Trabectedin and Radiotherapy in Endometrial Stromal Sarcoma: A Case Report.

Introduction: Endometrial stromal sarcoma (ESS) is a rare tumor that remains a diagnostic and therapeutic challenge to physicians worldwide. The metastatic setting implies a poor prognosis, with a 5-year survival rate below 40%. Patients with advanced-stage high-grade ESS (HG-ESS) have limited therapeutic options, often involving various chemotherapy regimens. Case Presentation: This report depicts the case of a 47-year-old female diagnosed with HG-ESS. She underwent several lines of treatment starting with radiotherapy and brachytherapy, followed by multiple lines of treatment including trabectedin over several months. After retreatment with trabectedin and achieving disease stabilization for 10 months, treatment was optimized by trabectedin combined with radiotherapy, leading to stable disease that is still ongoing and lasts for over 17 months. Conclusion: Our case underscores the challenging nature of treating patients with HG-ESS and highlights the safety of long-term retrial with trabectedin, coupled with radiotherapy administration. This approach maintained a durable stable disease response in the metastatic setting.

Erratum: Hindi, N., et al. Trabectedin Plus Radiotherapy for Advanced Soft-Tissue Sarcoma: Experience in Forty Patients Treated at a Sarcoma Reference Center. Cancers 2020, 12, 3740.

The authors noticed that content of "Conflicts of Interest" in the original version [...].

Trabectedin Plus Radiotherapy for Advanced Soft-Tissue Sarcoma: Experience in Forty Patients Treated at a Sarcoma Reference Center.

Symptomatic control and tumoral shrinkage is an unmet need in advanced soft-tissue sarcoma (STS) patients beyond first-line. The combination of trabectedin and radiotherapy showed activity in a recently reported clinical trial in this setting. This retrospective series aims to analyze our experience with the same regimen in the real-life setting. We retrospectively reviewed advanced sarcoma patients treated with trabectedin concomitantly with radiotherapy with palliative intent. Growth-modulation index (GMI) was calculated as a surrogate of efficacy. Forty metastatic patients were analyzed. According to RECIST, there was one (2.5%) complete response, 12 (30%) partial responses, 18 (45%) disease stabilizations, and nine (22.5%) progressions. After a median follow-up of 15 months (range 2-38), median progression-free survival (PFS) and overall survival (OS) were 7.5 months (95% CI 2.8-12.2) and 23.5 months (95% CI 1.1-45.8), respectively. Median GMI was 1.42 (range 0.19-23.76), and in 16 (53%) patients, it was >1.33. In patients with GMI >1.33, median OS was significantly longer than in those with GMI 0-1.33 (median OS 52.1 months (95% CI not reached) vs. 8.9 months (95% CI 6.3-11.6), p = 0.028). The combination of trabectedin plus radiotherapy is an active therapeutic option in patients with advanced STS, especially when tumor shrinkage for symptomatic relief is needed.

Trabectedin and RAdiotherapy in Soft Tissue Sarcoma (TRASTS): Results of a Phase I Study in Myxoid Liposarcoma from Spanish (GEIS), Italian (ISG), French (FSG) Sarcoma Groups.

BACKGROUND: Myxoid liposarcoma (ML) exhibits a special sensitivity to trabectedin (T) and radiation therapy (RT). Preclinical data suggest a synergistic effect. We aimed to study safety, feasibility and activity of the administration of pre-operative concurrent T and RT in patients affected by localized resectable ML. METHODS: Patients received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8 Gy/fraction). Dose Levels for T were: - 1 (1.1 mg/m2), 0 (1.3 mg/m2) and 1 (1.5 mg/m2). Primary endpoint was safety; antitumor activity was assessed by RECIST and Choi criteria. This study is registered at ClinicalTrials.gov, number NCT02275286. The phase 1 part of the study is complete and phase 2 is ongoing. FINDINGS: From February 2015 to May 2016, 14 patients (M/F 7/7), median age 36 years (range 24-70) and median tumor size 12.5 cm (range 7-17 cm), were enrolled. One dose limiting toxicity (G3 transaminitis) occurred at Level 0 and one (sepsis due to catheter infection) at Level 1. All patients completed RT. Five patients achieved PR (36%), 8 SD (57%), 1 distant PD (7%) by RECIST, while 12 achieved PR (86%), 1 SD (7%) and 1 distant PD (7%) by Choi criteria. Twelve patients underwent surgery. Median viable residual tumor was 5% (0-60). INTERPRETATION: T in combination with RT showed a favorable safety profile and antitumor activity in localized ML. T dose of 1.5 mg/m2 is the recommended dose for the phase 2 study, which is ongoing. FUNDING: This study was partially supported by Pharmamar.

