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Abstract Introduction: Currently, the most extensively tested treatments for immunoglobulin light chain amyloidosis (AL) are high dose melphalan followed by autologous stem cell transplantation (ASCT) and melphalan and dexamethasone (MDex). A recent randomized controlled trial comparing the two regimens showed MDex is at least equivalent if not superior to ASCT. Most patients with symptomatic systemic AL have a low plasma cell load; however, approximately 30% have bone marrow plasmacytosis greater than 20% but do not meet criteria for multiple myeloma with significant anemia or lytic bone disease. This leads to the speculation that the plasma cell biology (and therefore outcomes) might differ between low and high plasma cell burden AL. We undertook this study to address whether these two standard regimens are equally effective in AL patients with low and high plasma cell burden. Methods: Patients with confirmed AL treated with MDex were recruited for this study. Some of the patients treated were not ASCT candidates while others were eligible but favored MDex. Hematologic response was defined as 50% reduction in serum M-protein or 90% reduction in urine M-protein if one was present, otherwise a 50% reduction in serum free light chain levels was used. Organ involvement was defined according to the Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis. Patients were separated into a high and a low marrow plasma cells (PC) group based on their percentage of bone marrow plasma cells. Cutoff for the bone marrow plasmacytosis was calculated using receiver-operator characteristic (ROC) curve. Overall survival (OS) and progression free survival (PFS) were compared using Kaplan-Meier method. OS was also calculated for 342 AL patients treated with ASCT for comparison. Results: Seventy-three patients with AL received MDex between 05/01 and 05/07. Median follow-up was 16.8 months. At the time of the study, 42.5% had died. Calculating for OS and PFS, the best cutoff for bone marrow plasmacytosis was found to be 20%. In our cohort, 28.8% had >20% bone marrow plasmacytosis. Age (64.8 yr vs 61.0 yr, p = 0.61) and sex (81% male vs 63.4% male, p = 0.13) were similarly distributed between patients with high and low PC. Cardiac troponin T (cTnT) was also comparable between the 2 groups (0.03 ng/ml (high) vs 0.06 ng/ml (low), p = 0.41). Cardiac involvement were similar between high and low PC groups (78.9% vs 85.7% respectively, p = 0.49) but renal involvement was less common in the high PC group (70.6% vs 38.1%, p = 0.01). No differences were noted in the gastrointestinal and neurological involvement. Patients with high PC received a median of 4 cycles of MDex vs 5 in the low PC group (p = 0.68). Hematologic response was achieved in 75% of patients with high PC and 54.9% of the low’s (p = 0.11). A significant difference was noted in the PFS and OS between the 2 groups. The PFS and OS were 13.5m and 15.3m, respectively for patients with high PC but neither was reached in those with < 20% plasmacytosis (p=0.02 and p = 0.03 respectively). In the multivariate analysis, hematologic response, cardiac involvement and plasmacytosis >20% were independent predictors of PFS and OS. To determine if plasmacytosis had the same affect on survival of ASCT treated patients, 342 patients were analyzed. No relationship between OS and % of plasmacytosis was found. Conclusion: Our study suggests that ASCT and MDex may not be equivalent for all AL patients. Even though hematologic response rates were similar, patients with plasmacytosis >20% had a worse OS and PFS when treated with MDex. This disparity in survival was not evident in patients treated with ASCT. This effect was independent of cardiac involvement. If confirmed, this could have a significant impact on the choice of therapy for AL patients. The best therapy may be determined by the extent of marrow plasmacytosis, with higher plasma cells favoring high dose therapy.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder associated with varying degree of organ infiltration with light chain derived amyloid protein and consequent organ dysfunction. Various acquired coagulopathies, predominantly Factor X (FX) deficiency have been previously described in AL. The factor deficiencies are thought to be due to the direct binding of blood coagulation proteins to amyloid fibrils. Little is known regarding the prognostic significance of abnormal coagulation parameters in AL patients (pts). Methods: After Institutional Review Board approval, we performed a retrospective review of the medical records of 625 consecutive pts who had presented within 3 months of a diagnosis of AL to be evaluated at Mayo Clinic from June 2001 to June 2006. 540 pts had coagulation studies performed within 2 months of presentation. 51 of those pts were on oral anticoagulation and were excluded from the analysis. Results: Of the 489 pts included in the analysis, the median age was 62 years and 61% were male. The median overall survival (OS) of the entire cohort was 26.8 months. Table 1 lists the prevalence of abnormal coagulation tests in the remaining 489 patients. Prothrombin time (PT) was available in the majority of pts. 61 pts (12.6%) had elevated PT, and 63 pts (20.4%) had a decreased FX. 37 of the 61 pts with elevated PT had available FX levels, of which 31 (84%) of those had a decreased FX, suggesting that the cause of elevated PT was mostly due to a low FX. Indicators of hepatic involvement such as alkaline phosphatase and bilirubin levels were higher among the patients with prolonged PT and low FX. An elevated PT (more than 12.4 seconds) was strongly predictive of an adverse outcome, with a median OS of 8.7 months compared to a median OS of 29 months (p<0.0001) in pts with normal PT (Figure 1). Similarly, pts with decreased FX (less than 60% activity), was associated with significantly worse outcomes with a median OS of 14.9 months versus a median OS of 33 months (p<0.0001) in pts with normal FX (Figure 2). In a Cox proportional hazards model containing cardiac troponin (cTnT), NT-Pro BNP, serum alkaline phosphatase, and free light chain difference (involved minus uninvolved), prolonged PT or FX deficiency were independently prognostic for overall survival. Conclusion: Abnormalities of PT and FX are seen in a sizable proportion of pts with newly diagnosed AL. An elevated PT and or FX deficiency appear to adversely affect the outcome of these patients. It is likely that the elevated PT in these patients relate to FX deficiency in the majority which in turn may reflect the amyloid ‘burden’. The effect of other organ involvement like the hepatic involvement may also have an impact on FX and PT. Table 1. Prevalence of abnormal coagulation testing in patients with newly diagnosed primary systemic amyloidosis. Coagulation study N (Test results available) N of abnormal results (%) Elevated prothrombin time 486 61 12.6 Elevated activated partial thromboplastin time 312 48 15.4 Elevated thrombin time 315 84 26.7 Elevated fibrinogen 140 118 84.3 Decreased Factor II activity 62 26 41.9 Decreased Factor V activity 63 9 14.3 Decreased Factor VII activity 63 17 27 Decreased Factor X activity 309 63 20.4 Elevated D-dimer 130 72 55.4 Figure 1. Survival grouped by normal versus elevated Prothrombin time. Figure 1. Survival grouped by normal versus elevated Prothrombin time. Figure 2. Survival grouped by normal versus low Factor X levels. Figure 2. Survival grouped by normal versus low Factor X levels.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder with a poor survival, especially in patients (pts) with multiple organ involvement. For pts with limited organ involvement, high dose chemotherapy with autologous stem cell (SCT) support is an effective approach. However, the toxicity of SCT limits its widespread use. Melphalan and dexamethasone has been previously shown to be effective in pts ineligible for SCT. Methods: We reviewed our experience with melphalan and dexamethasone for treatment of AL. Eighty one pts were treated between 2001 and 2003; median age at start of therapy was 63 years (range, 38–80) and 56 pts (69%) were males. Among these, 46 pts (57%) had 2 or more major organs (cardiac, renal, hepatic) involved. Intravenous melphalan (IV) was used in 45 pts (56%), 32 (40%) received oral melphalan (PO) and the rest received cycles of both. The most common doses were 16 mg/m2 for IV administration (every 4–6 weeks) and 0.22 mg/kg for PO administration (every 4 weeks). Dexamethasone was usually given at a dose of 40 mg for the first 4 days of each cycle. Results: Patients received a median of 5 cycles (range; 1–17). At the time of analysis, 53 (65%) pts were alive with a median follow up of 10.8 months (range, 1.4–47.1).The estimated median overall survival (OS) was 25.6 months for the entire group, with the number or type of organs involved not impacting survival. Hematological response (HR) was defined by a 50% reduction in either serum M-spike, urine M-spike, or the absolute difference between the involved and uninvolved immunoglobulin free light chains. A HR was observed in 43 pts (67%) of the 64 pts measurable for HR by conventional criteria. Achievement of HR was associated with a superior OS with a median post-therapy OS that was not reached, while non-responders had a median OS of 11.1 months (p<0.0001) (Figure 1). Among these pts, an organ response as defined by conventional criteria, was seen in 14 pts (22%), which was significantly correlated with obtaining a hematological response (33% vs. 5%, p=0.01). A 25% reduction in the difference between the involved and uninvolved FLC strongly predicted prolonged OS, with a median post-therapy OS that was not reached for responders vs. 11.3 months for non-responders (p<0.0001) (Figure 2). A decrease in post-therapy brain natriuretic peptide (BNP) also predicted for a survival improvement, with the median OS not reached for responders vs. a median OS of 17 months for non-responders (p<0.016). Conclusion: Treatment with melphalan and dexamethasone is effective and a significant survival advantage is achieved in patients with a hematological response. FLC and BNP response can help identify patients that are likely to benefit from this therapy. Figure Figure Figure Figure

