Citations

213 Background: Daily oral prednisone (P) has been employed for the therapy of mCRPC, alone or in combination regimens. Despite palliative benefits and PSA responses, the overall clinical impact of P is unknown and it may foster resistance mechanisms. We performed a pooled analysis of control arms of randomized trials which either did or did not administer single agent P to evaluate its impact on overall survival (OS) and toxicities. Methods: Individual patient data from control arms ofrandomized trials of post-docetaxel men receiving placebo or P + placebo were eligible for analysis. Patient demographics, survival, and toxicity data were collected. The impact of P on OS and toxicities was investigated in Cox regression models adjusted for known clinical and laboratory prognostic factors. Statistical significance was defined as a p-value < 0.05 and all tests were two-sided. Results: The control arms of 2 randomized phase III trials were available totaling 794 men: the COU-AA-301 trial (n = 394) administered P plus placebo and the CA184-043 trial (n = 400) administered placebo alone. P plus placebo was not significantly associated with OS compared to placebo alone in a multivariable analysis (HR = 0.89 [95% CI 0.72-1.10], p = 0.27). Other factors associated with poor OS were Eastern Cooperative Oncology group (ECOG)-performance status (PS) ≥ 1, Gleason Score ≥ 8, liver metastasis, high PSA, hypoalbuminemia, and elevated LDH.In contrast, CTCAE grade ≥ 3 therapy-related toxicities were significantly increased with P plus placebo compared to placebo alone (HR = 1.48 (1.03-2.13), p = 0.034) in a multivariable analysis. Other baseline factors significantly associated with a higher risk of grade ≥ 3 toxicities were ECOG-PS ≥ 1, hypoalbuminemia and elevated LDH. Conclusions: P plus placebo compared with placebo alone for post-docetaxel men with mCRPC was not associated with extension of OS, but was associated with higher grade ≥ 3 toxicities. With the exception of the use of P in combination with abiraterone, P alone or in combination regimens should be questioned given its unclear palliative benefits and association with increased toxicities.

PURPOSE: To identify which patients with rhabdomyosarcoma and microscopic residual disease (group II) are likely to not respond to therapy. PATIENTS AND METHODS: Six hundred ninety-five patients with group II tumors received chemotherapy and 90% received radiation therapy on Intergroup Rhabdomyosarcoma Study (IRS)-I to IRS-IV (1972 to 1997). Tumors were subgrouped depending on the presence of microscopic residual disease only (subgroup IIa), resected positive regional lymph nodes, (subgroup IIb), or microscopic residual disease and resected positive regional lymph nodes (subgroup IIc). RESULTS: Overall, the 5-year failure-free survival rate (FFSR) was 73%, and patients with embryonal rhabdomyosarcoma treated on IRS-IV fared especially well (5-year FFSR, 93%; n = 90). Five-year FFSRs differed significantly by subgroup (IIa, 75% and n = 506; IIb, 74% and n = 101; IIc, 58% and n = 88; P = .0037) and treatment (IRS-I, 68%; IRS-II, 67%; IRS-III, 75%; IRS-IV, 87%; P < .001). Multivariate analysis revealed positive associations between primary site (favorable), histology (embryonal), subgroup IIa or IIb, treatment (IRS-III/IV), and better FFSRs. Patterns of treatment failure revealed local failure to be 8%, regional failure, 4%, and distant failure, 14%. The relapse pattern noted over the course of IRS-I to IRS-IV shows a decrease in the systemic relapse rates, particularly for patients with embryonal histology, suggesting that improvement in FFSRs is primarily a result of improved chemotherapy. CONCLUSION: Group II rhabdomyosarcoma has an excellent prognosis with contemporary therapy as used in IRS-III/IV, and those less likely to respond can be identified using prognostic factors: histology, subgroup, and primary site. Patients with embryonal rhabdomyosarcoma are generally cured, although patients with alveolar rhabdomyosarcoma or undifferentiated sarcoma, particularly subgroup IIc at unfavorable sites, continue to need better therapy.

PURPOSE: To evaluate the outcome of patients with rhabdomyosarcoma (RMS) treated with complete surgical resection and multiagent chemotherapy, with or without local radiotherapy (RT). PATIENTS AND METHODS: Four hundred thirty-nine patients with completely resected (ie, group I) RMS were further treated with chemotherapy (vincristine and actinomycin D ± cyclophosphamide, doxorubicin, and cisplatin) on Intergroup Rhabdomyosarcoma Studies (IRS) I to III between 1972 and 1991. Eighty-three patients (19%) also received local RT as a component of initial treatment. RESULTS: Eighty-six patients relapsed (10-year failure-free survival [FFS] 79%, overall survival 89%). Six percent of failure sites were local, 6% were regional, and 7% were distant. Poor prognostic factors were tumor size greater than 5 cm, alveolar or undifferentiated histology, primary tumor sites other than genitourinary, and treatment on IRS-I or II. For patients with embryonal RMS who were treated with RT, there was a trend for improved FFS but no difference in overall survival. On IRS-I and II, patients with alveolar or undifferentiated sarcoma who received RT compared with those who did not receive RT had greater 10-year FFS rates (73% v 44%, respectively; P = .03) and overall survival rates (82% v 52%, respectively; (P = .02). Such patients who received RT on IRS III also benefited more than those who did not receive RT (10-year FFS, 95% v 69%; P = .01; overall survival, 95% v 86%; P = .23). CONCLUSION: Patients with group I embryonal RMS have an excellent prognosis when treated with adjuvant multiagent chemotherapy without RT. Patients with alveolar RMS or undifferentiated sarcoma fare worse; however, FFS and overall survival are substantially improved when RT is added to multiagent chemotherapy (IRS-I and II). The best outcome occurred in IRS-III, when RT was used in conjunction with intensified chemotherapy.