Data on genetic associations of carotid atherosclerosis markers in Mexican American and European American rheumatoid arthritis subjects.

Carotid Intima-media thickness (CIMT) and plaque are well established markers of subclinical atherosclerosis and are widely used for identifying subclinical atherosclerotic disease. We performed association analyses using Metabochip array to identify genetic variants that influence variation in CIMT and plaque, measured using B-mode ultrasonography, in rheumatoid arthritis (RA) patients. Data on genetic associations of common variants associated with both CIMT and plaque in RA subjects involving Mexican Americans (MA) and European Americans (EA) populations are presented in this article. Strong associations were observed after adjusting for covariate effects including baseline clinical characteristics and statin use. Susceptibility loci and genes and/or nearest genes associated with CIMT in MAs and EAs with RA are presented. In addition, common susceptibility loci influencing CIMT and plaque in both MAs and EAs have been presented. Polygenic Risk Score (PRS) plots showing complementary evidence for the observed CIMT and plaque association signals are also shown in this article. For further interpretation and details, please see the research article titled "A Genetic Association Study of Carotid Intima-Media Thickness (CIMT) and Plaque in Mexican Americans and European Americans with Rheumatoid Arthritis" which is being published in Atherosclerosis (Arya et al., 2018) [1].(Arya et al., in press) Thus, common variants in several genes exhibited significant associations with CIMT and plaque in both MAs and EAs as presented in this article. These findings may help understand the genetic architecture of subclinical atherosclerosis in RA populations.

A genetic association study of carotid intima-media thickness (CIMT) and plaque in Mexican Americans and European Americans with rheumatoid arthritis.

BACKGROUND AND AIMS: Little is known about specific genetic determinants of carotid-intima-media thickness (CIMT) and carotid plaque in subjects with rheumatoid arthritis (RA). We have used the Metabochip array to fine map and replicate loci that influence variation in these phenotypes in Mexican Americans (MAs) and European Americans (EAs). METHODS: CIMT and plaque were measured using ultrasound from 700 MA and 415 EA patients with RA and we conducted association analyses with the Metabochip single nucleotide polymorphism (SNP) data using PLINK. RESULTS: In MAs, 12 SNPs from 11 chromosomes and 6 SNPs from 6 chromosomes showed suggestive associations (p < 1 × 10-4) with CIMT and plaque, respectively. The strongest association was observed between CIMT and rs17526722 (SLC17A2 gene) (ß ± SE = -0.84 ± 0.18, p = 3.80 × 10-6). In EAs, 9 SNPs from 7 chromosomes and 7 SNPs from 7 chromosomes showed suggestive associations with CIMT and plaque, respectively. The top association for CIMT was observed with rs1867148 (PPCDC gene, ß ± SE = -0.28 ± 0.06, p = 5.11 × 10-6). We also observed strong association between plaque and two novel loci: rs496916 from COL4A1 gene (OR = 0.51, p = 3.15 × 10-6) in MAs and rs515291 from SLCA13 gene (OR = 0.50, p = 3.09 × 10-5) in EAs. CONCLUSIONS: We identified novel associations between CIMT and variants in SLC17A2 and PPCDC genes, and between plaque and variants from COL4A1 and SLCA13 that may pinpoint new candidate risk loci for subclinical atherosclerosis associated with RA.

Use of Hydroxychloroquine Is Associated With Improved Lipid Profile in Rheumatoid Arthritis Patients.