Abstract Purpose: Patients with metastatic colorectal cancer refractory to chemotherapy have limited treatment options. Ensituximab (NEO-102) is a novel chimeric mAb targeting a variant of MUC5AC with specificity to colorectal cancer. Patients and Methods: Single-arm, phase II trial assessed the efficacy and safety of ensituximab in patients with advanced, refractory cancer who expressed MUC5AC antigen in tumor tissue. Ensituximab was administered intravenously every 2 weeks with 3 mg/kg as recommended phase II dose (RP2D). A minimum sample size of 43 patients was required on the basis of the assumption that ensituximab would improve median overall survival (OS) by 7 months using a one-sided significance level of 10% and 80% power. Written informed consent was obtained from all patients. Results: Sixty-three patients with advanced, refractory colorectal cancer were enrolled and 53 subjects were treated in phase II arm. Median age was 58 years and 46% of the patients were female. Among 57 evaluable patients, median OS was 6.8 months. No responses were observed, and stable disease was achieved in 21% of the patients. The most common treatment-related adverse events (AE) at RP2D included fatigue (38%), anemia (30%), nausea (15%), vomiting (11%), increased bilirubin (9%), constipation (8%), decreased appetite (6%), and diarrhea (6%). Serious AEs at least possibly related to ensituximab occurred in 4 patients and included anemia, nausea, increased bilirubin, and hypoxia. No patients discontinued treatment due to drug-related AEs. Conclusions: Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory colorectal cancer.

