Unmet Need For Therapies Research Articles

PCN174 ADVERSE EVENTS ASSOCIATED WITH IMMUNOTHERAPIES USED IN THE TREATMENT OF STAGE 3 AND 4 MELANOMA

Immunotherapy and targeted therapy have become standard treatments for patients with stage 3 and 4 melanoma. Despite their efficacy, both are associated with adverse events (AEs), which may be costly to manage. Data published on AEs associated with immunotherapies have not been reviewed in a targeted way over the past five years. This study aimed to identify the most frequently reported AEs associated with immunotherapies in the treatment of stage 3 and 4 melanoma. Targeted searches were conducted in the PubMed literature database to identify phase 3 studies reporting AEs associated with immunotherapies used in the treatment of stage 3 and 4 melanoma published in the past five years (January 1, 2014 to December 31, 2018). Study titles and abstracts were screened by two independent reviewers. Study design details and data on AEs by immunotherapy were extracted. AEs occurring in ≥10% of patients in any study group were recorded, in addition to grade ≥3 AEs occurring in ≥1% of patients. Twelve phase 3 studies reporting AEs associated with immunotherapies used in the treatment of stage 3 and 4 melanoma were included; all categorized AEs by grade (e.g., all, 1-2, ≥3). The following treatments were considered: ipilimumab, nivolumab, pembrolizumab, talimogene laherparepvec (T-VEC), and nivolumab plus ipilimumab. The most frequently reported AEs across all grades were fatigue, diarrhea, pruritus, rash, and nausea. Diarrhea, colitis, and fatigue were the most frequently reported grade ≥3 AEs. Certain all-grade AEs were associated with particular immunotherapies: fatigue with T-VEC (50-51% of patients), pruritis with ipilimumab (25-36% of patients), and diarrhea with nivolumab plus ipilimumab (44-45% of patients). Data from the last five years show that immunotherapies used in the treatment of stage 3 and 4 melanoma are associated with high rates of AEs. There is still substantial unmet need for therapies with improved safety profiles.

Extended-Release Amantadine for Levodopa-Induced Dyskinesia

ABSTRACTIntroduction: Levodopa-induced dyskinesia (LID) is a significant impediment to the long-term use of levodopa for Parkinson’s disease (PD). Relatively few studies exist that have described safe and effective therapy for LID. There is thus a significant need for therapy that can control LID to allow for greater sustainability of levodopa therapy. Amantadine extended release (ER) is currently the only FDA-approved medication for the treatment of LID. While other medications have demonstrated efficacy in treating the motor symptoms of PD, amantadine ER is the only one that has been shown, in several clinical trials, to reduce LID and reduce OFF time.Areas Covered: In this review, the authors present the findings of amantadine ER including its efficacy and safety. The authors also provide their expert perspectives on its use and its future prospects.Expert opinion: Several therapies are currently being used and studied for controlling LID, an unmet need in therapy for PD. Amantadine ER has potential to supplement levodopa therapy in PD and improve patient therapeutic outcomes.

The Bruton’s tyrosine kinase inhibitor acalabrutinib protects from anaphylaxis in a humanized mouse model

