential health fairs are a feasible method to increase HIV testing among African-born individuals in Seattle. The high prevalence of NCDs highlights the importance of integrating general preventive services within HIV testing programs in this population.

Patients with bone metastases secondary to breast cancer are pre-disposed to skeletal-related events (SREs), including spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (SB), and radiotherapy to bone (RT).To document current patterns of healthcare utilization and costs of SREs in patients with breast cancer and bone metastases.This was a retrospective, observational study using the Thomson MedStat MarketScan Commercial Claims and Encounters database from 9/2002 to 6/2011. Study subjects included all persons with claims for breast cancer and for bone metastases, and ≥1 claims for an SRE. Unique SRE episodes were identified based on a gap of at least 90 days without an SRE claim, and classified by treatment setting (inpatient or outpatient) and SRE type (SCC, PF, SB, or RT).Of 17,266 patients with breast cancer and bone metastases, 9142 (53%) had one or more SRE episodes. Among 5809 patients who met all other criteria, there were 7617 SRE episodes over mean (SD) follow-up of 17.2 (15.2) months. The percentage of episodes that required inpatient treatment ranged from 11% (RT) to 76% (SB). On average, inpatient SCC episodes (n=83 episodes) were most costly; while outpatient PF episodes (n=552 episodes) were least costly. Of the total SRE costs (mean [SE] $21,072 [$36,462]/episode), 36% were attributable to outpatient RT (n=5265 episodes) and 31% to inpatient PF (n=838 episodes).The administrative claims data used in this study may lack sensitivity and specificity for identification of clinical events and may not be generalizable to other populations. Also, for some SRE episode categories, the number of events was small and cost estimates may lack precision.In patients with breast cancer and bone metastases, SREs are associated with high costs and hospitalizations.

Cardiovascular disease (CVD) results in half of the non-communicable disease-related deaths worldwide. Rising treatment costs have increased the need for cost-utility models designed to compare the value of new and existing therapies. Cost-utility models require utilities, values representing the strength of preferences for various health states. This systematic literature review aimed to identify and evaluate utilities reported for stroke, myocardial infarction (MI) and angina. In total, 83 unique studies were identified that reported utilities for these events. Approximately two-thirds reported utility values for stroke, and most used the EuroQoL five dimension to derive utilities. Utility values were lower in patients who experienced cardiovascular (CV) events than in patients who did not. The utility estimates for each condition varied greatly, likely due to differences in assessment methodologies and patient populations. This variability must be considered when choosing values for cost-utility models. Comparisons among reported utilities are further complicated by inconsistent CV event definitions.

This analysis evaluated patient-reported outcomes and analgesic use in patients with bone metastases from solid tumours across three comparative studies of denosumab and zoledronic acid.Pooled data were analysed from three identically designed double-blind phase III studies comparing subcutaneous denosumab 120 mg with intravenous zoledronic acid 4 mg monthly in patients with bone metastases from breast cancer (n = 2,046), castration-resistant prostate cancer (n = 1,901) or other solid tumours (n = 1,597). Pain severity, pain interference, health-related quality of life and analgesic use were quantified.At baseline, approximately half of patients had no/mild pain (53 % [1,386/2,620] denosumab; 50 % [1,297/2,578] zoledronic acid). Denosumab delayed onset of moderate/severe pain by 1.8 months (median, 6.5 vs 4.7 months; hazard ratio, 0.83; 95 % CI, 0.76-0.92; p 0.001; 17 % risk reduction) and clinically meaningful increases in overall pain interference by 2.6 months (median, 10.3 vs 7.7 months; hazard ratio, 0.83; 95 % CI, 0.75-0.92; p 0.001; 17 % risk reduction) compared with zoledronic acid. Strong opioid use and worsening of health-related quality of life were less common with denosumab.Across three large studies of patients with advanced solid tumours and bone metastases, denosumab prevented progression of pain severity and pain interference more effectively than zoledronic acid.

