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Immune cell trafficking and surveillance within the ovary and fallopian tube are thought to impact fertility and also tumorigenesis in those organs. However, little is known of how native cells of the ovary and fallopian tube interact with resident immune cells. Interaction of the Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint with PD-L1 is associated with downregulated immune response. We have begun to address the question of whether PD-1 ligand or its receptors (PD-L1/-L2) can regulate immune cell function in these tissues of the female reproductive tract.PD-1 and ligand protein expression was evaluated in human ovary and fallopian tube specimens, the latter of which included stages of tubal cell transformation and early tumorigenesis. Ovarian expression analysis included the determination of the proteins in human follicular fluid (HFF) specimens collected during in vitro fertilization procedures. Finally, checkpoint bioactivity of HFF was determined by treatment of separately-isolated human T cells and the measurement of interferon gamma (IFNγ).We show that membrane bound and soluble variants of PD-1 and ligands are expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were present in HFF at bioactive levels that control T cell PD-1 activation and IFNγ production; full-length checkpoint proteins were found to be highly enriched in HFF exosome fractions.The detection of PD-1 checkpoint proteins in the human ovary and fallopian tube suggests that the pathway is involved in immunomodulation during folliculogenesis, the window of ovulation, and subsequent egg and embryo immune-privilege. Immunomodulatory action of receptor and ligands in HFF exosomes is suggestive of an acute checkpoint role during ovulation. This is the first study in the role of PD-1 checkpoint proteins in human tubo-ovarian specimens and the first examination of its potential regulatory action in the contexts of normal and assisted reproduction. This article is protected by copyright. All rights reserved.

TheProgrammed CellDeath Protein-1 (PD-1/PDCD-1/CD279) checkpoint has powerful immunomodulatory action, including in the context of cancer. PD-1 receptor activation by its ligands (PD-L1/2) is associated with downregulated immune response, and tumor cells can avoid surveillanceviaPD-1 and/or ligand expression. While receptor expression is largely limited to lymphoid, myeloid, and tumor cells, we show that membrane bound and soluble variants of PD-1 and ligands are also expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were highly enriched in exosome fractions in human follicular fluid at bioactive levels that can control T cell PD-1 activation. PD-1 checkpoint signaling may be involved in physiological ovarian functions including follicle, and ultimately, germline and embryo immune-privilege.

Fibroid uterus can be managed medically, surgically, or through non-extirpative procedures, depending on the clinical situation. Myomectomy may be beneficial, especially to those desiring to preserve the uterus and/or fertility, with outcomes comparable to those of hysterectomy, with a laparoscopic approach being favored when feasible. For definitive therapy, hysterectomy can be pursued where the surgical approach should be individualized. Comparison of robotic-assisted laparoscopic approach shows that the robotic approach may be favored for cases with higher complexity and multiple fibroids in myomectomy; however, no clear advantage is seen with hysterectomy at this time, necessitating further research in the area of robotics for hysterectomy in benign uterine mass treatment to justify the cost.

Endometriosis is a common disease affecting reproductive age women. Pain is one of the most common symptoms associated with endometriosis. When medical therapy has failed or in known deeply infiltrating endometriosis, surgical management is warranted. Laparoscopy is the gold standard for diagnosis and treatment of endometriosis. Recent developments in surgery have shown the feasibility of robotic surgery for endometriosis, although these methods have not been shown to be superior to conventional laparoscopy. Enhanced imaging techniques including fluorescence imaging and narrow band imaging have also been studied. However, long-term clinical benefits have yet to be demonstrated.