There is an unmet need for therapies that can prevent anaphylaxis. Acalabrutinib is a well-tolerated, FDA approved drug for leukemia that targets Bruton’s tyrosine kinase (BTK), an enzyme also thought to be essential for IgE receptor signaling in human mast cells and basophils. We tested the hypothesis that acalabrutinib administration would prevent anaphylaxis in a humanized mouse model. NSG-SGM3 mice were engrafted with human CD34+ cells at age 3-4 weeks. 16 weeks after engraftment, passive systemic anaphylaxis (PSA) was induced by intravenous sensitization with human anti-NP-IgE and challenge 24 hours later with intravenous injection of NP-BSA. Mice were pre-treated with acalabrutinib or vehicle control via oral gavage prior to challenge. Anaphylactic responses were assessed using core body temperature and clinical scoring. NSG-SGM3 mice engrafted with human CD34+ cells showed good engraftment of human mast cells in addition to excellent PSA responses. Increasing the challenge dose of NP-BSA from 5 to 500 μg resulted in increased severity of anaphylaxis, from mild to fatal responses. Two doses of 15 mg/kg acalabrutinib administered 16 and 4 hours prior to challenge completely mitigated, and 1.5 mg/kg partially mitigated, responses to moderate PSA compared to mice gavaged with vehicle. NSG-SGM3 humanized mice represent a unique model for the study of anaphylaxis where the severity of response can be controlled by varying the amount of allergen used for challenge. Furthermore, pretreatment with just two doses of acalabrutinib completely prevented PSA in these mice, suggesting that BTK inhibitors may be able to prevent IgE-mediated anaphylaxis in humans.

Comparison of Induction Strategies and Responses for Acute Myeloid Leukemia Patients after Resistance to Hypomethylating Agents for Antecedent Myeloid Malignancy

Comparison of Induction Strategies and Responses for Acute Myeloid Leukemia Patients after Resistance to Hypomethylating Agents for Antecedent Myeloid Malignancy

Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers.

Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvβ3/galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvβ3-expressing KRAS-mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancers, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors.Significance: There is a significant unmet need for therapies targeting KRAS-mutant cancers. Here, we identify integrin αvβ3 as a biomarker to identify mutant KRAS-addicted tumors that are highly sensitive to inhibition of galectin-3, a glycoprotein that binds to integrin αvβ3 to promote KRAS-mediated activation of AKT. Cancer Discov; 7(12); 1464-79. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.

Budget Impact Analysis of Supra-Ciliary Microstent Device Utilization In Primary open Angle Glaucoma Patients In A Spanish Hospital Outpatient Setting

Minimally Invasive Glaucoma Surgery (MIGS) devices fill an unmet need in therapy between topical pharmacological medicines and more invasive filtration procedures. This study evaluates the budget impact of using a new supra-ciliary microstent (Alcon Laboratories) device in Spanish hospitals as a stand-alone procedure or in conjunction with cataract surgery primary open angle glaucoma (POAG) patients where previous treatments have failed. A budget impact model (BIM) from a Spanish hospital outpatient perspective was developed using Microsoft® Excel®. Population and cost estimates were derived from published sources. POAG disease characteristics were obtained from the literature and an online survey of 40 practicing glaucoma/cataract specialists in Spain. Comparators and market share data were obtained from independent market research. Resource use assumptions associated with each intervention were obtained through survey results and from interviews with four key opinion leaders. Costs included published device costs, post-procedure follow-up care, and facility costs. An estimated 227,248 trabeculectomy, laser assisted trabeculoplasty or MIGS POAG interventions will occur over five years, 21,452 of which will use supra-ciliary microstent. The use of supra-ciliary microstent will have a low budget impact of 5.3% in the first year (€1,116,370) and an average budget impact of 8.2% over five years, with cost increases primarily driven by patients shifting from lower cost laser trabeculoplasty procedures. However, total intervention costs for supra-ciliary microstent (€1774) are lower than total intervention costs for the other included MIGS procedures (trabecular micro-bypass generation 1: €1829; subconjunctival gelatin stent: €2744) and similar to the common, but invasive trabeculectomy surgery (€1762). MS cost offsets were driven by decreases in procedure-related resource use and post-procedure follow-up care. Univariate sensitivity analyses confirm that model results are robust. The introduction of supra-ciliary microstent will have a minimal budget impact in Spain while increasing access to a valuable, minimally invasive treatment alternative for glaucoma.

Potential Role of Exosomes in Mending a Broken Heart: Nanoshuttles Propelling Future Clinical Therapeutics Forward.

