Bharathi Lingala

In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study

We have developed and previously reported on a therapeutic vaccination strategy for indolent B-cell lymphoma that combines local radiation to enhance tumor immunogenicity with the injection into the tumor of a TLR9 agonist. As a result, antitumor CD8(+) T cells are induced, and systemic tumor regression was documented. Because the vaccination occurs in situ, there is no need to manufacture a vaccine product. We have now explored this strategy in a second disease: mycosis fungoides (MF). We treated 15 patients. Clinical responses were assessed at the distant, untreated sites as a measure of systemic antitumor activity. Five clinically meaningful responses were observed. The procedure was well tolerated and adverse effects consisted mostly of mild and transient injection site or flu-like symptoms. The immunized sites showed a significant reduction of CD25(+), Foxp3(+) T cells that could be either MF cells or tissue regulatory T cells and a similar reduction in S100(+), CD1a(+) dendritic cells. There was a trend toward greater reduction of CD25(+) T cells and skin dendritic cells in clinical responders versus nonresponders. Our in situ vaccination strategy is feasible also in MF and the clinical responses that occurred in a subset of patients warrant further study with modifications to augment these therapeutic effects. This study is registered at www.clinicaltrials.gov as NCT00226993.

Improved responsiveness and reduced sample size requirements of PROMIS physical function scales with item response theory

IntroductionThe Health Assessment Questionnaire Disability Index (HAQ) and the SF-36 PF-10, among other instruments, yield sensitive and valid Disability (Physical Function) endpoints. Modern techniques, such as Item Response Theory (IRT), now enable development of more precise instruments using improved items. The NIH Patient Reported Outcomes Measurement Information System (PROMIS) is charged with developing improved IRT-based tools. We compared the ability to detect change in physical function using original (Legacy) instruments with Item-Improved and PROMIS IRT-based instruments.MethodsWe studied two Legacy (original) Physical Function/Disability instruments (HAQ, PF-10), their item-improved derivatives (Item-Improved HAQ and PF-10), and the IRT-based PROMIS Physical Function 10- (PROMIS PF 10) and 20-item (PROMIS PF 20) instruments. We compared sensitivity to detect 12-month changes in physical function in 451 rheumatoid arthritis (RA) patients and assessed relative responsiveness using P-values, effect sizes (ES), and sample size requirements.ResultsThe study sample was 81% female, 87% Caucasian, 65 years of age, had 14 years of education, and had moderate baseline disability. All instruments were sensitive to detecting change (< 0.05) in physical function over one year. The most responsive instruments in these patients were the Item-Improved HAQ and the PROMIS PF 20. IRT-improved instruments could detect a 1.2% difference with 80% power, while reference instruments could detect only a 2.3% difference (P < 0.01). The best IRT-based instruments required only one-quarter of the sample sizes of the Legacy (PF-10) comparator (95 versus 427). The HAQ outperformed the PF-10 in more impaired populations; the reverse was true in more normal populations. Considering especially the range of severity measured, the PROMIS PF 20 appears the most responsive instrument.ConclusionsPhysical Function scales using item improved or IRT-based items can result in greater responsiveness and precision across a broader range of physical function. This can reduce sample size requirements and thus study costs.

Better assessment of physical function: item improvement is neglected but essential