Introduction: Maternal obesity is an independent risk factor for reduced reproductive fitness. Decreased secretion of FSH in women with obesity is well documented but poorly understood. Furthermore, obese women secrete less protein and steroid hormones from their ovaries. In mice, prior studies have demonstrated that pulsatile release of FSH enhances ovarian function and fertility. Hypothesis: We hypothesize that insufficient FSH pulsatility, as seen in women with obesity, results in inadequate folliculogenesis and reduced ovarian steroid production. We attempt to correct pulsatile FSH secretion in obese women by administering exogenous FSH to compensate for the suppressed circulating ovarian hormones. Our primary outcome is the change in peak inhibin B between pre- and post-treatment. We present results from our interim analysis. Methods: Reproductive aged, regularly menstruating, normal weight (NW) (BMI 18.5-24.9) and obese (OB) (BMI >30) women were recruited for a 26hr study during the early follicular phase. Frequent blood sampling (q10min) for 10h was performed to obtain baseline hormone levels. At 10h, 3 mg of cetrorelix, a gonadotropin hormone antagonist, was given followed by a secondary dose (0.25mg) 6h later. At this time, hourly IV recombinant (r)FSH (30IU) was initiated and frequent blood sampling continued for 10h. LH, FSH, estradiol (E2) were measured by immunoassay (Advia Centaur XP, Siemens). Inhibin B was measured using an ELISA kit (Ansh labs). Differences between groups were modeled by linear regression, adjusted for age and cycle day (continuous). The relationship between change in peak inhibin B and change in peak E2 was estimated in a linear regression. Results: A total of 36 participants (19 NW and 17 OB) were included in our interim analysis. There were no differences in age, cycle day of study, race, and waist/hip ratio. Inhibin B and E2 rises following the intervention were statistically significant within each group. Peak Inhibin B and E2 levels following intervention were lower in obese women compared to normal weight (133.4 vs 202.5 pg/mL and 85.8 vs 126.4 pg/mL, respectively). The difference in pre and post peak inhibin B levels trended lower in the obese group (-40.1 (95%CI: -86.2, 6.1, p=0.087). No difference was seen in maximal E2 response. There was no relationship between inhibin B and E2 response [0.08 (95%CI -0.26, 0.42), p=0.634]. Conclusions: These early results suggest obese women may have a lower response to pulsatile rFSH as compared to normal weight counterparts even with intravenous administration. We speculate this may be due to decreased uptake of rFSH in obese patients or a sign of ovarian dysfunction in obese women. Additional subjects are recruited to detect these differences.

Drug shortages pose a significant public health concern in the United States, and cancer drugs are among those most affected. Shortages present serious safety risks for patients and substantial burden on providers and the healthcare system. Multifaceted drivers of this complex problem include manufacturing disruptions, raw material shortages, regulatory issues, market dynamics, and limited financial incentives that reward quality and production of off-patent drugs. Oncology drugs in short supply have resulted in substitution of less effective or more toxic alternatives, medication errors, and treatment delays, and are especially concerning for medications with no adequate substitute. Consequently, patient outcomes such as disease progression and survival have been adversely affected. Furthermore, emerging gray markets have contributed to cost-prohibitive markups and introduction of counterfeit products that compromise patient safety. The Food and Drug Administration plays a key role in preventing and managing pharmaceutical shortages, largely through regulations requiring early notification of manufacturing interruptions. Other proposed strategies similarly target upstream causes and center on reducing regulatory hurdles for manufacturers and increasing incentives for market entry and quality improvement. Despite progress in preventing supply disruptions, continued exploration of underlying systemic drivers remains critical to informing long-term solutions and alleviating the clinical and economic impact of drug shortages.

Drug shortages pose a significant public health concern in the United States, and cancer drugs are among those most affected. Shortages present serious safety risks for patients and substantial burden on providers and the healthcare system. Multifaceted drivers of this complex problem include manufacturing disruptions, raw material shortages, regulatory issues, market dynamics, and limited financial incentives that reward quality and production of off-patent drugs. Oncology drugs in short supply have resulted in substitution of less effective or more toxic alternatives, medication errors, and treatment delays, and are especially concerning for medications with no adequate substitute. Consequently, patient outcomes such as disease progression and survival have been adversely affected. Furthermore, emerging gray markets have contributed to cost-prohibitive markups and introduction of counterfeit products that compromise patient safety. The Food and Drug Administration plays a key role in preventing and managing pharmaceutical shortages, largely through regulations requiring early notification of manufacturing interruptions. Other proposed strategies similarly target upstream causes and center on reducing regulatory hurdles for manufacturers and increasing incentives for market entry and quality improvement. Despite progress in preventing supply disruptions, continued exploration of underlying systemic drivers remains critical to informing long-term solutions and alleviating the clinical and economic impact of drug shortages.