BACKGROUND/PURPOSE: We examined the association between hydroxychloroquine (HCQ) and plasma lipid and glucose levels in rheumatoid arthritis (RA) cohort. METHODS: This is a retrospective cohort analysis of 1261 RA patients comparing fasting lipid profiles and plasma glucose between patients who were and were not taking HCQ. We divided patients into 3 groups based on HCQ exposure during follow-up: those who had never taken HCQ, those who took it intermittently, and those who took it continuously. We used multivariable models and propensity scoring to compensate for the effect of nonrandom treatment assignment. RESULTS: We followed 1261 RA patients for a total of 4605 observations between 1996 and 2014. After adjusting for age, sex, ethnicity, other disease-modifying antirheumatic drugs (DMARDs), lipid-lowering medications, body mass index (BMI), and smoking, patients taking HCQ at baseline had significantly lower total cholesterol (TC) (P ≤ 0.001), low-density lipoprotein (LDL) (P ≤ 0.001), triglycerides (P = 0.013), and lipid profile ratios TC/high-density lipoprotein (HDL) (P ≤ 0.001) and LDL/HDL (P ≤ 0.001), as well as higher HDL (P ≤ 0.001).In longitudinal analyses, after adjusting for confounders, patients who continuously took HCQ showed significantly lower TC, LDL, TC/HDL, and LDL/HDL and higher HDL (P ≤ 0.01). Fasting plasma glucose levels were not significantly associated with HCQ exposure. CONCLUSIONS: Hydroxychloroquine use was associated with lower lipid levels but not with the plasma glucose in this RA cohort. These findings support the need for a randomized trial to establish the role of HCQ in cardiovascular disease prevention in RA patients.

Genetic Variants Influencing Joint Damage in Mexican Americans and European Americans With Rheumatoid Arthritis.

Joint destruction in rheumatoid arthritis (RA) is heritable, but knowledge on specific genetic determinants of joint damage in RA is limited. We have used the Immunochip array to examine whether genetic variants influence variation in joint damage in a cohort of Mexican Americans (MA) and European Americans (EA) with RA. We studied 720 MA and 424 EA patients with RA. Joint damage was quantified using a radiograph of both hands and wrists, scored using Sharp's technique. We conducted association analyses with the transformed Sharp score and the Immunochip single nucleotide polymorphism (SNP) data using PLINK. In MAs, 15 SNPs from chromosomes 1, 5, 9, 17 and 22 associated with joint damage yielded strong p-values (p < 1 × 10(-4) ). The strongest association with joint damage was observed with rs7216796, an intronic SNP located in the MAP3K14 gene, on chromosome 17 (ß ± SE = -0.25 ± 0.05, p = 6.23 × 10(-6) ). In EAs, 28 SNPs from chromosomes 1, 4, 6, 9, and 21 showed associations with joint damage (p-value < 1 × 10(-4) ). The best association was observed on chromosome 9 with rs59902911 (ß ± SE = 0.86 ± 0.17, p = 1.01 × 10(-6) ), a synonymous SNP within the CARD9 gene. We also observed suggestive evidence for some loci influencing joint damage in MAs and EAs. We identified two novel independent loci (MAP3K14 and CARD9) strongly associated with joint damage in MAs and EAs and a few shared loci showing suggestive evidence for association.

Mortality in Rheumatoid Arthritis (RA): factors associated with recording RA on death certificates.

BACKGROUND: Death certificates can be used to assess disease prevalence and incidence; however, rheumatoid arthritis (RA) often remains unreported in death certificates. We sought to determine to what extent RA is underreported and what demographic and clinical characteristics could predict mention of RA in the death certificate. METHODS: We recruited 1328 patients with RA from private, public and military rheumatology practices and followed them prospectively for yearly evaluations. A rheumatologist assessed clinical characteristics of RA and comorbidities at each evaluation. Deaths were identified through family members, other physicians, obituaries and public death databases. All were confirmed with state-issued death certificates. Patients with and without RA in death certificate were compared using bivariate and multivariate analyses. RESULTS: By December 2013, 326 deaths had occurred. We received and reviewed death certificates for all confirmed deaths, of which 58 (17.7 %) mentioned RA on the death certificate. Bivariate analysis revealed that younger age, a greater number of deformities, higher Sharp score and lower socioeconomic status were each associated with recording RA. Multivariable analyses revealed that comorbidity [OR (95 % CI) = 0.84 (0.73, 0.97); P = 0.022] was inversely associated with listing RA on the death certificate, while the number of deformities [OR (95 % CI) = 1.04 (1.00, 1.07); P = 0.033] and a certified physician's signature on the death certificate [OR (95 % CI) = 4.79 (1.35, 16.9); P = 0.015] increased likelihood of reporting RA. CONCLUSION: In this cohort, RA was not listed in over 80 % of death certificates. Younger patients with fewer comorbidities and more joint deformities were more likely to have RA reported. DISCUSSION: RA is often not included in death certificates. The findings of this study suggest that older patients may have a greater number of comorbidities, thus decreasing the likelihood that RA be included when completing the death certificate.