To document the risk of skeletal complications in patients with bone metastases from breast cancer (BC), lung cancer (LC), or prostate cancer (PC) in routine clinical practice. We used data from two large US health systems to identify patients aged ≥18 years with primary BC, LC, or PC and newly diagnosed bone metastases between January 1, 1995 and December 31, 2009. Beginning with the date of diagnosis of bone metastasis, we estimated the cumulative incidence of skeletal-related events (SREs) (spinal cord compression, pathologic fracture, radiation to bone, bone surgery), based on review of medical records, accounting for death as a competing risk. We identified a total of 621 BC, 477 LC, and 721 PC patients with newly diagnosed bone metastases. SREs were present at diagnosis of bone metastasis in 22.4, 22.4, and 10.0 % of BC, LC, and PC patients, respectively. Relatively few LC or PC patients received intravenous bisphosphonates (14.8 and 20.2 %, respectively); use was higher in patients with BC, however (55.8 %). In BC, cumulative incidence of SREs during follow-up was 38.7 % at 6 months, 45.4 % at 12 months, and 54.2 % at 24 months; in LC, it was 41.0, 45.4, and 47.7 %; and in PC, it was 21.5, 30.4, and 41.9 %. More than one half of patients with bone metastases had evidence of SREs (BC: 62.6 %; LC: 58.7 %; PC: 51.7 %), either at diagnosis of bone metastases or subsequently. SREs are a frequent complication in patients with solid tumors and bone metastases, and are much more common than previously recognized in women with BC.

UNLABELLED Intracranial hypertension (IH) has been associated with hypocortisolism caused by either primary adrenocortical insufficiency or corticosteroid withdrawal. METHOD The authors describe a case of IH in association with Sheehan syndrome (SS) in a postpartum 29-year-old woman. RESULTS The clinical manifestations of IH resolved with corticosteroid replacement. CONCLUSIONS This case supports a causal role of hypocortisolism in IH. The authors are unaware of previous reports of hypocortisolism caused by SS leading to IH.

Background: Bone metastases are common in women with advanced breast cancer and are frequently associated with skeletal-related events (SREs). The burden of individual SRE types on health resource utilization (HRU) indicators in breast cancer has been only minimally described. Methods: The aim of this ongoing observational, prospective, multinational study is to assess, by tumor type, the amount of HRU associated with different SRE types including pathologic fracture, surgery or radiation to bone, and spinal cord compression. Patients with breast, prostate, or lung cancer and bone metastases or multiple myeloma were enrolled after experiencing a SRE. Inpatient hospitalizations, length of stay, outpatient visits, emergency room visits, nursing home/long-term care facility stays, home health visits, procedures, and medications were collected for the period 90 days prior to enrollment and prospectively to a maximum of 18 months. Each patient could contribute multiple SREs. The investigator determined which HRU were attributed to each SRE. This abstract describes interim analysis data from the US breast cancer cohort; final analysis data will be available 9/2010. Results: As of 12/1/2009, 67 patients contributed 119 SREs for the HRU analyses across 25 US sites. Patient mean [SD] age was 61 [12] years, all patients were female, and 27% discontinued the study (most due to death). Mean duration of follow-up was 9.9 months. HRU for each of the SRE types are shown in the table. Table. Mean and median number of HRU per SRE during the study period by SRE type in patients with breast cancer Conclusion: In this interim analysis of advanced breast cancer patients in the US, SREs are associated with considerable HRU, with the nature and extent of HRU varying depending on the SRE type. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-06.

In a recently completed trial of breast cancer patients with bone metastases, denosumab, a fully human monoclonal anti-RANKL antibody, was superior to zoledronic acid (ZA) in delaying/preventing skeletal-related events. Between-treatment differences in patient-reported pain interference with daily functioning were assessed. Eligible breast cancer patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg (double-bind, double-dummy design). Patients completed the Brief Pain Inventory (BPI) to assess pain severity and interference with daily functioning (range 0 [does not interfere]-10 [interferes completely]) at baseline (BL), day 8, and before each monthly visit through end of study. The BPI interference scale generated a total interference score as well as an activity subscale (interference with walking, general activity, and work) and an affective subscale (interference with relations with others, enjoyment of life, and mood). Analyses were conducted on all randomized patients with ≥1 PRO assessment and were performed through week 73, when 30% of patients had dropped out due to death, disease progression, or consent withdrawal. Subgroups included patients with no/mild and moderate/severe worst pain at BL. Analyses included time to improvement (≥2-point decrease) or worsening (≥2-point increase) in pain interference, mean change from baseline, and proportion of patients with improving or worsening pain interference scores. Time to improvement in pain interference with activity (PIWA) tended to occur more quickly with denosumab compared with ZA (N=1124; median: 70 days denosumab v 86 days ZA; P=0.09), and time to worsening PIWA tended to be longer with denosumab compared with ZA (N=1676; median: 394 days denosumab v 310 days ZA; P=0.13). In patients with no/mild pain at BL, denosumab also demonstrated a trend for shorter time to improvement in PIWA (N=388; 93 days denosumab v 120 days ZA; P=0.06) and longer time to worsening PIWA (N=755; 369 days denosumab v 232 days ZA; P=0.12). Overall, a greater proportion of patients on denosumab had improvement in PIWA on study than ZA (Figure). Findings were similar with the total interference score and affective subscale. Figure Proportion of Patients With Improvement in Pain Interference With Activity (≥2-point decrease from BL)* Daily functioning (total interference and interference with activity and affect) tended to be less disrupted by pain in patients on denosumab compared with ZA. Decreased pain interference showed a trend to occur more quickly with denosumab. Overall, a greater proportion of denosumab patients reported decreased pain interference than ZA patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-01.