18585 Background: The Quality of life (QOL) and psychosocial needs of the 30–40% of prostate cancer patients who experience biochemical recurrence are not known. The impact of having a rising PSA, anticipation of undergoing PSA testing, and living with prostate cancer may increase psychological distress and decrease QOL. Aim: to evaluate the psychosocial treatment needs of men with biochemical recurrence of prostate cancer (br-PCa) and to develop a treatment to address these needs. Methods: 28 men with br-PCa, 58–87 years, were enrolled. A qualitative research approach was used, consisting of six, 2 hour, semi-structured, focus groups containing 4–6 men per group. Data were content coded and grouped into categories following the structure of the focus group guide. The major conceptual themes were then summarized by 2 independent reviewers. Discrepancies were discussed with a third researcher until a consensus was reached. These results were used to guide development of a multi-disciplinary quality of life intervention. Results: Participants defined QOL as the ability to stay active both physically and mentally without limitation in the performance of usual activities. There was a consensus that prostate cancer led to substantial anxiety related to PSA testing, treatment side effects, and fear of recurrence. Participants were enthusiastic about receiving adjuvant multidisciplinary treatment for prostate cancer focusing on anxiety management, nutrition, exercise, management of treatment side effects, and medical education. Participants desired a male group leader and feedback was mixed regarding whether spouses should be involved. Conclusions: Men with br-PCa report experiencing substantial anxiety and were enthusiastic about receiving a structured intervention to these needs. Based on our findings an intervention has been developed and is currently being compared to usual care. No significant financial relationships to disclose.

18552 Background: We reviewed Palliative Care Consultation Service (PCCS) referrals to attempt to promote earlier referrals, and to improve overall patient care. Methods: Eligibility for PCCS referral is life expectancy of one year or less. Data was collected prospectively on the first 461 referrals (452 individual patients) over the initial 30-month period (January 1, 2003 to July 1, 2005). Additional factors were retrospectively abstracted from documentation. Kaplan-Meier survival analysis was then performed. Results: 452 patients were seen (mean age 71.9 years), and 387 (86%) have died. Median length of inpatient stay was 8 days, with PCCS consultation requested 3 days prior to discharge. 107 patients (24%) died prior to hospital discharge. 345 patients survived to discharge, 236 (68%) died within 3 months, and 262 (76%) died within 6 months. Median survival from consultation to death was 12 days and after hospital discharge was 6 days. Secondary analysis determined that patients with malignancy had longer median survival from discharge to death than those with other diagnoses (11 days versus 3 days, p = 0.025). Median survival was longer with referrals from general surgery and surgical specialties (37 days and 8 days, respectively), compared to hematology-oncology and critical care (2 days and 0 days, respectively). Conclusions: The primary goal of the PCCS is to provide symptom control and maximize quality of life at the end of life. These data suggest palliative care services are unnecessarily delayed until too late. Education is necessary to facilitate earlier PCCS intervention. Survival analysis suggests providers are more likely to consider PCCS involvement in patients with malignancy compared with other diseases. Critical care and hematology-oncology, showed the lowest median survivals. Education efforts must be focused on these areas. Programs are underway to identify eligible patients earlier in their disease process, and educate providers about key end-of-life services provided to patients and families. No significant financial relationships to disclose.