Clinical and laboratory factors associated with interstitial lung disease in rheumatoid arthritis.

OBJECTIVE: The objective of this study is to examine the clinical, genetic, and environmental factors associated with interstitial lung disease (ILD) in rheumatoid arthritis (RA). METHOD: We recruited patients with RA from rheumatology practices at the time of a scheduled visit. Each patient participated in a comprehensive assessment that included ascertainment of age, sex, joint tenderness and swelling, subcutaneous nodules, disease severity, use of methotrexate and prednisone, smoking status, rheumatoid factor (RF), antibodies against cyclic citrullinated peptide (anti-CCP),erythrocyte sedimentation rate (ESR), the 28-joint Disease Activity Score (DAS28), and the presence of the HLA-DRB1 shared epitope (SE). As part of a thorough quantification of comorbidity, we identify all comorbid conditions, including ILD. We examined variables associated with ILD using logistic regression. We tested interaction terms between SE and other covariates. RESULTS: We studied 779 RA patients, among whom, ILD was recognized clinically in 69 (8.8 %). Variables significantly associated with ILD in a multivariable analysis included male sex, RA duration, the ESR, the DAS28, anti-CCP, and RF. There was a significant interaction between the HLA-DRB1 SE and smoking, ILD being associated with smoking only in the presence of SE. The association between ILD and anti-CCP, RF, and the ESR displayed a biological gradient, higher titers being more strongly associated with ILD. CONCLUSION: Anti-CCP antibodies and the RF may be pathogenically related to ILD. The association between ILD and smoking is dependent on the HLA-DRB1 SE, which may reflect gene-environment interaction.

Association of socioeconomic status with treatment delays, disease activity, joint damage, and disability in rheumatoid arthritis.

OBJECTIVE: To examine the association of socioeconomic status (SES) and delays in disease-modifying antirheumatic drug (DMARD) treatment with clinical measures in rheumatoid arthritis (RA) patients. METHODS: RA patients were recruited from rheumatology practices. We assessed SES based on education, occupation, and income, and divided patients into tertiles. The time from RA symptom onset to DMARD initiation (DMARD lag) was determined by self-report of the 2 dates, and distance to the rheumatologist (Distance) was obtained from Google Maps. We examined disease activity, determined by the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR); joint damage, determined from hand radiographs by Sharp scores; and physical disability, determined by the modified Health Assessment Questionnaire (M-HAQ). We used linear regression models to examine the relationship between clinical measures and SES, Distance, and DMARD lag. RESULTS: We recruited 1,209 RA patients, 1,159 of whom had received DMARD treatment. Mean ± SD DMARD lag was 6.9 ± 9.0 years. On average, patients with lower SES waited 8.5 ± 10.2 years after onset of RA symptoms to begin DMARD treatment, compared to those in the middle and upper SES tertiles who waited 6.1 ± 7.9 years (P = 0.002) and 6.1 ± 8.6 years (P = 0.009), respectively. Each year of delayed treatment was associated with a DAS28-ESR increase of 0.02 (P ≤ 0.001), a Sharp score increase of 1.33 (P ≤ 0.001), and an M-HAQ score increase of 0.01 (P ≤ 0.001). CONCLUSION: Low SES was associated with delay in DMARD initiation, and both were independently associated with worse clinical measures in RA. Strategies to reduce treatment delay in low-SES RA patients are needed.

Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis.

OBJECTIVE: To estimate atherosclerosis progression and identify influencing factors in rheumatoid arthritis (RA). METHODS: We used carotid ultrasound to measure intima-media thickness (IMT) in RA patients, and ascertained cardiovascular (CV) risk factors, inflammation markers and medications. A second ultrasound was performed approximately 3 years later. We calculated the progression rate by subtracting the baseline from the follow-up IMT, divided by the time between the two scans. We used logistic regression to identify baseline factors predictive of rapid progression. We tested for interactions of erythrocyte sedimentation rate (ESR) with CV risk factors and medication use. RESULTS: Results were available for 487 RA patients. The mean (SD) common carotid IMT at baseline was 0.571 mm (0.151). After a mean of 2.8 years, the IMT increased by 0.050 mm (0.055), p≤0.001, a progression rate of 0.018 mm/year (95% CI 0.016 to 0.020). Baseline factors associated with rapid progression included the number of CV risk factors (OR 1.27 per risk factor, 95% CI 1.01 to 1.61), and the ESR (OR 1.12 per 10 mm/h, 95% CI 1.02 to 1.23). The ESR×CV risk factor and ESR×medication product terms were significant, suggesting these variables modify the association between the ESR and IMT progression. CONCLUSIONS: Systemic inflammation and CV risk factors were associated with rapid IMT progression. CV risk factors may modify the role of systemic inflammation in determining IMT progression over time. Methotrexate and antitumour necrosis factor agents may influence IMT progression by reducing the effect of the systemic inflammation on the IMT.

Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis.

OBJECTIVE: To delineate daily and cumulative glucocorticoid dose thresholds associated with increased mortality rates in rheumatoid arthritis (RA). METHODS: We studied RA patients recruited from rheumatology clinics. Annually, we assessed the glucocorticoid dose, demographic, socioeconomic, clinical, and laboratory features of RA, cardiovascular (CV) risk factors, and vital status. We used Cox proportional hazards regression to assess associations between the daily or cumulative glucocorticoid dose and death, adjusting for potential confounders and for the propensity to receive glucocorticoids. We tested strata of the glucocorticoid dose to delineate the threshold associated with death. RESULTS: We studied 779 RA patients with a total of 7,203 person-years of observation, during which 237 of them died, yielding a mortality rate of 3.2 per 100 person-years (95% confidence interval [95% CI] 2.8-3.7). One hundred twenty of the deaths were due to CV causes, yielding a CV mortality rate of 1.8 (95% CI 1.5-2.1). Exposure to glucocorticoids was associated with a dose-dependent increase in death from all causes, with a ratio (HR) of 1.07 per mg of prednisone per day (95% CI 1.05-1.08). Compared to patients who were not receiving corticosteroids, the minimum daily prednisone dose threshold associated with an increase in all-cause mortality was 8-15 mg, with an adjusted HR of 1.78 (95% CI 1.22-2.60). For the cumulative dose of glucocorticoids, the minimum dosage associated with all-cause mortality was 40 gm (HR 1.74 [95% CI 1.25-2.44]). CONCLUSION: Glucocorticoid use in RA is associated with a dose-dependent increase in mortality rates, with a daily threshold dose of 8 mg, at which the number of deaths increased in a dose-dependent manner. These findings may assist clinicians in selecting the appropriate glucocorticoid dosage for RA patients who require these agents.

Does the "Hispanic paradox" occur in rheumatoid arthritis? Survival data from a multiethnic cohort.