IntroductionPhysical function is a key component of patient-reported outcome (PRO) assessment in rheumatology. Modern psychometric methods, such as Item Response Theory (IRT) and Computerized Adaptive Testing, can materially improve measurement precision at the item level. We present the qualitative and quantitative item-evaluation process for developing the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function item bank.MethodsThe process was stepwise: we searched extensively to identify extant Physical Function items and then classified and selectively reduced the item pool. We evaluated retained items for content, clarity, relevance and comprehension, reading level, and translation ease by experts and patient surveys, focus groups, and cognitive interviews. We then assessed items by using classic test theory and IRT, used confirmatory factor analyses to estimate item parameters, and graded response modeling for parameter estimation. We retained the 20 Legacy (original) Health Assessment Questionnaire Disability Index (HAQ-DI) and the 10 SF-36s PF-10 items for comparison. Subjects were from rheumatoid arthritis, osteoarthritis, and healthy aging cohorts (n = 1,100) and a national Internet sample of 21,133 subjects.ResultsWe identified 1,860 items. After qualitative and quantitative evaluation, 124 newly developed PROMIS items composed the PROMIS item bank, which included revised Legacy items with good fit that met IRT model assumptions. Results showed that the clearest and best-understood items were simple, in the present tense, and straightforward. Basic tasks (like dressing) were more relevant and important versus complex ones (like dancing). Revised HAQ-DI and PF-10 items with five response options had higher item-information content than did comparable original Legacy items with fewer response options. IRT analyses showed that the Physical Function domain satisfied general criteria for unidimensionality with one-, two-, three-, and four-factor models having comparable model fits. Correlations between factors in the test data sets were > 0.90.ConclusionsItem improvement must underlie attempts to improve outcome assessment. The clear, personally important and relevant, ability-framed items in the PROMIS Physical Function item bank perform well in PRO assessment. They will benefit from further study and application in a wider variety of rheumatic diseases in diverse clinical groups, including those at the extremes of physical functioning, and in different administration modes.

Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry.

To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)–associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US.

Disability in rheumatoid arthritis in the era of biological treatments

Objective Rheumatoid arthritis (RA) is a disabling disease. The authors studied the impact of new, expensive and occasionally toxic biological treatments on disability outcomes in real-world populations of patients with RA. Methods The authors analysed Health Assessment Questionnaire Disability Index data on 4651 adult patients with RA collected prospectively from 1983 to 2006. They studied trends in disability using multilevel mixed-effects multivariable linear regression (mixed) models that adjusted for the effects of time trends in gender, ethnicity, age, smoking behaviour and disease duration. Results Overall, the patients were predominantly female (76%), were predominantly white (88%), had 13 years of education and have had RA for 13 years, on average. The time period from 1983 to 2006 saw major increases in the use of disease-modifying agents and biological agents, and a decrease in smoking. After adjustments, the disability rates declined at annual rates of 1.7% (1.5–1.8%) overall and 2.7% (2.4–3.1%) among men. The annual rate of disability declines in the biological era was greater than that in the preceding period, suggesting accelerated improvement. These declines were documented in all patient subgroups such as men, women, African–Americans, obese, older age groups and early disease (p<0.001), but not among the 1401 patients (where disability remained stable) who died on follow-up. Conclusion Aggressive use of traditional disease-modifying agents and introduction of biological agents were associated with substantial gains in disability outcomes. Our finding supports the prevailing notion that ‘tight inflammation control’ is a desirable therapeutic strategy.

Revisiting Low-Dose Total Skin Electron Beam Therapy in Mycosis Fungoides

PURPOSE Total skin electron beam therapy (TSEBT) is a highly effective treatment for mycosis fungoides (MF). The standard course consists of 30 to 36 Gy delivered over an 8- to 10-week period. This regimen is time intensive and associated with significant treatment-related toxicities including erythema, desquamation, anhydrosis, alopecia, and xerosis. The aim of this study was to identify a lower dose alternative while retaining a favorable efficacy profile. METHODS AND MATERIALS One hundred two MF patients were identified who had been treated with an initial course of low-dose TSEBT (5-<30 Gy) between 1958 and 1995. Patients had a T stage classification of T2 (generalized patch/plaque, n = 51), T3 (tumor, n = 29), and T4 (erythrodermic, n = 22). Those with extracutaneous disease were excluded. RESULTS Overall response (OR) rates (>50% improvement) were 90% among patients with T2 to T4 disease receiving 5 to <10 Gy (n = 19). In comparison, OR rates between the 10 to <20 Gy and 20 to <30 Gy subgroups were 98% and 97%, respectively. There was no significant difference in median progression free survival (PFS) in T2 and T3 patients when stratified by dose group, and PFS in each was comparable to that of the standard dose. CONCLUSIONS OR rates associated with low-dose TSEBT in the ranges of 10 to <20 Gy and 20 to <30 Gy are comparable to that of the standard dose (≥ 30 Gy). Efficacy measures including OS, PFS, and RFS are also favorable. Given that the efficacy profile is similar between 10 and <20 Gy and 20 and <30 Gy, the utility of TSEBT within the lower dose range of 10 to <20 Gy merits further investigation, especially in the context of combined modality treatment.