8527 Background: Minority patients (MP) suffer deficits in access to care and socioeconomic status. This study uses a patient-level pooled analysis to explore whether these deficits translate into quality of life (QOL) differences between MP and non-MP on clinical trials. Method: Baseline QOL scores were combined from 47 clinical trials (6,513 patients) conducted either at the Mayo Clinic Cancer Center or in the North Central Cancer Treatment Group. QOL scales used were the Uniscale, Linear Analogue Self Assessment (LASA), Symptom Distress Scale (SDS), Profile of Mood States (POMS) and Functional Assessment of Cancer Therapy - General (Fact-G). Fisher’s Exact tests and linear regression adjusted for age, site, and performance score. Survival data was compared using the method of Kaplan-Meier. Results: Eight percent (531) of patients self-reported as MP (0.45% American Indian/Alaskan Native, 0.7% Asian, 5% Black/African American, 1.5% Hispanic, 0.1% Native Hawaiian and 0.3% Other). MP had no meaningful deficits in overall QOL or the SDS and were slightly worse on FACT-G total score, physical, social/family, functional, and SDS nausea severity. MP among lung cancer patients reported greater nausea (58 vs 69) and sleep problems (34 vs 54), with neurological cancers reported worse emotional well-being (53 vs 74), and with GI tumors had lower social/family well-being (60 vs 67). Regression models confirmed these results. Median survival time was shorter for MP (198 vs 310 days, p=0.001) but was not significant after adjusting for disease severity. Conclusions: MP on these clinical trials did not report large QOL deficits at baseline relative to non-MP. MP did indicate small deficits in physical, social, and emotional subscales. MP experienced large tumor-specific deficits for a few QOL domains that might bear further attention. [Table: see text] No significant financial relationships to disclose.

Background: Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. Methods: We assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry. Results: Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P =0.3), equally likely to be female (44% versus 48%, P =0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P =0.0004), prior antiarrhythmic drug use (52% versus 40%, P =0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P =0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P =0.003; cardioversion: 12.2% versus 5.9%, P =0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P =0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P =0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve ( P <0.05 for each). Conclusions: In this national registry of patients with AF, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient-reported outcomes in AF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.

AbstractMuch of the similarities of the tissue characteristics, pathologies and mechanisms of heterotopic ossification (HO) formation are shared between HO of tendon and ligament (HOTL). Unmet need and no effective treatment has been developed for HOTL, primarily attributable to poor understanding of cellular and molecular mechanisms. HOTL forms via endochondral ossification, a common process of most kinds of HO. HOTL is a dynamic pathologic process that includes trauma/injury, inflammation, mesenchymal stromal cell (MSC) recruitment, chondrogenic differentiation and, finally, ossification. A variety of signal pathways involve HOTL with multiple roles in different stages of HO formation, and here in this review, we summarize the progress and provide an up‐to‐date understanding of HOTL.

Abstract Context Glucagon increases energy expenditure; consequently, glucagon receptor agonists are in development for the treatment of obesity. Obesity negatively affects the reproductive axis, and hypogonadism itself can exacerbate weight gain. Therefore, knowledge of the effects of glucagon receptor agonism on reproductive hormones is important for developing therapeutics for obesity; but reports in the literature about the effects of glucagon receptor agonism on the reproductive axis are conflicting. Objective The objective of this work is to investigate the effect of glucagon administration on reproductive hormone secretion in healthy young men. Design A single-blinded, randomized, placebo-controlled crossover study was conducted. Setting The setting of this study was the Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy eugonadal men (mean ± SEM: age 25.1 ± 1.0 years; body mass index 22.5 ± 0.4 kg/m2; testosterone 21.2 ± 1.2 nmol/L) participated in this study. Intervention An 8-hour intravenous infusion of 2 pmol/kg/min glucagon or rate-matched vehicle infusion was administered. Main Outcome Measures Luteinizing hormone (LH) pulsatility; LH, follicle-stimulating hormone (FSH), and testosterone levels were measured. Results Although glucagon administration induced metabolic effects (insulin area under the curve: vehicle 1065 ± 292 min.µU/mL vs glucagon 2098 ± 358 min.µU/mL, P &lt; .001), it did not affect LH pulsatility (number of LH pulses/500 min: vehicle 4.7 ± 0.4, glucagon 4.2 ± 0.4, P = .22). Additionally, there were no significant differences in circulating LH, FSH, or testosterone levels during glucagon administration compared with vehicle administration. Conclusions Acute administration of a metabolically active dose of glucagon does not alter reproductive hormone secretion in healthy men. These data are important for the continued development of glucagon-based treatments for obesity.