Background: Patients with breast cancer and bone metastases often experience skeletal-related events (SREs) and pain, which may impact health-related quality of life (HRQoL). Denosumab is a fully human monoclonal antibody against RANKL shown to be superior in delaying/preventing SREs and more effective in delaying moderate or severe pain in patients with advanced breast cancer compared with zoledronic acid (ZA). Previously reported results from this study population showed that both denosumab and ZA patients showed improvement or maintenance in HRQoL relative to baseline (BL), and a greater proportion of denosumab-treated patients had a clinically meaningful improvement in HRQoL. We now describe the effect of denosumab and ZA treatment on HRQoL among patients with varying degrees of pain at BL. Methods: Enrolled patients received subcutaneous (SC) denosumab 120 mg or intravenous (IV) ZA 4 mg every 4 weeks in a double-blind, double-dummy fashion. Pain was evaluated using the Brief Pain Inventory — Short Form (BPI). Patients were divided into 2 subgroups based on the level of pain reported at BL: no/mild pain or moderate/severe pain. Patients completed the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at BL, day 8, and before each monthly visit to assess overall HRQoL. Higher scores (range 0 to 108) represent better HRQoL. Improvement, maintenance, and worsening of HRQoL were assessed through month 18, when 30% of patients had dropped out due to death, disease progression, or withdrawal of consent. A change of ≥5 points (increase or decrease) in the FACT-G total score was considered a meaningful improvement. Results: Among patients who reported no/mild pain at baseline, more denosumab-treated patients had a ≥5-point increase in their FACT-G score from month 4 onwards. Over the 18 month period, an average of 4.1% more (range: −0.6% to 9.3%) denosumab-treated patients experienced meaningful improvement in HRQoL than ZA-treated patients. There were also fewer denosumab-treated patients experiencing ≥5-point decrease in HRQoL over 18 months (average of 2.4% fewer [range:-4.4% to 6.3% fewer]). Similar patterns were also noted for patients with moderate/severe pain at baseline. An average of 3.0% more (range:-1.7% to 7.9%) denosumab-treated patients had ≥5-point increase in FACT-G scores compared with ZA-treated patients over 18 months. A lower proportion of denosumab-treated patients (3.5% fewer [range: −1.1% to 11.5% fewer]) than ZA-treated patients had a decrease ≥5-points in their FACT-G score over 18 months. Conclusion: In patients with breast cancer and bone metastases, a greater proportion treated with denosumab than ZA had a meaningful improvement in HRQoL regardless of their pain level at BL. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-05.

