Citations

341 Background: Precursors to 1/3 of colorectal cancer (CRC), serrated polyps have historically been underdetected by screening due to their inconspicuous, nonhemorrhagic, and proximal nature. New generation sDNA-MT show high sensitivity for both CRC and advanced adenomas (Gastroenterology 2012;142:248), but screen detection of serrated polyps by this approach requires further validation. Aim: To assess and compare noninvasive detection of sessile serrated polyps >1cm (SSP) by sDNA-MT and a commercial quantitative FIT. Methods: In a blinded prospective study, a single stool sample used for both tests was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy (criterion standard). All 29 patients with SSP were included as cases and all 232 with no neoplastic findings as controls. Buffered stool samples were processed and frozen on receipt; Exact Sciences performed sDNA-MT in batches using optimized analytical methods (Gastroenterology 2012;142:S770). The sDNA-MT panel targets methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, β-actin, and hemoglobin. FIT (Polymedco OC-FIT Check) was performed in separate lab <2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100). Results: Age/sex distributions were similar in cases and controls: 40% vs 45% > 65 years and 51% vs 59% women, p=NS respectively. SSP median size was 1.2cm (range 1-3cm), 93% were proximal, and 64% had synchronous diminutive polyps. Among sDNA-MT markers, mBMP3 proved highly discriminant for SSP detection (AUC=0.87, p<0.00001); other DNA markers were less informative and provided no incremental sensitivity. Hemoglobin alone showed no discrimination (AUC=0.50, p=NS). At matched specificities, SSP detection by stool mBMP3 was significantly greater than by either FIT-50 or FIT-100 (Table). Conclusions: From a screening and surveillance setting, SSP can be detected noninvasively by stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection. [Table: see text]

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: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy.PATIENTS AND METHODS: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20+B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass ≥ 5 cm.RESULTS: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/μL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease (≥ 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody).CONCLUSION: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.

Attenuated Edmonston lineage measles virus (MV-Edm) vaccine strains can preferentially infect and lyse a wide variety of cancer cells. Oncolytic MV-Edm derivatives are genetically engineered to express the human carcinoembryonic antigen (MV-CEA virus) or the human sodium iodide symporter (MV-NIS virus) and are currently being tested in clinical trials against ovarian cancer, glioblastoma multiforme, multiple myeloma, mesothelioma, head and neck cancer, breast cancer and malignant peripheral nerve sheath tumors. This review describes the basic and preclinical data that facilitated the clinical translation of MV-Edm strains, and summarizes the clinical results of this oncolytic platform to date. Furthermore, we discuss the latest clinically relevant MV-Edm vector developments and creative strategies for future translational steps.

AbstractPatients with indolent non‐Hodgkin lymphoma (NHL) have multiple treatment options yet there is no consensus as to the best initial therapy. Lenalidomide, an immunomodulatory agent, has single agent activity in relapsed lymphoma. This trial was conducted to assess feasibility, efficacy, and safety of adding lenalidomide to rituximab, cyclophosphamide, and dexamethasone (LR‐CD) in untreated indolent NHL patients requiring therapy. This was a single institution phase II trial. Treatment consisted of IV rituximab 375 mg/m2 day 1; oral lenalidomide 20 mg days 1–21; cyclophosphamide 250 mg/m2 days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, 15, and 22 of a 28‐day cycle. Treatment continued 2 cycles beyond best response for a maximum of 12 cycles without rituximab maintenance. Thirty‐three patients were treated. Median age was 68 (43–83 years). 39% had stage IV disease. Histologic subtypes included 8 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL) (1 splenic, 2 extranodal, and 4 nodal), 15 Waldenström's macroglobulinemia (WM), 1 lymphoplasmacytic lymphoma, 1 small lymphocytic lymphoma, and 1 low‐grade B‐cell lymphoma with plasmacytic differentiation (unable to be classified better as MZL or LPL). Hematologic toxicity was the most common adverse event. Median time of follow‐up was 23.4 months (range 1.8–50.9). The overall response rate was 87.9%, with 30.3% complete response. The median duration of response was 38.7 months. The median progression free survival was 39.7 months, while median overall survival (OS) has not yet been reached. Lenalidomide can be safely added to a simple regimen of rituximab, oral cyclophosphamide, and dexamethasone and is an effective combination as initial therapy for low‐grade B‐cell NHL.

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.

AbstractPatients with light chain amyloidosis (AL) often have delayed diagnosis and present with significant symptomatology; this may result in decreased quality of life (QOL). We prospectively employ a “Hematology Patient Reported Symptom Screen” (HPRSS), which is three questions about fatigue, pain, and QOL, scored 0–10. The aim of this study is to better understand QOL and determine if HPRSS parameters predict for clinical outcomes. From 2009 to 2014, 302 newly diagnosed AL patients were included. Baseline median scores [interquartile range] for fatigue, pain, and QOL were 6 [3,7], 2 [0,5], 5 [3,8], respectively. Median overall survival was 53 months, with 102 (34%) deaths in the first year. There were significant differences in baseline HPRSS between those that lived longer than one year and early death patients in the domains of fatigue (5 [IQR 3, 7] vs. 7 [IQR 5, 8], P < 0.0001) and QOL (6 [IQR 4, 8] vs. 5 [IQR 3, 7], P = 0.006). On univariate analysis fatigue, QOL, physician‐reported performance status, autologous stem cell transplant (ASCT), and Mayo stage were prognostic for survival. On multivariate analysis Mayo stage, ASCT, and baseline fatigue remained independently prognostic. When analyses were restricted to the 125 patients with HPRSS measurements at 12 months, we found that over time QOL scores improved significantly 6 [IQR 3.5, 8] → 7 [IQR 5, 8] (P = 0.01). Asking AL patients to rate their fatigue and QOL has predictive value. Baseline patient reported fatigue is an independent prognostic factor for survival. Survival at one year was associated with significant improvement in QOL.