Mechanical or Biologic Prostheses for Aortic-Valve and Mitral-Valve Replacement

BACKGROUND In patients undergoing aortic‐valve or mitral‐valve replacement, either a mechanical or biologic prosthesis is used. Biologic prostheses have been increasingly favored despite limited evidence supporting this practice. METHODS We compared long‐term mortality and rates of reoperation, stroke, and bleeding between inverse‐probability‐weighted cohorts of patients who underwent primary aortic‐valve replacement or mitral‐valve replacement with a mechanical or biologic prosthesis in California in the period from 1996 through 2013. Patients were stratified into different age groups on the basis of valve position (aortic vs. mitral valve). RESULTS From 1996 through 2013, the use of biologic prostheses increased substantially for aortic‐valve and mitral‐valve replacement, from 11.5% to 51.6% for aortic‐valve replacement and from 16.8% to 53.7% for mitral‐valve replacement. Among patients who underwent aortic‐valve replacement, receipt of a biologic prosthesis was associated with significantly higher 15‐year mortality than receipt of a mechanical prosthesis among patients 45 to 54 years of age (30.6% vs. 26.4% at 15 years; hazard ratio, 1.23; 95% confidence interval [CI], 1.02 to 1.48; P=0.03) but not among patients 55 to 64 years of age. Among patients who underwent mitral‐valve replacement, receipt of a biologic prosthesis was associated with significantly higher mortality than receipt of a mechanical prosthesis among patients 40 to 49 years of age (44.1% vs. 27.1%; hazard ratio, 1.88; 95% CI, 1.35 to 2.63; P<0.001) and among those 50 to 69 years of age (50.0% vs. 45.3%; hazard ratio, 1.16; 95% CI, 1.04 to 1.30; P=0.01). The incidence of reoperation was significantly higher among recipients of a biologic prosthesis than among recipients of a mechanical prosthesis. Patients who received mechanical valves had a higher cumulative incidence of bleeding and, in some age groups, stroke than did recipients of a biologic prosthesis. CONCLUSIONS The long‐term mortality benefit that was associated with a mechanical prosthesis, as compared with a biologic prosthesis, persisted until 70 years of age among patients undergoing mitral‐valve replacement and until 55 years of age among those undergoing aortic‐valve replacement. (Funded by the National Institutes of Health and the Agency for Healthcare Research and Quality.)

Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Postarthroplasty Mortality: A Cross-sectional Analysis from the Nationwide Inpatient Sample

Objective. Systemic lupus erythematosus (SLE) is a disease of considerable morbidity, and this may place patients at greater risk for poor in-hospital postoperative outcomes for procedures such as arthroplasty. Our aim was to test this hypothesis. Methods. We compared the in-hospital postoperative mortality risk for patients with SLE undergoing hip and knee arthroplasty to those with rheumatoid arthritis (RA) and the general population without either condition, using data from the Nationwide Inpatient Sample (1993–2006). We performed parallel, weighted, multivariable logistic regressions to calculate mortality risk stratified by joint site, type of admission, hospital type, income category, race, length of stay, surgical indication, and medical comorbidities. Results. The unadjusted mortality rates (per 1000 procedures) for patients with SLE, patients with RA, and controls were 7.4, 3.0, and 6.5, respectively, for nonelective procedures and 2.4, 1.3, and 1.8 for elective procedures. After adjustment for potential confounders, patients with SLE had an OR of 4.0 (95% CI 1.9–8.0) for postoperative mortality with hip replacements and an OR of 1.2 (95% CI 0.2–7.5) for mortality with knee replacements. Mortality risk of patients with RA was not different from that of controls. The adjusted risk estimates for those who underwent arthroplasty before and after 2002 and those who underwent surgery for nonfracture indications were similar. Conclusion. Arthroplasty, especially of hips, in patients with SLE is associated with relatively higher postoperative mortality risk.