Narrowing the racial/ethnic and socioeconomic disparities in breast and cervical cancer requires an in-depth understanding of motivation for adherence to cancer screening and follow-up care. To inform patient-centered interventions, this study aimed to identify reasons why low-income women adhered to or delayed breast or cervical cancer screening, follow-up and treatment despite access to cancer care-related services.Semistructured qualitative interviews were conducted among women with access to cancer care-related services receiving care at an academic cancer center, federally qualified health centers, or free clinics in the Chicago metropolitan area. Transcripts were coded and analyzed for themes related to rationales for adherence.Among 138 participants, most were African American (46%) or Hispanic (36%), English speaking (70%), and between ages 41 and 65 years (64%). Primary drivers of nonadherence included lack of knowledge of resources, denial or fear, competing obligations, and embarrassment. Facilitators included abnormality identification, patient activation, provider-initiated actions, and motivation from family or friends.Interventions targeting increased adherence to care among low-income and ethnic minority women should direct efforts to proactive, culturally and patient-informed education that enables patients to access resources and use the health care system, address misconceptions about cancer, ensure health care providers' communication of screening guidelines, and leverage the patient's social support network.

Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society.A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the study's publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another.Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from $50,600 to $92,700. The addition of temozolomide (TMZ) and bevacizumab to glioblastoma treatment regimens has resulted in increased overall costs for glioma care. Although health care costs are now less front-loaded, they have increased over the course of illness. Analysis using a willingness-to-pay threshold of $50,000 per quality-adjusted life-year suggests that the benefits of TMZ fall on the edge of acceptable therapies. Furthermore, indirect medical costs, such as productivity losses, are not trivial.With increased chemotherapy use for malignant glioma, the paradigm for treatment and associated out-of-pocket and total medical costs continue to evolve. Larger out-of-pocket costs may influence the choice of chemotherapeutic agents, the economic implications of which should be evaluated prospectively.

Purpose Colorectal cancer (CRC) screening remains underutilized in the United States. Prior studies reporting the cost effectiveness of randomized interventions to improve CRC screening have not been replicated in the setting of small physician practices. We recently conducted a randomized trial evaluating an academic detailing intervention in 264 small practices in geographically diverse New York City communities. The objective of this secondary analysis is to assess the cost effectiveness of this intervention. Methods A total of 264 physician offices were randomly assigned to usual care or to a series of visits from trained physician educators. CRC screening rates were measured at baseline and 12 months. The intervention costs were measured and the incremental cost-effectiveness ratio (ICER) was derived. Sensitivity analyses were based on varying cost and effectiveness estimates. Results Academic detailing was associated with a 7% increase in CRC screening with colonoscopy. The total intervention cost was $147,865, and the ICER was $21,124 per percentage point increase in CRC screening rate. Sensitivity analyses that varied the costs of the intervention and the average medical practice size were associated with ICERs ranging from $13,631 to $36,109 per percentage point increase in CRC screening rates. Conclusion A comprehensive, multicomponent academic detailing intervention conducted in small practices in metropolitan New York was clinically effective in improving CRC screening rates, but was not cost effective.

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.

Background The patient voice remains underrepresented in clinical and public health interventions. To inform interventions that strive to improve access to breast and cervical cancer screening and follow-up among low-income populations, we explored recommendations from low-income women pursuing health care in the safety net. Methods Semi-structured interviews were conducted among women receiving follow-up care for an abnormal breast or cervical cancer screening result or a positive cancer diagnosis in federally qualified health centers, free clinics, or an academic cancer center in the Chicago metropolitan area. Findings Of the 138 women interviewed in the parent study, 52 women provided recommendations for improving access to screening and follow-up care. Most were between 41 and 65 years old (62%) and African American (60%) or White (25%). Recommendations included strengthening community-based health education with more urgent messaging, strategic partnerships, and active learning experiences to increase patient engagement, which women regarded as a key driver of access. Women also suggested increasing access by way of changes to health care delivery systems and policy, including more direct patient–provider and patient–clinic communications, addressing delays caused by high patient volume, combining preventive services, expanding insurance coverage, and adjusting screening guidelines. Conclusions This exploratory study demonstrates important insights from the patient lens that may help to increase the acceptability and efficacy of community and clinical interventions aimed at improving access to breast and cervical cancer screening and follow-up. Further research is needed to identify appropriate integration of patient input into interventions, practice, and policy change.