437 Background: Optimizing post-operative clinical management for early-stage (I/II) colorectal cancer (CRC) patients (pts) is a significant unmet medical need. We hypothesized that a molecular prognostic test using primary CRC tissue would better predict the chances of tumor R within 36 months (mo) than current NCCN Clinical Practice Guidelines (NCCN). Methods: Pts had tumor R by 36 mo (n=46) or confirmed non-recurrence (NR) for ≥36 mo (n=69) after surgery; none had received neoadjuvant or adjuvant therapy. Archival formalin-fixed paraffin-embedded primary adenocarcinoma tissues (median storage 7 years; range 4-15) obtained at initial surgical resection with curative intent were retrieved for 86 stage I/II (pT1-4 pN0 M0) colon cancer and 29 stage I (pT1-2, pN0 M0) rectal cancer pts from 2 US and 2 European sites that were different from those previously used to generate the molecular test. Tumor gene expression was assessed by qRT-PCR with custom 384- well TaqMan Low Density Arrays (Applied Biosystems) using RNA that had satisfied a set of rigorous quality control parameters. Results: For stages I/II CRC (n=115), the dichotomous rule correctly classified 32/46 R and 38/69 NR pts: sensitivity (S) 0.70, specificity (SP) 0.55. High-risk pts had a significantly higher probability of R by 36 mo than low-risk pts: PPV 0.51, NPV 0.73; hazard ratio (HR) 2.06 (95% CI: 1.10 to 3.86; p=0.020). NCCN (V.1.2011) was not able to differentiate 36-mo R vs NR in this population: S 0.72, SP 0.42, PPV 0.45, NPV 0.69; HR 1.38 (95% CI: 0.73 to 2.63; p=0.315). The SP of the molecular test was significantly greater than that for NCCN (p=0.05). For stage I pts (n=29; 13R, 16NR), the prognostic accuracy of the test (0.79; 23/29) surpassed that for NCCN (0.55; 16/29). Conclusions: External validation of a 5-gene prognostic rule confirmed its ability to differentiate early stage CRC pts at high risk vs low risk for R within 36 mo after surgery better than current NCCN Guidelines, especially for stage I. The improved specificity and high sensitivity of the molecular test confirm its potential utility for optimizing post-op clinical management of early stage CRC. [Table: see text]

Background Soluble ST2 is a biomarker that is elevated in certain systemic inflammatory diseases. Comorbidity‐driven microvascular inflammation is postulated to play a key role in heart failure with preserved ejection fraction ( HF p EF ) pathophysiology, but data on how sST 2 relates to clinical characteristics or inflammatory conditions or biomarkers in HF p EF are limited. We sought to determine circulating levels and clinical correlates of sST 2 in HF pEF. Methods and Results At enrollment, patients (n=174) from the Phosphodiesterase‐5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial of sildenafil in HF p EF had sST 2 levels measured. Clinical characteristics; cardiac structure and function; exercise performance; and biomarkers of neurohumoral activation, systemic inflammation and fibrosis, and myocardial necrosis were assessed in relation to sST 2 levels. Median sST 2 levels in male and female HFpEF patients were 36.7 ng/mL (range 30.9–49.2 ng/mL; reference range 4–31 ng/mL) and 30.8 ng/mL (range 25.3–39.3 ng/mL; reference range 2–21 ng/mL), respectively. Among HF p EF patients, higher sST 2 levels were associated with the presence of diabetes mellitus; atrial fibrillation; renal dysfunction; right ventricular pressure overload and dysfunction; systemic congestion; exercise intolerance; and biomarkers of systemic inflammation and fibrosis, neurohumoral activation, and myocardial necrosis ( P <0.05 for all). sST 2 was not associated with left ventricular structure or left ventricular systolic or diastolic function. Conclusions In HF p EF , sST 2 levels were associated with proinflammatory comorbidities, right ventricular pressure overload and dysfunction, and systemic congestion but not with left ventricular geometry or function. These data suggest that sST2 may be a marker of systemic inflammation in HF p EF and potentially of extracardiac origin. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00763867.

SummaryErysipelothrix rhusiopathiae is a facultatively anaerobic Gram‐positive bacillus found mostly in swine, fish and sheep. E. rhusiopathiae classically causes cutaneous eruptions in butchers, fish handlers and veterinarians. Based solely on case reports, 90% of E. rhusiopathiae bloodstream infections (BSI) have been associated with infective endocarditis (IE). To assess the true frequency of IE in E. rhusiopathiae BSI as well as other clinical associations, we performed a retrospective cohort analysis of E. rhusiopathiae BSI at Mayo Clinic. This is a single‐centre, retrospective study conducted between 1/1/1994 and 20/6/2016 at Mayo Clinic in Rochester, MN. Medical records were reviewed for demographics, E. rhusiopathiae BSI, anti‐microbial susceptibilities, incidence of IE, patient comorbidities, intensive care unit (ICU) admission and duration of antibiotics. Five cases of E. rhusiopathiae BSI were identified. Risk factors included animal exposures, immunosuppression, diabetes and kidney disease. All cases involved penicillin‐sensitive strains and high‐grade BSI. Four cases showed no signs of IE on transesophageal echocardiogram. All patients recovered fully with intravenous antibiotics. Our retrospective review illustrates that E. rhusiopathiae can cause invasive BSI in the absence of IE and that the previously reported 90% association between BSI and IE may be overestimated due to reporting bias. E. rhusiopathiae should be suspected in any patient with Gram‐positive bacilli in blood cultures and the aforementioned risk factors. A limitation of our study was the low sample size, and future studies may involve multicentre collaborations and the use of polymerase chain reaction (PCR) or serologic testing to increase the number of diagnoses..