Low-level lead exposure and the prevalence of gout: an observational study.

BACKGROUND Blood lead levels (BLLs) less than 1.21 µmol/L (<25 µg/dL) among adults are considered acceptable by current national standards. Lead toxicity can lead to gouty arthritis (gout), but whether the low lead exposure in the contemporary general population confers risk for gout is not known. OBJECTIVE To determine whether BLLs within the range currently considered acceptable are associated with gout. DESIGN Population-based cross-sectional study. SETTING The National Health and Nutrition Examination Survey for 2005 through 2008. PATIENTS 6153 civilians aged 40 years or older with an estimated glomerular filtration rate greater than 10 mL/min per 1.73 m2. MEASUREMENTS Outcome variables were self-reported physician diagnosis of gout and serum urate level. Blood lead level was the principal exposure variable. Additional data collected were anthropometric measures, blood pressure, dietary purine intake, medication use, medical history, and serum creatinine concentration. RESULTS The prevalence of gout was 6.05% (95% CI, 4.49% to 7.62%) among patients in the highest BLL quartile (mean, 0.19 µmol/L [3.95 µg/dL]) compared with 1.76% (CI, 1.10% to 2.42%) among those in the lowest quartile (mean, 0.04 µmol/L [0.89 µg/dL]). Each doubling of BLL was associated with an unadjusted odds ratio of 1.74 (CI, 1.47 to 2.05) for gout and 1.25 (CI, 1.12 to 1.40) for hyperuricemia. After adjustment for renal function, diabetes, diuretic use, hypertension, race, body mass index, income, and education level, the highest BLL quartile was associated with a 3.6-fold higher risk for gout and a 1.9-fold higher risk for hyperuricemia compared with the lowest quartile. LIMITATION Blood lead level does not necessarily reflect the total body lead burden. CONCLUSION Blood lead levels in the range currently considered acceptable are associated with increased prevalence of gout and hyperuricemia.

Midterm survival after thoracic endovascular aortic repair in more than 10,000 Medicare patients

OBJECTIVE Aneurysms and dissections of the descending thoracic aorta represent a complex substrate with a variety of therapeutic options. The introduction of thoracic endovascular aortic repair (TEVAR) has revolutionized the treatment of thoracic aortic disease. However, longitudinal analyses of post-TEVAR outcomes appropriately stratified by aortic disease remain limited. METHODS A total of 11,996 patients undergoing TEVAR from 2005-2010 were identified from the Medicare/Centers for Medicare and Medicaid Services database. Patients were stratified by underlying aortic disease and the presence of Current Procedural Terminology (CPT) codes. Survival was assessed using Kaplan-Meier analysis. Cox proportional hazards analysis determined predictors of survival from TEVAR. RESULTS After TEVAR, patients had a median survival of 57.6 months (95% confidence interval, 54.9-61.3 months). Although patients without CPT codes had significantly fewer recorded comorbidities, TEVAR survival was comparable between patients with and without CPT codes (56.3 vs 59.5 months, P = .54). The early and late incidence of death varied significantly by aortic disease. Patients with aortic rupture, acute aortic dissection, and aortic trauma had the highest early incidence of death, whereas late survival was highest in patients with acute aortic dissection, aortic trauma, and isolated thoracic aortic aneurysm. Although hospital TEVAR volume was not associated with survival, an independent hospital effect (determined by using a mixed-effect Cox model) associated certain hospitals with a hazard for death 50% of what it was at other hospitals. CONCLUSIONS TEVAR has been applied to a multitude of aortic diseases in the Medicare population; early and late post-TEVAR survival varies by aortic disease. The late incidence of death remains high in TEVAR recipients, although certain aortic diagnoses such as acute aortic dissection, aortic trauma, and isolated thoracic aortic aneurysm were associated with improved late survival. An independent hospital effect, but not hospital volume, is correlated with post-TEVAR survival. Future analyses of TEVAR outcomes using the Medicare database should adjust for underlying aortic diagnoses and the presence of CPT codes.