To explore patient perceptions of patient-provider communication in breast and cervical cancer-related care among low-income English- and Spanish-speaking women, we examined communication barriers and facilitators reported by patients receiving care at safety net clinics. Participants were interviewed in English or Spanish after receiving an abnormal breast or cervical cancer screening test or cancer diagnosis. Following an inductive approach, interviews were coded and analyzed by the language spoken with providers and patient-provider language concordance status. Of 78 participants, 53 % (n = 41) were English-speakers and 47 % (n = 37) were Spanish-speakers. All English-speakers were language-concordant with providers. Of Spanish-speakers, 27 % (n = 10) were Spanish-concordant; 38 % (n = 14) were Spanish-discordant, requiring an interpreter; and 35 % (n = 13) were Spanish mixed-concordant, experiencing both types of communication throughout the care continuum. English-speakers focused on communication barriers, and difficulty understanding jargon arose as a theme. Spanish-speakers emphasized communication facilitators related to Spanish language use. Themes among all Spanish-speaking sub-groups included appreciation for language support resources and preference for Spanish-speaking providers. Mixed-concordant participants accounted for the majority of Spanish-speakers who reported communication barriers. Our data suggest that, although perception of patient-provider communication may depend on the language spoken throughout the care continuum, jargon is lost when health information is communicated in Spanish. Further, the respective consistency of language concordance or interpretation may play a role in patient perception of patient-provider communication.

Background Patient navigation programs have been launched nationwide in an attempt to reduce racial/ethnic and socio-demographic disparities in cancer care, but few have evaluated outcomes in the prostate cancer setting. The National Cancer Institute-funded Chicago Patient Navigation Research Program (C-PNRP) aims to implement and evaluate the efficacy of a patient navigation intervention for predominantly low-income minority patients with an abnormal prostate cancer screening test at a Veterans Affairs (VA) hospital in Chicago. Methods/Design From 2006 through 2010, C-PNRP implemented a quasi-experimental intervention whereby trained social worker and lay health navigators worked with veterans with an abnormal prostate screen to proactively identify and resolve personal and systems barriers to care. Men were enrolled at a VA urology clinic and were selected to receive navigated versus usual care based on clinic day. Patient navigators performed activities to facilitate timely follow-up such as appointment reminders, transportation coordination, cancer education, scheduling assistance, and social support as needed. Primary outcome measures included time (days) from abnormal screening to diagnosis and time from diagnosis to treatment initiation. Secondary outcomes included psychosocial and demographic predictors of non-compliance and patient satisfaction. Dates of screening, follow-up visits, and treatment were obtained through chart audit, and questionnaires were administered at baseline, after diagnosis, and after treatment initiation. At the VA, 546 patients were enrolled in the study (245 in the navigated arm, 245 in the records-based control arm, and 56 in a subsample of surveyed control subjects). Discussion Given increasing concerns about balancing better health outcomes with lower costs, careful examination of interventions aimed at reducing healthcare disparities attain critical importance. While analysis of the C-PNRP data is underway, the design of this patient navigation intervention will inform other patient navigation programs addressing strategies to improve prostate cancer outcomes among vulnerable populations.

Purpose Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. Methods We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Results Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non–orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non–orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. Conclusion AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