Patients with bone metastasis secondary to prostate or breast cancer or multiple myeloma are predisposed to skeletal-related events (SREs), such as surgery or radiation to the bone, pathologic fracture, and spinal cord compression. Inpatient costs of these and other SREs represent an estimated 49%-59% of total costs related to SREs. However, information on payer costs for hospitalizations associated with SREs is limited, especially for costs associated with specific SREs by tumor type.To examine costs from a payer perspective for SRE-associated hospitalizations among patients with multiple myeloma or bone metastasis secondary to prostate or breast cancer.Patients with SRE hospitalizations were selected from the MarketScan commercial and Medicare databases (January 1, 2003, through June 30, 2009). Sampled patients had at least 2 medical claims with primary or secondary ICD-9-CM diagnosis codes for prostate cancer, breast cancer, or multiple myeloma and at least 1 subsequent hospitalization with principal diagnosis or procedure codes indicating bone surgery, pathologic fracture, or spinal cord compression. For patients with prostate cancer or breast cancer, a diagnosis code for bone metastasis was also required. If secondary diagnoses or procedure codes for SREs were present in the claim, they were used to more precisely identify the type of SRE for which the patient was treated, resulting in 3 mutually exclusive categories: spinal cord compression with or without pathologic fracture and/or surgery to the bone; pathologic fracture with or without surgery to the bone; and only surgery to the bone. Related readmissions within 30 days of a previous SRE-associated hospitalization date of discharge were excluded to minimize the risk of underestimating costs. Mean health plan payments per hospitalization, measured as net reimbursed amounts paid by the health plan to a hospital after subtracting patient copayments and deductibles, were analyzed by cancer type and type of SRE.A total of 555 patients contributed 572 hospitalizations that met the study criteria for prostate cancer, 1,413 patients contributed 1,542 hospitalizations for breast cancer, and 1,361 patients contributed 1,495 hospitalizations for multiple myeloma. The mean age range was 61 to 72 years, and the mean length of stay per admission was 5.9 to 11.6 days across the 3 tumor types. The ranges of mean health plan payment per hospital admission across tumor types were $43,691-$59,854 for spinal cord compression, with or without pathologic fracture and/or surgery to the bone; $22,390-$26,936 for pathologic fracture without spinal cord compression, with or without surgery to the bone; and $31,016-$42,094 for surgery to the bone without pathologic fracture or spinal cord compression.The inpatient costs associated with treating SREs are significant from a payer perspective. Our study used a systematic process for patient selection and mutually exclusive categorization by SRE type and provides a per episode estimate of the inpatient financial impact of cancer related SREs assessed in this study from a third-party payer perspective.

To describe the origin and development of the Division of Plastic and Reconstructive Surgery at the Queen's University School of Medicine (Kingston, Ontario).Resarch ethics board approval and privacy agreements from the Kingston General Hospital (KGH, Kingston, Ontario) medical archives were obtained. Primary and secondary data sources were identified. A systematic examination of newspaper archives, research literature, KGH medical advisory committee meeting minutes, and testimonies from Dr Kenneth Wyllie and Dr John Davidson were obtained.In 1949, Dr Albert Ross Tilley arrived at Queen's University in Kingston, Ontario. There, Tilley initiated the Burn Unit at the KGH and began monthly teaching during the academic semester. Ken Wyllie (Meds '55), Lloyd Carlson (Meds '57) and John Emery (Meds '57) were the notable progeny of his early initiatives. In 1963, Kenneth Wyllie founded the Division of Plastic and Reconstructive Surgery in Kingston, Ontario, having completed plastic surgery training in Toronto and Edinburgh with experiences in Stockholm (Sweden), Paris (France) and Baltimore (Maryland, USA). He was shortly joined by Pat Shoemaker (Meds '66). John Davidson (Meds '82) arrived in 1989, bringing an interest in microsurgery and critical inquiry to the division. Five notable surgeons, Cartotto (Meds '88), Watkins, Watters, Meathrel (Meds '03) and McKay, further enhanced the Division's clinical and academic mission.The collective activity of the Division of Plastic and Reconstructive Surgery at Queen's School of Medicine in its 66-year history has encouraged more than 40 others to pursue distinguished careers in the specialty throughout North America, including three past presidents of the Canadian Society of Plastic Surgeons.Décrire les origines et l’évolution de la division de chirurgie plastique et reconstructive de la faculté de médecine de l’université Queen’s, à Kingston, en Ontario.Les chercheurs ont obtenu l’approbation du comité d’éthique de la recherche et signé une entente de confidentialité avec les archives médicales duEn 1949, le docteur Albert Ross Tilley est arrivé à l’université Queen’s de Kingston, en Ontario. Il a créé la division des grands brûlés du KGH et s’est mis à donner des séances de formation mensuelles pendant le semestre universitaire. Ken Wyllie (promotion 1955), Lloyd Carlson (promotion 1957) et John Emery (promotion 1957) sont des émules remarquables de ces premières initiatives. En 1963, Kenneth Wyllie a fondé la division de chirurgie plastique et reconstructive à Kingston, en Ontario, après avoir acquis une formation en chirurgie plastique à Toronto et à Étdimbourg et de l’expérience à Stockholm (Suède), Paris (France) et Baltimore (Maryland, États-Unis). Il a vite été rejoint par Pat Shoemaker (promotion 1966). John Davidson (promotion 1982) est arrivé en 1989, avec un intérêt pour la microchirurgie et l’examen critique de la division. Cinq chirurgiens réputés, les docteurs Cartotto (promotion 1988), Watkins, Watters, Meathrel (promotion 2003) et McKay, ont amélioré la mission clinique et universitaire de la division.Pendant ses 66 ans d’histoire, l’activité collective de la division de chirurgie plastique et reconstructive de la faculté de médecine de l’université Queen’s a encouragé plus de 40 autres médecins à mener une carrière distinguée dans cette spécialité en Amérique du Nord, y compris trois anciens présidents de la Société canadienne des chirurgiens plasticiens.