OBJECTIVE: Despite lower socioeconomic status (SES) and higher disease burden, Hispanics in the US paradoxically display equal or lower mortality on average than non-Hispanic whites. Our objective was to determine if the "Hispanic paradox" occurs among patients with rheumatoid arthritis (RA). METHODS: In a cohort of 706 RA patients, we compared differences in RA severity and comorbidity between Hispanic and non-Hispanic white ethnic groups at baseline. Cox proportional hazards models were used to estimate and compare mortality risk between Hispanics and non-Hispanic whites. RESULTS: We studied 706 patients with RA, of whom 434 were Hispanic and 272 were non-Hispanic white. Hispanics had significantly lower SES, greater inflammation, as well as higher tender and swollen joint counts. Patients were observed for 6,639 patient-years, during which time 229 deaths occurred by the censoring date (rate 3.4 per 100 person-years; 95% confidence interval 3.0, 3.9). Age- and sex-adjusted mortality was not significantly different between the 2 ethnic groups (hazard ratio [HR] 0.96). After adjustment for comorbidities, RA severity, and level of acculturation, mortality among Hispanics was lower (HR 0.56, P = 0.004). CONCLUSION: Despite greater severity in most clinical manifestations and lower SES among Hispanics, paradoxically, their mortality was not increased. Further research is needed to understand the mechanisms underlying this survival paradox.

Carotid atherosclerosis predicts incident acute coronary syndromes in rheumatoid arthritis.

OBJECTIVE: The role of atherosclerosis in the acute coronary syndromes (ACS) that occur in patients with rheumatoid arthritis (RA) has not been quantified in detail. We undertook this study to determine the extent to which ACS are associated with carotid atherosclerosis in RA. METHODS: We prospectively ascertained ACS, defined as myocardial infarction, unstable angina, cardiac arrest, or death due to ischemic heart disease, in an RA cohort. We measured carotid atherosclerosis using high-resolution ultrasound. We used Cox proportional hazards models to estimate the association between ACS and atherosclerosis, adjusting for demographic features, cardiovascular (CV) risk factors, and RA manifestations. RESULTS: We performed carotid ultrasound on 636 patients whom we followed up for 3,402 person-years. During this time, 84 patients experienced 121 new or recurrent ACS events, a rate of 3.5 ACS events per 100 patient-years (95% confidence interval [95% CI] 3.0-4.3). Among the 599 patients without a history of ACS, 66 incident ACS events occurred over 3,085 person-years, an incidence of 2.1 ACS events per 100 person-years (95% CI 1.7-2.7). The incidence of new ACS events per 100 patient-years was 1.1 (95% CI 0.6-1.7) among patients without plaque, 2.5 (95% CI 1.7-3.8) among patients with unilateral plaque, and 4.3 (95% CI 2.9-6.3) among patients with bilateral plaque. Covariates associated with incident ACS events independent of atherosclerosis included male sex, diabetes mellitus, and a cumulative glucocorticoid dose of ≥ 20 gm. CONCLUSION: Atherosclerosis is strongly associated with ACS in RA. RA patients with carotid plaque, multiple CV risk factors (particularly diabetes mellitus or hypertension), many swollen joints, and a high cumulative dose of glucocorticoids, as well as RA patients who are men, are at high risk of ACS.

Effects of covariates and interactions on a genome-wide association analysis of rheumatoid arthritis.

While genetic and environmental factors and their interactions influence susceptibility to rheumatoid arthritis (RA), causative genetic variants have not been identified. The purpose of the present study was to assess the effects of covariates and genotype x sex interactions on the genome-wide association analysis (GWAA) of RA using Genetic Analysis Workshop 16 Problem 1 data and a logistic regression approach as implemented in PLINK. After accounting for the effects of population stratification, effects of covariates and genotype x sex interactions on the GWAA of RA were assessed by conducting association and interaction analyses. We found significant allelic associations, covariate, and genotype x sex interaction effects on RA. Several top single-nucleotide polymorphisms (SNPs) (~22 SNPs) showed significant associations with strong p-values (p < 1 x 10-4 - p < 1 x 10-24). Only three SNPs on chromosomes 4, 13, and 20 were significant after Bonferroni correction, and none of these three SNPs showed significant genotype x sex interactions. Of the 30 top SNPs with significant (p < 1 x 10-4 - p < 1 x 10-6) interactions, ~23 SNPs showed additive interactions and ~5 SNPs showed only dominance interactions. Those SNPs showing significant associations in the regular logistic regression failed to show significant interactions. In contrast, the SNPs that showed significant interactions failed to show significant associations in models that did not incorporate interactions. It is important to consider interactions of genotype x sex in addition to associations in a GWAA of RA. Furthermore, the association between SNPs and RA susceptibility varies significantly between men and women.