Abstract 892 Background: The thienopyridines, ticlopidine and clopidogrel, have been associated with thrombotic thrombocytopenia purpura (TTP). However, few studies have reported information on antibodies to ADAMTS13 among patients with thienopyridine-associated TTP. We previously reported on two mechanistic pathways of thienopyridine-associated TTP with some overlapping features. Evaluation of ADAMTS13 autoantibodies was undertaken to improve understanding of these syndromes. Methods: Clinical and laboratory findings were evaluated for 30 ticlopidine-, 10 clopidogrel-associated TTP cases, and 54 cases of idiopathic TTP. Results: Among patients with thienopyridine-induced TTP, those with a history of ticlopidine versus clopidogrel use were more likely to present with severe thrombocytopenia (platelet < 20,000) (90% versus 13%), severe ADAMTS13-deficiency (80% versus 0%), and neutralizing antibodies to ADAMTS13 (100% versus 0%), and were less likely to have less than a two week history of thienopyridine exposure (0% versus 50%) (p Conclusion: Ticlopidine causes TTP by a pathway involving a neutralizing autoantibody to ADAMTS13 while clopidogrel causes TTP by an ADAMTS13-independent pathway. Although ADAMTS13 autoantibodies are present in both idiopathic and ticlopidine-associated TTP, spontaneous relapses are not seen in ticlopidine-associaated TTP, suggesting that drug-dependent antibodies are present. Clopidogrel associated TTP is distinct from idiopathic TTP in that ADAMTS13 autoantibodies are absent and response to TPE is poor. Disclosures: No relevant conflicts of interest to declare.

e16083 Background: Growing numbers of prostate cancer patients experience biochemical relapse (PSA failure) after initial treatment. LhRH agonist (hormonal) therapy can reduce PSA levels, but there is no clear evidence that it slows disease progression or reduces mortality. Quality of Life (QoL) issues are essential when deciding between observation (OBS) versus hormonal castration following biochemical relapse. We evaluated health related quality of life and treatment satisfaction among prostate cancer patients who experience PSA failure. Methods: Eligibility criteria were receipt of primary therapy for prostate cancer followed by a PSA nadir and subsequent PSA rise to at least 0.2 ng/ml. Data sources include medical records and interviewer administered surveys on health- related QoL at baseline, 3 and 12 months. Results: Castrated versus observed patients who are satisfied with their sexual activity report similar health-related QoL, with the exception of higher rates of maintaining an erection (73.3% vs. 32.0%) and not having prostate cancer affect sexual activity (66.7% vs. 28.6%). Castrated and expectant management patients with low levels of satisfaction and sexual activity report similar health-related QoL. Conclusions: Among patients with PSA Failure, the only health-related QOL difference is reflected in sexual activity related to erectile dysfunction, but not sexual satisfaction among patients who all have a high level of treatment decision satisfaction and sexual activity. [Table: see text] [Table: see text]

5131 Background: HT may lower PSA, but it may also cause hot flashes and sexual dysfunction. OBS is not associated with hot flashes or lower testosterone production, but PSA may rise. Examining patient satisfaction with treatment decision making, treatment choice, and HRQOL may help improve disease management. We compared treatment satisfaction and HRQOL of patients who chose OBS over HT. Methods: The Comprehensive Multicenter Prostate Adenocarcinoma Registry (COMPARE) is an observational registry of men with PSA failure. Data from patient-reported questionnaires were analyzed for patients treated with OBS or HT. Results: 674 patients (82%) chose OBS; 147 (18%) chose HT. The median time between cancer diagnosis and registry enrollment was 6 years. Of men on OBS, 85%, 83%, and 71% were satisfied with treatment decision process, treatment choice, and treatment outcome, respectively. Men on HT had similar rates of satisfaction (82%, 75%, and 71%). Men initially treated with brachytherapy/surgery were less satisfied with OBS. Men initially treated with external beam radiation were less satisfied with HT. Patients reported similar problems with urinary, sexual, and bowel function. Conclusions: Men with PSA failure seem content with treatment choice and decision making and have low rates of urinary/bowel problems. Rates of sexual dysfunction in both groups are similar. Clinical trials may help determine if HT improves long-term outcomes (e.g. overall survival), since short-term patient reported satisfaction is similar between OBS and HT. The reported rate of sexual dysfunction is lower than expected. [Table: see text] [Table: see text]