The factors that contribute to the magnitude of placebo analgesia have, until recently, been elusive. This review explores the roles of external factors, such as conditioning, and experienced factors, such as expectation and desire for pain reduction, in placebo analgesia. Placebo analgesia effects have been found to reflect decreases in pain beyond that accounted for by the natural history of a pain condition. These effects clearly are influenced by the effectiveness of previous active treatments (ie, conditioning) as well as by environmental factors that provide cues/suggestions for analgesia. However, external factors are effective insofar as they provide expectations for pain reduction and a lowering of desire for relief. Experienced factors, such as expectation and desire for relief, also are integral dimensions of some human emotional states, such as anxiety. We present an explanation of placebo analgesia that suggests that it is the result of mechanisms that also regulate emotional states.

Giant cell tumor of bone (GCTB) is an aggressive primary osteolytic tumor. GCTB often involves the epiphysis, usually causing substantial pain and functional disability. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κΒ ligand (RANKL), is an effective treatment option for patients with advanced GCTB. This analysis of data from an ongoing, open-label study describes denosumab's effects on pain and analgesic use in patients with GCTB.Patients with unresectable disease (e.g. sacral or spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into Cohort 1 (N = 170), and patients with resectable disease whose planned surgery was associated with severe morbidity (e.g. joint resection, limb amputation, or hemipelvectomy) were enrolled into Cohort 2 (N = 101). Patients received denosumab (120 mg) subcutaneously every four weeks, with additional doses on study days 8 and 15. Patients assessed worst pain severity with the Brief Pain Inventory - Short Form (BPI-SF) at baseline, at each visit for the first six months, and every three months thereafter.Clinically relevant pain improvement was reported by 29% of patients in Cohort 1 and 35% in Cohort 2 during week 1 and by ≥ 50% of patients in each cohort at each study visit from months 2-30. Median time to clinically relevant improvement was 30 (95% CI 16, 57) days in Cohort 1 and 15 (95% CI 15, 29) days in Cohort 2. Results in patients with moderate/severe pain at baseline were similar. Fewer than 30% of patients in Cohort 1 and 10% in Cohort 2 experienced clinically relevant pain worsening at any visit through 27 months. Most patients had no/low analgesic use during the study.Most patients treated with denosumab experienced clinically relevant decreases in pain within two months.

The purpose of this paper is to document the use of intravenous (IV) bisphosphonates for prevention of skeletal-related events (SREs) in patients with bone metastases (BM) due to breast cancer (BC), lung cancer (LC), or prostate cancer (PC).Using data from two large US health systems, we identified all patients aged ≥ 18 years with primary BC, LC, or PC and newly diagnosed BM between 1/1/1995 and 12/31/2009. Starting with the diagnosis of BM, we reviewed medical and administrative records for evidence of receipt of IV bisphosphonates (zoledronic acid or pamidronate) and occurrence of SREs. Initiation of IV bisphosphonates prior to occurrence of an SRE was designated "primary prophylaxis"; use following an SRE was designated "secondary prophylaxis".We identified a total of 1,193 patients with newly diagnosed BM, including 400 with BC, 332 with LC, and 461 with PC. Use of IV bisphosphonates was substantially higher in BC (55.8 % of all patients) than in LC (14.8 %) or PC (20.2 %). Use of IV bisphosphonates was fairly evenly split between primary and secondary prophylaxis in BC (26.3 vs. 29.5 %, respectively) and PC (10.6 vs 9.5 %); in LC, however, primary prophylaxis was much less common than secondary prophylaxis (4.8 vs 9.9 %).Almost one half of all patients with BM due to BC, and substantially more with LC and PC, do not receive IV bisphosphonates. Among patients receiving such therapy, treatment often is not initiated until after the occurrence of an SRE. Our study suggests that IV bisphosphonates may be substantially underutilized in patients with BM due to these common cancers.