Stem cell transplantation therapy is a promising adjunct for regenerating damaged heart tissue; however, only modest improvements in cardiac function have been observed due to poor survival of transplanted cells in the ischemic heart. Therefore, there remains an unmet need for therapies that can aid in attenuating cardiac damage. Recent studies have demonstrated that exosomes released by stem cells could serve as a potential cell-free therapeutic for cardiac repair. These exosomes/nanoshuttles, once thought to be merely a method of waste disposal, have been shown to play a crucial role in physiological functions including short- and long-distance intercellular communication. In this review, we have summarized studies demonstrating the potential role of exosomes in improving cardiac function, attenuating cardiac fibrosis, stimulating angiogenesis, and modulating miRNA expression. Furthermore, exosomes carry an important cargo of miRNAs and proteins that could play an important role as a diagnostic marker for cardiovascular disease post-myocardial infarction. Although there is promising evidence from preclinical studies that exosomes released by stem cells could serve as a potential cell-free therapeutic for myocardial repair, there are several challenges that need to be addressed before exosomes could be fully utilized as off-the-shelf therapeutics for cardiac repair.

Musculoskeletal Involvement in Systemic Sclerosis: An Unexplored Aspect of the Disease

Musculoskeletal (MSK) symptoms in patients with systemic sclerosis (SSc) include articular involvement (arthralgia, synovitis, contractures), which is often an early phenomenon and significantly contributes to the disability. Predominantly the hands are affected. Consensus in outcome measures of articular involvement is missing. Health Assessment Questionnaire Disability Index (HAQ-DI), Cochin Hand Function Scale (CHFS), Hand Mobility Index in Scleroderma (HAMIS), and Disease Activity Score of 28 Joints (DAS28) may be used for the assessment of different aspects of joint involvement. There is an unmet need for therapies confirmed by randomized controlled clinical trials (RCTs) to treat both synovitis and non-inflammatory joint involvement. The few rehabilitation studies that have been conducted have shown some promising efficacy. Muscle involvement may be an early symptom. The presence of clinically meaningful muscle involvement often heralds an unfavourable prognosis. The histology of muscle biopsy shows a variable picture including inflammation and necrosis. Besides, signs of acute neurogenic atrophy have been recently described as a previously underestimated contributor to muscle weakness. Similar to articular involvement, the lack of classification criteria on inflammatory and non-inflammatory SSc-associated myopathies, and the lack of validated core set of outcome measures makes it difficult to perform RCTs. The SSc-specific fibrinous tenosynovitis (tendon-friction rubs /TFRs/) is a frequent finding in SSc. Patients with TFR are at increased risk of developing renal, vascular, cardiac and gastrointestinal involvement and have reduced survival rates. Changes of fibrinous tenosynovitis can be objectively detected by ultrasound and may be used as an outcome measure in the treatment of MSK involvement.

Effects of sclerostin antibodies in animal models of osteoporosis

There is an unmet need for therapies that can restore bone strength and reduce fracture risk among patients at high risk of osteoporotic fracture. To address this need, bone-forming therapies that increase osteoblast activity are required to help restore bone structure and strength. Sclerostin is now recognized as a target for osteoporosis therapy. Sclerostin is predominantly secreted by the osteocyte and acts as an extracellular inhibitor of canonical Wnt signaling by binding to the receptors lipoprotein receptor-related protein-4, 5 and 6. Monoclonal antibodies to sclerostin (Scl-Ab) have been used in both clinical and in preclinical studies of osteoporosis with beneficial outcomes for bone density, structure, strength and fracture risk reduction. In this review paper, we summarize the current literature describing the effects of Scl-Ab in animal models of osteoporosis. In addition, we report new pharmacologic data from three animal studies of Scl-Ab: 1) a 12-month study evaluating bone quality in ovariectomized (OVX) rats; 2) a 6-month study evaluating bone structure and strength in adolescent cynomolgus monkeys; and 3) the effects of transition from Scl-Ab to vehicle or the RANKL inhibitor osteoprotegerin-Fc in OVX rats. Together, these results demonstrate that inhibition of sclerostin by Scl-Ab increased bone formation, and decreased bone resorption, leading to improved bone structure, bone mass and bone strength while maintaining bone quality in multiple animal models of osteoporosis. Further, gains in bone mass induced by Scl-Ab treatment were preserved by antiresorptive agents such as a RANKL inhibitor as a follow-on therapy. The bone-forming effects of Scl-Ab were unaffected by pre- or co-treatment with a bisphosphonate, and were restored following a treatment-free period after initial dosing. These data support the clinical development of Scl-Ab for treatment of conditions with low bone mass such as postmenopausal and male osteoporosis.

Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized, global, placebo-controlled study

Veliparib is a potent, orally bioavailable, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that crosses the blood–brain barrier and has been shown to potentiate the effects of radiation in preclinical and early clinical studies. This phase 2, randomized, global study evaluated the efficacy and safety of veliparib in combination with whole-brain radiation therapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC). Three-hundred and seven patients with brain metastases from NSCLC were randomized 1:1:1 to WBRT (30 Gy in 10 fractions) plus 50 mg veliparib twice daily (BID; n = 103), 200 mg veliparib BID (n = 102), or placebo BID (n = 102). Treatment began within 28 days of diagnosis. Tumor response and safety were assessed; the primary endpoint was overall survival (OS). Patients who received ≥1 dose of treatment were included in the safety analysis. All randomized patients were included in the efficacy endpoint analyses. Patient characteristics were well balanced between treatment arms. Median OS was 185 days for patients treated with WBRT plus placebo and 209 days for WBRT plus veliparib (50 or 200 mg). No statistically significant differences in OS, intracranial response rate, and time to clinical or radiographic progression between any of the treatment arms were noted. No differences were observed in adverse events (all grades) across treatment arms; nausea, fatigue, alopecia, and headache were the most commonly reported. No new safety signals were identified for veliparib. A significant unmet need for therapies that improve the outcomes of patients with brain metastases from NSCLC remains.

Estimated Budget Impact of Increased Use of Mirabegron, A Novel Treatment for Overactive Bladder.

BACKGROUND: Oral pharmacological treatment for overactive bladder (OAB) consists of antimuscarinics and the beta-3 adrenergic agonist mirabegron. Antimuscarinic adverse events (AEs) such as dry mouth, constipation, and blurry vision can result in frequent treatment discontinuation rates, leaving part of the OAB population untreated. Antimuscarinics also contribute to a patient’s anticholinergic cognitive burden (ACB), so the Beers Criteria recommends cautious use of antimuscarinics in elderly patients who take multiple anticholinergic medications or have cognitive impairment. Since mirabegron does not affect the cholinergic pathways, it is unlikely to contribute to a patient’s ACB. OBJECTIVE: To estimate the health care costs associated with the pharmacological treatment of OAB with mirabegron and antimuscarinics from U.S. commercial payer and Medicare Advantage perspectives, using a budget impact model. METHODS: For this budget impact model, 2 analyses were performed. The primary analysis estimated the b...

Unmet Need for Therapy Among Children with Autism Spectrum Disorder: Results from the 2005-2006 and 2009-2010 National Survey of Children with Special Health Care Needs.

We examined population-based trends in unmet need for therapy service in children with autism spectrum disorder (ASD) compared to other children with special health care needs (CSHCN), and identified factors associated with unmet need for therapy. A pooled cross-sectional comparison of the 2005-2006 and 2009-2010 waves of the National Survey for Children with Special Health Care Needs (NS-CSHCN) was used. Weighted bivariate analyses were used to compare children ages 3-17 years with ASD (n = 5113) to other CSHCN (n = 71,294) on unmet need for therapy services. Survey weighted multivariate models were used to examine child, family, and contextual characteristics associated with unmet need. A greater percentage of children with ASD across both surveys were reported to need therapy than other children with CSHCN. Among children with a reported need, children with ASD were 1.4 times more likely to report an unmet need for therapy compared to other CSHCN (OR 1.42, 95 % CI 1.18-1.71). Variables significantly associated with unmet need for therapy services included not receiving a well-child visit in the past year (OR 5.81, CI 3.83-8.81), surveyed in 2009 (OR 1.42, CI 1.18-1.71), child being female (OR 1.27, CI 1.05-1.53), uninsured (OR 1.72, CI 1.15-2.56), and having greater functional limitation (OR 2.44, CI 1.80-3.34). Children with ASD require supportive services such as occupational, physical, and speech therapy but are less likely to receive such services than other CSHCN. Receiving a well-child visit in the past year was strongly associated with receipt of needed therapy services.