solely related to the study, presumably at the physician’s discretion. Additionally, the author postulated that this cost separation is necessary since sponsors, rather than institutions, should cover sponsor-related costs; presently some of these costs are borne by physicians and medical centers. The author also proffers the use of marginal cost estimation of services as calculated based on averaging flat rates to assist in determining cost allocation. Jacobs next recommends a series of steps designed to further delineate costs prior to pursuing a contractual relationship with a study sponsor. For these steps, Jacobs proposes the evaluation of the study contract to determine depth of reimbursement and allocation of off-label medications. His model urges physicians to make a concerted effort to renegotiate contracts that fail the above costs tests and where negotiations fail, to redirect these efforts towards study protocol revisions that are in line with existing cost structures at the medical institution. Institutions and physicians are also encouraged to underwrite observational study costs or refer patients to community institutions with better cost structures and comparable cancer therapies. There are some practical questions that arise in interpreting these findings and recommendations. What is the clinical impact of demonstrating separated costs in the context of clinical trials? For trials that have the potential to prolong survival and improve quality of life, costs negotiations could insert negative outcomes into the equation. Furthermore, clinical trial costs may also be affected by factors that are not mediated through the trial and by mechanisms that are independent of the trial process. Some of these factors include unexpected opportunity costs and costs related to adverse drug reactions or events. Regulatory mandates and subject response to therapies might also lead to prolongation of trials and increase in costs. In our prior pilot study that investigated clinical trial costs we also found that detailed economic information was critiSpecial challenges are frequently encountered when trying to increase patient recruitment into clinical trials. In clinical trials, it is necessary that large numbers of patients are recruited to allow for subject stratification for large variables, thereby contributing greatly to slow progress in reaching recruitment targets. While clinical trials are critical to improving patient outcomes in all areas, including cancer, strategy modifications are essential to balance recruitment efforts against trial costs. The allocation of scarce health care resources is increasingly based upon economic evaluations of health care interventions. Since clinical trials have the potential to dissipate many of these resources they must be conducted with costs in mind. In the current issue of OnkOlOgie, Jacobs reports on the pressures faced by clinicians to increase patient participation in clinical trials and the attendant financial impact on medical institutions that choose to do so [1]. Concerned about the difficulties inherent in separating medical care from ‘study care’ for patients enrolled in clinical trials, the author postulates that clinical trial costs should be reimbursed in concert with standard of care cancer costs. He utilizes a decision-making algorithmic process to determine participation in clinical trials based on economic and budget impacts. The economic model presented was derived from both prospective and retrospective studies evaluating the procedures and costs associated with clinical trial protocols for breast and ovarian cancer. Procedures and cost estimates were obtained from consultations with a center that manages clinical trials and with several hospital departments. Jacobs found that, to control for clinical trial costs, a network of providers with expertise in economics is needed; costs should be summed from individual costs of each service provided based on a detailed research protocol. The author also found that costs must be separated by those that are directed towards medically-related interventions and those that are

Background: The accelerated approval (AA) regulation (21CFR314.510 Subpart H) is granted by the Food and Drug Administration (FDA) when drugs for serious medical illnesses are shown to be an improvement over available therapy. AA provides an option to use surrogate outcomes considered likely to predict clinical benefit. AA was initially developed to hasten access to HIV drugs, then, in 1995, AA was extended to cancer indications. Sponsors receiving AA are required to confirm clinical benefit (termed subpart H trials). Policy makers have several raised concerns: AA is no longer relevant today as the approval bar via this mechanism has been raised too high; many drugs that received AA did not complete subpart H trials; and some drugs approved by AA were subsequently found to be unsafe or ineffective. Methods: Using publicly available databases, we compared safety, efficacy, clinical development times, and subpart H completion rates for FDA-approved new molecular entities (NMEs) for hematologic and solid tumor cancers from 1995–2008. Results: 37% of all oncology NMEs received AA versus regular approval (64% during 1995–2003 and 33% during 2004–2008). Twenty oncology NMEs received FDA approval for hematologic malignancies (lymphomas, leukemias, Kaposi’s sarcoma, and myelodysplastic syndromes), accounting for 34% of regular approvals and 53% of AAs for oncology NMEs. Compared to NMEs approved for solid tumors, NMEs approved for hematologic malignancies were more likely to involve Orphan Drug indications (95% vs. 32%); to have shorter development times, defined as the interval between investigational new drug filing and marketing approval, (median 5.6 vs. 7.8 years); and to be approved based on phase II studies (65% vs. 29%). Prior to 2004, development times were similar for solid tumor and hematologic malignancy NMEs. Since 2004, development times have decreased by more than 2 years for hematologic malignancy NMEs, but not for solid tumor NMEs. 50% of NMEs approved for hematologic malignancies versus 71% of NMEs for solid tumor diagnoses are included in first-line cancer regimens in current National Comprehensive Cancer Network guidelines. Drugs approved for solid tumor and hematologic indications have similar safety profiles and efficacy; respectively, 30% and 38% carried black box warnings at initial approval, and 15% and 10% had black box warnings added post-approval. Studies confirming efficacy were completed for 89% of NMEs receiving AA for solid tumor indications versus 30% for NMEs receiving AA for hematologic malignancy indications. Concern that sponsors are not completing subpart H commitments has led the FDA to move from basing AA on final results of single-arm phase II trials to interim results of phase III trials. Conclusions: AAs for hematologic malignancy indications are less likely to complete Subpart H commitments. In the current era, development times for NMEs are shorter for hematologic malignancy versus solid tumor indications, principally related to the approval based on Phase II versus Phase III studies. Establishing a global policy that AA approval for cancer drugs should be based on interim results of phase III analyses rather than on final analyses of phase II trials may hamper development of novel therapies for hematologic malignancies. Solide tumor indications Hematologic malignancy indications 1995–2003 (n=21) 2004–2008 (n=10) 1995–2003 (n=11) 2004–2008 (n=9) Drugs receivving AA (%) 29 30 64 33 Orphan drugs (%) 24 40 100 78 Of AAs, Subpart H completion (%) 100 66 27 0 Approval based on phase II trial (%) 33 0 73 78 Median development time (years) 8.4 7.8 8.8 5.2