Purpose Cancer patients with bone metastases (BMets) are predisposed to skeletal complications. Bone-targeted therapies such as denosumab or intravenous bisphosphonates (IVBs) reduce the risk of these complications. This study characterized patterns of IVB use in these patients in the USA. Methods This was a retrospective, observational study using the Truven Health MarketScan® Commercial and Medicare databases (2002–2011). Subjects with ≥1 claims of diagnosis of breast, lung, or prostate cancer (BC, LC, or PC) and ≥1 claims of BMets diagnosis were included. The date of first BMet diagnosis claim was the “index date.” Key exclusion criteria were diagnosis of other primary cancer, receipt of IVB, or

Patients with bone metastases secondary to prostate cancer are predisposed to skeletal-related events (SREs), including spinal cord compression, pathological fracture, surgery to bone and radiotherapy to bone. The objective of this study was to document current patterns of healthcare utilization and costs of SREs in patients with prostate cancer and bone metastases.This was a retrospective, observational study using the Thomson MedStat MarketScan Commercial Claims and Encounters database from September 2002 to June 2011. Study subjects included all persons with claims for prostate cancer and for bone metastases, and one or more claims for an SRE. Unique SRE episodes were identified based on a gap of at least 90 days without an SRE claim, and classified by treatment setting (inpatient or outpatient) and SRE type (spinal cord compression, pathological fracture, surgery to bone or radiotherapy).Of 3919 patients with prostate cancer and bone metastases, 2090 (53%) had one or more SRE episodes. Among 1237 patients who met all other criteria, there were 1623 SRE episodes over a mean (s.d.) follow-up of 16.1 (12.9) months. The percent of episodes that required inpatient treatment ranged from 14% (radiotherapy) to 82% (surgery to bone). On average, inpatient episodes with surgery to bone (n = 36 episodes) were most costly (mean (s.e.) $88,838 ($11,830)/episode), whereas outpatient episodes with surgery to bone (n = 8 episodes) were least costly (mean (s.e.) $4749 ($1690)/episode). Of the total SRE costs (mean (s.e.) $20,984 ($951)/episode), 41% were attributable to outpatient radiotherapy (n = 1169 episodes), 23% to inpatient radiotherapy (n = 184 episodes), and 19% to inpatient treatment of pathological fractures (n = 101 episodes).In patients with prostate cancer and bone metastases, SREs are associated with high costs and hospitalizations.

Purpose: Denosumab was shown to be superior to zoledronic acid in preventing skeletal related events (SRE) in patients with breast cancer and bone metastases in a randomized, double-blind phase III study. We evaluated further results from this study related to skeletal complications and health-related quality of life (HRQoL). Experimental Design: Patients were randomized 1:1 to receive subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. Analyses reported here include the proportion of patients with one or multiple on-study SREs, time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in HRQoL (functional assessment of cancer therapy–general). Results: Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%, P = 0.006). The incidence of first radiation to bone was 12% (n = 123) with denosumab versus 16% (n = 162) with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid (HR, 0.74; 95% confidence interval [CI], 0.59–0.94, P = 0.012) and prolonged the time to first SRE or hypercalcemia of malignancy by 18% (HR, 0.82; 95% CI, 0.70–0.95; P = 0.007). Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels. Conclusions: Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained HRQoL, providing an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer. Clin Cancer Res; 18(17); 4841–9. ©2012 AACR.

BACKGROUND: In this study, the authors evaluated the effect of denosumab versus zoledronic acid (ZA) on pain in patients with advanced breast cancer and bone metastases. METHODS: The prevention of pain, reduction in pain interference with daily life activities, and the proportion of patients requiring strong opioid analgesics were assessed in a randomized, double-blind, double-dummy phase 3 study comparing denosumab with ZA for preventing skeletal-related events in 2046 patients who had breast cancer and bone metastases. Patients completed the Brief Pain Inventory-Short Form at baseline and monthly thereafter. RESULTS: Fewer patients who received denosumab reported a clinically meaningful worsening of pain severity (≥2-point increase) from baseline compared with patients who received ZA, and a trend was observed toward delayed time to pain worsening with denosumab versus ZA (denosumab, 8.5 months; ZA, 7.4 months; P = .08). In patients who had no/mild pain at baseline, a 4-month delay in progression to moderate/severe pain was observed with denosumab compared with ZA (9.7 months vs 5.8 months; P = .002). Denosumab delayed the time to increased pain interference by approximately 1 month compared with ZA (denosumab, 16.0 months; ZA, 14.9 months; P = .09). The time to pain improvement (P = .72) and the time to decreased pain interference (P = .92) were similar between the groups. Fewer denosumab-treated patients reported increased analgesic use from no/low use at baseline to strong opioid use. CONCLUSIONS: Denosumab demonstrated improved pain prevention and comparable pain palliation compared with ZA. In addition, fewer denosumab-treated patients shifted to strong opioid analgesic use. Cancer 2012. © 2012 American Cancer Society.