How Are Perceived Unmet Need for Therapy and Durable Medical Equipment Services Associated with Quality of Life Measures Among Children with Special Healthcare Needs?

How Are Perceived Unmet Need for Therapy and Durable Medical Equipment Services Associated with Quality of Life Measures Among Children with Special Healthcare Needs?

Access to Therapy Services for Children With Autism Spectrum Disorder: A Population-Based Analysis

Abstract Date Presented 4/17/2015 Children with autism spectrum disorder (ASD) are significantly more likely to have an unmet need for therapy than children with attention-deficit/hyperactivity disorder (ADHD), but they are similar in unmet needs compared with children with cerebral palsy (CP). We identify barriers to appropriate care in children with special health care needs and areas for future inquiry.

Arterial and venous thrombosis following trauma and major orthopedic surgery: molecular mechanisms and strategies for intervention.

A variety of harmful effects can be triggered by trauma and major orthopedic surgery. One of the key players involved in this process is thrombin. The clinical consequence of this process has, for several decades, been considered to be formation of deep vein thrombosis and pulmonary embolism. Controlling thrombin generation and activation has therefore been the goal of thromboprophylaxis regimens administered to patients suffering from trauma or undergoing major surgery. Protecting patients from venous thromboembolism has, for many years, been the main goal of preventive strategies. However, our knowledge of cell destruction and release of substances that may cause organ damage has expanded in recent years. Release of molecules such as RNA and histones from destroyed tissues may cause cell destruction and organ damage at distal sites if released in huge amounts and disseminated systemically. This new knowledge points toward an unmet need for therapies that prevent both vascular events and organ deterioration. This article briefly reviews molecular mechanisms associated with the occurrence of vascular events and cellular destruction in patients with major bone damage caused by trauma.

To attend or not attend? A critical review of the factors impacting on initial appointment attendance from an approach–avoidance perspective

BackgroundA large proportion of initial therapy appointments are not attended. Whether this reflects service-user choice or an unmet need for therapy, non-attendance can impact on patients, therapists, services and research evaluation.AimsTo understand the complexities of this phenomenon, this paper reviews the mental health literature to gain further insight into how predictor variables can influence professional help-seeking decisions.MethodsThis review reveals a modest success at identifying specific demographic and psychological factors, yet methodological issues surrounding data collection techniques have often led to contradictory and inconclusive findings.ConclusionsThis paper examines the possibility that approach–avoidance conflict [Kushner, M.G. & Sher, K.J. (1989, 1991). Fear of psychological treatment and its relation to mental health service avoidance. Professional Psychology: Research and Practice, 20, 251–257; The relation of treatment fearfulness and psychological service utilization: An overview. Professional Psychology: Research and practice, 22, 196–203] could explain the contradictions in the literature because, in this model, different factors involved in driving engagement versus avoidance become more salient depending on a dynamic interplay of timing, the individual and their service context. The core principles behind this approach–avoidance conceptualisation are explained and further avenues for research are identified.