Background : Many idiopathic thrombotic thrombocytopenia purpura (TTP) patients have severe deficiency of ADAMTS13, an enzyme that cleaves ultralarge von Willebrand multimers. We recently reported that thienopyridine-associated TTP is characterized by an immunologic pathway with severe ADAMTS13 deficiency and a non-immunologic pathway with higher ADAMTS13 activity levels. We now compare findings for idiopathic and thienopyridine-associated TTP patients. Methods : Clinical findings and laboratory findings were evaluated for 51 idiopathic and 39 thienopyridine-associated TTP. Results: Clinical findings were similar between idiopathic and thienopyridine-associated TTP for both severe ADAMTS13 deficient and non-deficient patients. Differences were noted in gender and age, relapse rates, and survival. Conclusion : Among TTP patients with ADAMTS13 deficiency, relapses are frequent in idiopathic TTP patients and Rituximab may be useful, while for thienopyridine-associated TTP patients spontaneous relapse are rare as long as no re-exposure occurs. Among ADAMTS13 non-deficient patients, survival is high following therapeutic plasma exchange (TPE) for idiopathic patients but not for thienopyridine-associated TTP patients. Despite similarities, idiopathic and thienopyridine associated TTP probably have different initiating factors. ADAMTS13 activity and clinical characteristics in idiopathic and thienopyridine-associated TTP Idiopathic severe ADAMTS13 deficiency (n=29) †Thienopyridine severe ADAMTS13 deficiency (n=26) Idiopathic non-severe ADAMTS13 deficiency (n=22) †Thienopyridine non-severe ADAMTS13 deficiency (n=13) *p2.5 mg/dl* 11% 27% 48% 46% 30-day survival 96% 85% 90% 62% Long-term relapse* 42% 8% 0% 0% Neutralizing autoantibodies to ADAMTS13 (prior to TPE) § 79% 100% 27% 0% Neutralizing autoantibodies to ADAMTS 13 (measured at remission) § 55% 33%‡ 33% 0%