INTRODUCTION AND OBJECTIVES: Men with castrate-resistant prostate cancer (CRPC) who develop bone metastases may experience pain that seriously impacts function and quality of life. A recent randomized phase 3 trial demonstrated superiority of denosumab to zoledronic acid (ZA) for prevention of skeletal complications of bone metastases in men with CRPC. Here we report the results of pain interference (PI) with daily functioning. METHODS: Patients with CRPC and 1 site of bone metastasis received either subcutaneous (SC) denosumab 120 mg and intravenous (IV) placebo (n 950) or IV ZA 4 mg and SC placebo (n 951) every 4 weeks. PI with daily functioning (overall; activity [general activity, walking, work]; and affect [mood, enjoyment of life, relations with others]) was assessed using the Brief Pain Inventory at baseline and before each monthly visit. Responses on a scale of 0 (no) to 10 (complete) interference were analyzed for all randomized patients through month 18, when 50% of patients had dropped out due to death, disease progression, or consent withdrawal. RESULTS: Overall, from month 1 to 18, the average relative proportion of patients who reported increased PI ( 2 point increase) was 5% greater in the ZA group than in the denosumab group. Among patients with no/mild pain at baseline (56%), 13% more in the ZA group had increased PI relative to denosumab. For PI activity and affect domains, overall relative proportional differences between ZA and denosumab were 6% and 5%, respectively, favoring denosumab. For patients with no/mild pain at baseline, the average relative proportional differences for both domains were 13% each (Figure: Activity). CONCLUSIONS: In this trial of men with CRPC and bone metastases, denosumab was associated with a reduced incidence of increased pain interference over the study period compared with ZA, and this was further accentuated in patients with no or mild pain at baseline. Effective management of the impact of pain on patients’ daily lives is important to minimize patients’ distress and maintain quality of life. Preservation of physical function and mood, particularly in the early stages of treatment, contributes substantially towards this goal.

With increasing healthcare resource constraints, it has become important to understand the incremental cost-effectiveness of new medicines. Subcutaneous denosumab is superior to intravenous zoledronic acid (ZA) for the prevention of skeletal-related events (SREs) in patients with advanced solid tumors and bone metastases. This study sought to determine the lifetime cost-effectiveness of denosumab vs ZA in this setting, from a US managed-care perspective.A lifetime Markov model was developed, with relative rate reductions in SREs for denosumab vs ZA derived from three pivotal Phase 3 trials involving patients with castration-resistant prostate cancer (CRPC), breast cancer, and non-small-cell lung cancer (NSCLC), and bone metastases. The real-world SRE rates in ZA-treated patients were derived from a large commercial database. SRE and treatment administration quality-adjusted life year (QALY) decrements were estimated with time-trade-off studies. SRE costs were estimated from a nationally representative commercial claims database. Drug, drug administration, and renal monitoring costs were included. Costs and QALYs were discounted at 3% annually. One-way and probabilistic sensitivity analyses were conducted.Across tumor types, denosumab was associated with a reduced number of SREs, increased QALYs, and increased lifetime total costs vs ZA. The costs per QALY gained for denosumab vs ZA in CRPC, breast cancer, and NSCLC were $49,405, $78,915, and $67,931, respectively, commonly considered good value in the US. Costs per SRE avoided were $8567, $13,557, and $10,513, respectively. Results were sensitive to drug costs and SRE rates.Differences in pain severity and analgesic use favoring denosumab over ZA were not captured. Mortality was extrapolated from fitted generalized gamma function beyond the trial duration.Denosumab is a cost-effective treatment option for the prevention of SREs in patients with advanced solid tumors and bone metastases compared to ZA. The overall value of denosumab is based on superior efficacy, favorable safety, and more efficient administration.