The chemokine receptor CX3CR1 is directly involved in the arrest of breast cancer cells to the skeleton

IntroductionSkeletal metastases from breast adenocarcinoma are responsible for most of the morbidity and mortality associated with this tumor and represent a significant and unmet need for therapy. The arrival of circulating cancer cells to the skeleton depends first on the adhesive interactions with the endothelial cells lining the bone marrow sinusoids, and then the extravasation toward chemoattractant molecules produced by the surrounding bone stroma.We have previously shown that the membrane-bound and cell-adhesive form of the chemokine fractalkine is exposed on the luminal side of human bone marrow endothelial cells and that bone stromal cells release the soluble and chemoattractant form of this chemokine. The goal of this study was to determine the role of fractalkine and its specific receptor CX3CR1 in the homing of circulating breast cancer cells to the skeleton.MethodsWe employed a powerful pre-clinical animal model of hematogenous metastasis, in which fluorescent cancer cells are identified immediately after their arrival to the bone. We engineered cells to over-express either wild-type or functional mutants of CX3CR1 as well as employed transgenic mice knockout for fractalkine.ResultsCX3CR1 protein is detected in human tissue microarrays of normal and malignant mammary glands. We also found that breast cancer cells expressing high levels of this receptor have a higher propensity to spread to the skeleton. Furthermore, studies with fractalkine-null transgenic mice indicate that the ablation of the adhesive and chemotactic ligand of CX3CR1 dramatically impairs the skeletal dissemination of circulating cancer cells. Finally, we conclusively confirmed the crucial role of CX3CR1 on breast cancer cells for both adhesion to bone marrow endothelium and extravasation into the bone stroma.ConclusionsWe provide compelling evidence that the functional interactions between fractalkine produced by both the endothelial and stromal cells of bone marrow and the CX3CR1 receptor on breast cancer cells are determinant in the arrest and initial lodging needed for skeletal dissemination.

90Y-Ibritumomab Tiuxetan Followed by Rituximab Is a Safe Treatment Option for Relapsed or Refractory Diffuse Large B-Cell Non-Hodgkin s Lymphoma

AbstractAbstract 2866 Introduction:Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy and is generally responsive to anthracycline-containing chemotherapy. However, 60% of patients (pts) will relapse after their first line treatment. At the time of relapse the only curative approach includes the use of a stem cell transplant (SCT). The incidence of DLBCL increases with age which creates a subset of pts who are not candidates for first line anthracycline-based chemotherapy, and a large subset of pts who are not candidates for SCT due to advanced age and/or co-morbidities. Thus, there is a significant unmet need for therapies with a low toxicity profile in elderly or medically unfit pts with DLBCL. 90Y-ibritumomab tiuxetan (90Y-IT) is an anti-CD20 murine antibody linked with a beta-emitting isotope approved for use in indolent lymphoma. Maintenance rituximab (R) has been reported to increase response rates and prolong remission duration in some lymphomas. We performed a phase II multicenter clinical trial to examine the efficacy of 90Y-IT induction followed by maintenance R in pts with DLBCL. Patients and Methods:Eligible pts were either intolerant of anthracycline-based chemotherapy or had relapsed or refractory CD20+ DLBCL with measurable disease. Pts had to be ineligible for SCT for reasons other than failure to harvest stem cells. Bone marrow involvement by lymphoma of less than 25% based on bilateral bone marrow aspirate and biopsy was required. R 250 mg/m2 was administered IV immediately followed by 111In-ibritumomab tiuxetan. Nuclear scans were performed at 24 and 48 hours to insure there was no altered biodistribution. On day 8 a second infusion of R 250 mg/m2 followed by 0.4 mCi/kg (for pts with a baseline platelet count >150,000/mm3) or 0.3 mCi/kg 90Y-IT (for pts with a baseline platelet count 100,000-149,000/mm3) was given. Pts with multiple extranodal sites or prior bone marrow involvement received CNS prophylaxis with intrathecal methotrexate or cytarabine. Maintenance R 375 mg/m2 was given on weeks 3–6, then weekly × 4 every 6 months × 4 cycles or until progression. Results:Between 10/2003 and 9/2009, 25 pts have been treated. During the course of the study, the ownership of the therapeutic agent changed three times and therefore enrollment was interrupted on two occasions. The median age of pts was 79 (range 45–91), 36% pts had a sIPI score 3 or more. The median number of prior regimens is 2 [0-5]. The 90Y-IT treatment regimen produced an overall response rate of 36% [9 pts] with 28% CR [7 pts]. To date, the mean OS is 18 months (median 8.1 months) with a median follow-up of 11.2 months. Among responding pts, the median OS has not been reached with a median follow-up of over 26.2 [0.1-71.4] months. Thirteen pts died within the first year, 6 patients (24%) continue to be in remission greater than 18 months, and 4 patients (16%) remain in long-term remission [39.9-71.4 months]. The most frequently observed toxicity was hematologic. Eleven percent of pts had grade 4 neutropenia with only one patient experiencing febrile neutropenia, and 16% of pts experienced grade 4 thrombocytopenia. There were no unexpected non-hematologic toxicities except for 1 patient that experienced extravasation. One late-occurring case of MDS/AML was reported that is possibly related to the study regimen, and one case of adenocarcinoma of the GI tract that is likely unrelated. Of note, none of the pts that progressed on the chemotherapy preceding this study achieved a response to the study regimen. Conclusions:The 90Y-IT treatment regimen has an acceptable toxicity profile in elderly or heavily pretreated pts with DLBCL. The two week outpatient 90Y-IT infusion produces response rates and durations similar to that of more prolonged cytotoxic chemotherapy regimens. Progression on previous chemotherapy predicts for poor response to 90Y-IT. Treatment with 90Y-IT can provide durable remission to a select subset of pts who are not candidates for SCT, or intensive anthracycline based chemotherapy. Disclosures:Off Label Use: We are describing a phase II study of the use of 90Y-Ibritumomab Tiuxetan for treatment of diffuse large B-cell lymphoma. Current FDA approved use of 90Y-Ibritumomab Tiuxetan includes relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) or previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy. Joyce:Spectrum Pharmaceuticals, Inc.: Research Funding; Cell Therapeutics Inc: Research Funding; Biogen Idec: Research Funding.