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that presents with microangiopathic hemolytic anemia and thrombocytopenia, fevers, renal insufficiency and neurologic features. We reviewed clinical, laboratory, and outcome data for TTP cases with severely deficient versus non-severely deficient ADAMTS13 activity levels. Methods: Mean and median data were from the Surveillance, Epidemiology and Risk Factors for TTP (SERF-TTP) study group for idiopathic TTP cases, the Canadian Apheresis Group (CAG), and five published series (Zheng 2004, Raife 2004, Vesely 2003 (Oklahoma TTP-HUS Registry), Matsumoto 2004 (Japan Referral Center), Bennett 2007). Results: Compared to TTP cases with near-normal ADAMTS13 activity levels (n= 282), TTP cases with severe ADAMTS13-deficiency (n=185) were more likely to have severe thrombocytopenia, normal renal function and neutralizing ADAMTS13 antibodies. Severe ADAMTS13 deficient TTP cases have better overall survival after therapeutic plasma exchange (TPE) but are more likely to relapse. TTP patients with severe ADAMTS13 deficiency were primarily categorized as idiopathic or ticlopidine-associated, while TTP patients with non-severely deficient ADAMTS13 activity levels were frequently categorized as idiopathic, secondary to drugs (clopidogrel, quinine), stem cell transplantation, or cancer. Conclusions: Severe ADAMTS13 deficiency is most commonly idiopathic, has better survival following TPE, and a 35–40% spontaneous relapse rate. By contrast, non-ADAMTS13 deficient TTP cases are usually associated with an underlying disorder or external insults. Amongst this cohort, four series have 47–62% survival rates and three series, which contain mostly idiopathic cases, have 83–90% survival rates following TPE. From this, we propose that TTP may occur by three possible mechanism; ADAMTS13-deficient (antibody-mediated), an immunologic mediated pathway independent of ADAMTS13 (i.e. quinine) that is responsive to TPE, and endothelial injury related TTP that is unresponsive to TPE. Platelet count mean (x10^9/L) Creatinine mean (mg/dl) ADAMTS13 neutralizing antibodies (%) Survival % Relapse % * 15%) SERF-TTP (n=22) 57 3.9 35 90 0 Raife (n=57) * 44 2.7 83 9 Canada (n=17) 57 4.1 88 Zheng (n=13) 40 3.0 0 54 Bennett (n=13) 62 Japan (n=66) 9 62 Oklahoma (n=94 ) 23 47 3

Background: The Surveillance, Epidemiology & Risk Factors for TTP (SERF-TTP) study is the largest prospective cohort of idiopathic TTP cases to date. Methods: Patients with first episode of idiopathic TTP were enrolled at 11 sites in the US. Exclusion criteria include solid organ or allogeneic stem cell transplant, anti-neoplastic therapy or malignancy. All patients underwent therapeutic plasma exchange (TPE). Remission is defined as platelet count >150,000/mm3. ADAMTS13 activity was measured by fluorescence resonance energy transfer assay (FRETS-vWF73, Peptides Int.). ADAMTS13 inhibitor was assessed by ELISA (Technozym ADAMTS13 INH ELISA, Technoclone) and functional inhibition of normal ADAMTS13 activity (modified FRETS). Differences between the groups was evaluated by Chi-square test, t-test or Fisher’s exact test. Results: Complete data is available for 57 cases. 84% were female & median age was 42. ADAMTS13 was severely deficient (50%) in 39%. Adverse events were frequent & most commonly include citrate toxicity and allergic reactions. Long-term followup was available for 56 patients, and overall relapse rate was 25% with median time to relapse of 11 months. The relapse rate was 41% in patients with severe ADAMST13 deficiency & 0% in patients with normal ADAMTS13 activity (p=0.0077). Conclusions: Severe ADAMTS13 deficiency does not define all cases of idiopathic TTP, yet is associated with a unique syndrome characterized by severe thrombocytopenia, normal renal function, presence of ADAMTS13 neutralizing autoantibodies & high risk of relapse. Non-ADAMTS13 deficient idiopathic TTP has clinical features similar to thrombotic microangiopathies associated with stem cell transplant or drugs such as quinine, yet has a better than expected overall survival after TPE. There is likely an alternate disease mechanism for this cohort, possibly immunologic, which may be responsive to TPE and warrants further study. ADAMTS13 < 10% n=30 ADAMTS13 > 50% n=22 p-value * t-test, ** Fisher’s Exact Test, # Chi-Square Test Presenting Labs Hemoglobin (mean) 8.5 9.2 0.22* Platelet count (mean x10^9/L) 19 57 150,000) 9.7 9.2 0.89* Early remission (< 8 days) % 73 57 0.20# 30 day Exacerbation rate % 35 28 0.63# 30 day Survival % 96.6 90.0 0.56** Long-term Relapse % 41 0 0.0077**