Stoner, Julie A.

Abstract The immunopathogenesis of autoimmune myocarditis and dilated cardiomyopathy (DCM) in humans is unpredictable and pathogenic mechanisms undefined. The aim was to investigate potential autoimmune mechanisms in human autoimmune myocarditis and heart failure. Our evidence for a Th17 immunophenotype in human myocarditis/DCM(n=40) included reduced CD4+CD25+FoxP3+ Tregulatory cells(0.0006), elevated Th17 cells(0.0008) and increased Th17-promoting cytokines(IL-6 and TGF-beta). Th1(IFNγ+) cells were not significantly elevated(p=0.7184). IL-6(<0.0001), TGF-beta(0.0001), IL-23(0.0003), and GM-CSF+ T cells(0.0006) were significantly elevated. IL-17A+ cells were prevalent in biopsies from human myocarditis, non-recovery associated with persistence of IL-17A cytokines and heart failure associated with elevated Th17 cells in peripheral blood. To identify a potential mechanism to promote a Th17 pro-inflammatory pathogenesis in the heart, novel TLR ligands of human cardiac myosin (HCM) (peptides S2-16 and S2-28) promoted myocarditic PBMCs/CD14+ monocytes to produce Th17 cytokines(IL-23 p=0.0289; IL-6,TGF-beta p<0.0001). TLR ligand stimulation of PBMCs/ monocytes was abrogated by antibodies blocking TLR2, IL-6, IL-17A/23, and GM-CSF. Our translational study suggested human myocarditis/DCM may be controlled by a Th17 phenotype including reduced Treg, elevated Th17 cells, and pro-inflammatory and pro-fibrotic Th17 cytokines triggered by cardiac myosin TLR ligands potentially released from heart.

Abstract PURPOSE: Rheumatoid arthritis (RA) has been associated with an increased risk of non-Hodgkin’s lymphoma (NHL). We describe the characteristics of NHL patients with antecedent RA. METHODS: Records of the Nebraska Lymphoma Study Group (NLSG) registry between 1982–2004 and the Mayo Clinic lymphoma registry between 1988–1998 were systematically reviewed for RA diagnosis and classified by the quality of supporting evidence. We abstracted available follow-up data through July 1, 2004. Definite cases had either a documented RA diagnosis from a trained rheumatologist or met 4 of 7 American College of Rheumatology criteria. Probable RA cases had a non-rheumatologist diagnosis of RA in addition to one of the following: 1) radiographic joint erosions; 2) disease-modifying anti-rheumatic drug (DMARD) use or; 3) RA-associated deformities (i.e., ulnar drift, swan-neck deformities). Five-year overall survival (OAS), event-free survival (EFS), and rates of treatment response were determined. RESULTS: We identified 74 RA cases (54 definite and 20 probable) with concomitant NHL. These patients had a mean age of 67 + 8 years and were predominantly Caucasian (82%) and female (64%). Of the probable RA cases, a majority had documented DMARD use (n=17). Approximately half of the cases used methotrexate (55%) and were deceased (52%) by the common closing date. The most common NHL subtypes included B-DLCL (n=31), B-FL-1/B-FL-2 (n=12), B-FL-3 (n=6), and B-BL/B-BLL (n=4). Of the remaining 21 cases, most were of B-cell origin (n=13) and included B-EMZL (n=3), B-LPL (n=3), B-UCL (n=2), B-UCL-LG (n=2), B-DFL-2 (n=1), B-MCL (n=1), and B-SLL (n=1). The remaining NHL subtypes included NHL-NOS (n=7) or T-PTCL-LC (n=1). B-symptoms were present for 6 (19%) patients with B-DLCL and none of the patients with B-FL-1/B-FL-2. Complete response rates to NHL treatment were 48% in B-DLCL and 33% in B-FL-1/B-FL-2. For B-DLCL and B-FL-1/B-FL-2, respectively, the five-year OAS was 54% (95% CI 36%–69%) and 65% (95% CI 31%–85%) while the five-year EFS was 48% (95% CI 36%–69%) and 56% (95% CI 24%–79%). For all NHL cases the 5-year OAS was 58% (95% CI 47%–69%) and the 5-year EFS was 49% (95% CI 37%–59%). CONCLUSIONS: Lymphomas developing in the context of RA most often include diffuse large B-cell and follicular subtypes. Complete response rates to standard treatment for these major subtypes ranged from 33 to 48%. For RA patients developing NHL, five-year overall- and event-free survival rates are approximately 50%.