Antibodies to human serum amyloid P component eliminate visceral amyloid deposits

Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one per thousand deaths in developed countries1. Localised amyloid can also be very serious, for example cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present1. There is therefore a major unmet medical need for therapy which safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor protein can arrest amyloid accumulation1. Unfortunately control of fibril protein production is not possible in some forms of amyloidosis and in others is often slow and hazardous1. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar, plasma glycoprotein, serum amyloid P component (SAP)2, 3. Here we show that administration of anti-human SAP antibodies to mice with amyloid deposits containing human SAP, triggers a potent, complement dependent, macrophage-derived giant cell reaction which swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-D-proline compound, CPHPC4, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis.

The Use of Alefacept in the Treatment of Psoriasis

Psoriasis is a chronic, incurable disease with associated morbidity and a profound negative impact on the quality of life of affected patients. Current systemic therapies for moderate to severe psoriasis are effective but have potential for side effects, and may require chronic, continual use, as most are suppressive in nature. For example, cyclosporine is associated with hypertension, with functional and structural damage to the kidneys. Methotrexate can result in hepatotoxicity with psoriasis and requires liver biopsy for monitoring. Long-term use of psoralen plus ultraviolet A (PUVA) is associated with higher risk of nonmelanoma and possibly melanoma skin cancer. Given the chronic nature of psoriasis and the limitation of existing therapies, there is an unmet need for therapies with fewer side effects and durable remissions. 1,2 There has been considerable progress in understanding the pathophysiology of psoriasis and this has resulted in the development of targeted biologic therapies. Biologic agents are emerging that target pathogenic T-cells directly (i.e., reduction in pathogenic T-cells, inhibition of T-cell activation, prevention of T-cell trafficking) or target pathogenic cytokines [e.g., tumor necrosis factor (TNF)-a], resulting in favorable efficacy and improved safety in comparison with the currently available systemic therapies. 2