Abstract Introduction Cancer associated thrombosis is the second most common cause of mortality among patients with malignancy. While preventive low molecular weight heparin is effective in preventing venous thromboembolism (VTE), lack of agreement on risk stratification methods have precluded its widespread use. The most studied VTE prediction tool is the Khorana score, but it does not capitalize on the use of novel biomarkers. We aimed to evaluate the value of biomarkers in prediction of VTE among patients with active cancer receiving outpatient chemotherapy. Methods We prospectively collected pre-chemotherapy blood samples on adult patients with solid organ tumors. We excluded patients on anticoagulation and those unable or unwilling to consent. Along with demographics and cancer specific variables, potential novel predictors of VTE were selected a priori and included: coated platelets (CP), D dimer (DD), protein C (PC), fibrin monomers (FM), mean platelet volume (MPV), platelet microparticles (PMP). Type of cancer was grouped according to the Khorana score (Very high risk: Stomach, Pancreas; High risk: Lung, Gynecologic, Bladder, Testicular; Low/Moderate risk: all other sites). VTE events were adjudicated at 6 months of follow up. For all statistical analyses we used SAS 9.2 (SAS Institute Inc., Cary, NC, USA). A p value of <0.05 was considered as statistically significant. We only performed univariate analysis at this point of our study due to the stage of recruitment and period of follow-up. Results We have recruited a total of 101 patients (mean + standard deviation age 59.7+11 years, 68% female), 20% of the 75 patients with complete follow up have developed a VTE. We found no significant association between the incidence of VTE and age, gender, or baseline Khorana score. The variables associated with incident VTE were: BMI (odds ratio [OR] 8.5 for BMI<25 kg/m2, p<0.001), type of cancer (OR 14.5 for very high risk compared to high risk, p<0.01) and protein C (OR 3.3 for protein C<110ug/mL the lowest tertile, p=0.05). The rest of the tested potential biomarkers did not have a strong association with incident VTE in the current analysis (Table). Twenty percent of the patients were on aspirin and none of them developed VTE compared to 23% of those not taking aspirin who developed VTE, (p=0.2). Conclusion Pre Chemotherapy level of Protein C is a potential biomarker for the incidence of VTE. We confirm that cancer type and BMI are predictors of cancer associated VTE. In addition, lower BMI is not usually recognized as a potential predictor of VTE in other prediction scores. We were underpowered to detect differences in the VTE incidence according to Khorana score. Finally, aspirin may have a role in outpatient cancer associated VTE prevention and deserves further investigation. Disclosures: Tafur: Stago Diagnostica: Research Funding. Rathbun:Stago Diagnostica: Research Funding.

In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4 + IL17 + T cells and Th17-promoting cytokines IL-6, TGF-β, and IL-23 as well as GM-CSF–secreting CD4 + T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14 + monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17–producing T cells and IL-17–promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3 + Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-β, IL-6, and IL-23 from myocarditic CD14 + monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option.

The majority of intermediate‐risk rhabdomyosarcoma (RMS) patients have gross residual disease (Group III) after their first operative procedure. It is currently not known if local control rates can be maintained when, following induction chemotherapy, the radiation therapy (RT) dose is decreased after a delayed primary excision (DPE). To answer this question we evaluated patients enrolled on COG D9803 (1999–2005) who had Group III tumors of the bladder dome, extremity or trunk (thorax, abdomen and pelvis) were candidates for DPE at Week 12 if the primary tumor appeared resectable. RT dose was then adjusted by the completeness of DPE: no evidence of disease 36 Gy, microscopic residual 41.4 Gy and gross residual disease (GRD) 50.4 Gy. A total of 161 Group III patients were evaluated (24 bladder dome, 63 extremity and 74 trunk). Seventy‐three patients (45%) underwent DPE which achieved removal of all gross disease in 61 (84%) who were then eligible for reduced RT dose (43/73 received 36 Gy, 19/73 received 41.4 Gy). The local 5‐year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) was similar to IRS‐IV, which did not encourage DPE and did not allow for DPE adapted RT dose reduction. In conclusion, DPE was performed in 45% of Group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk) and 84% of those who had DPE were eligible for RT dose reduction. Local control outcomes were similar to historic results with RT alone.

Purpose The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC). Patients and Methods Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided α level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC. Results A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups. Conclusion For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.

Purpose Although preliminary studies suggest that non-Hodgkin's lymphoma (NHL) complicating rheumatoid arthritis (RA) may be a clinically distinct entity compared with that occurring in the general population, studies examining the impact of antecedent RA on survival are limited. In this prospective study, we examined the association of RA with survival in patients with NHL. Patients and Methods Using two large lymphoma registries, we identified patients with evidence of RA preceding NHL. Survival in RA patients was compared with that of controls using proportional hazards regression, adjusting for the effects of age, sex, lymphoma diagnosis-to-treatment lag time, calendar year, International Prognostic Index score, and NHL grade. Results The frequency of NHL subtypes was similar in RA patients (n = 65) and controls (n = 1,530). Compared with controls, RA patients with NHL had similar overall survival (hazard ratio [HR] = 0.95; 95% CI, 0.70 to 1.30) but were at lower risk of lymphoma progression or relapse (HR = 0.41; 95% CI, 0.25 to 0.68) or death related to lymphoma or its treatment (HR = 0.60; 95% CI, 0.37 to 0.98), but were more than twice as likely to die from causes unrelated to lymphoma (HR = 2.16; 95% CI, 1.33 to 3.50). Conclusion RA is associated with improved NHL-related outcomes, including a 40% reduced risk of death occurring as a result of lymphoma or its treatment and approximately a 60% lower risk of lymphoma relapse or progression compared with non-RA controls. However, the survival advantage gained in RA from the acquisition of lymphomas with favorable prognoses is negated through an increased mortality from other comorbid conditions.