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The impact of residual symptoms following recovery from immune-mediated thrombotic thrombocytopenic purpura (iTTP) on activities of daily living during remission is not routinely discussed or evaluated by hematologists. This study used qualitative methodology to understand 3 issues from the patient’s perspective: the most important symptoms during remission, the impact of these symptoms on their daily activities, and the effectiveness of communication with hematologists. Oklahoma and Ohio patients participated in either focus groups or individual interviews. Eligibility included age ≥18 years, ADAMTS13 deficiency (

Objective Stakeholders involved in developing recommendations need to have a common understanding of health outcomes and the perspective of affected individuals. In this paper we report on the development and application of health outcome descriptors (HODs) to inform decision-making by panels developing guideline recommendations. Study Design and Setting Ten American Society of Hematology guideline panels addressing the management of venous thromboembolism developed HODs, rated their importance and health utility, applied them to prioritize outcomes, and to balance potential benefits and harms to formulate recommendations. Results It was feasible to involve 18 panelists in developing 127 HODs. There was high agreement (82%) across the ten panels about outcomes perceived as critical or important for decision-making. Panelists’ utility ratings of the outcomes were strongly correlated with panelists’ outcome importance ratings (Pearson's r=-0.88). HODs were incorporated into Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence-to-decision (EtD) frameworks to support a shared understanding of health outcomes in panel deliberations. Conclusion HODs serve as a valuable tool to promote an explicit, common understanding of health outcomes during clinical guideline development and across different stakeholders. They are helpful across multiple steps of guideline development to facilitate panels’ judgements, aiming to avoid variable implicit interpretations of health outcomes.

Objectives One essential requirement of trustworthy guidelines is that they should be based on systematic reviews of the best available evidence. The GRADE Working Group has provided guidance for evaluating the certainty of evidence based on several domains. However, for many clinical questions, published evidence may be limited, too indirect or simply not exist. In this brief report (GRADE notes), we describe our method of developing evidence-based recommendations when publisheddirect evidence was lacking. Study Design and Setting When direct published literature was absent, an expert evidence survey was administered to panel members about their unpublished observations and case series. Focus was on collecting data about cases and outcome, not panel opinions. Results Out of 26 questions prioritized by the panel for pediatric venous thromboembolism, 12 had no, very limited, or very low certainty of evidence to inform them. The panel survey was administered for these questions. Conclusions Areas of sparse evidence often reflect key questions that are critical to address in clinical practice guidelines due to the uncertainty among health care providers. The expert evidence approach used in this study is one method for panels totransparently deal with the lack of published evidence to directly inform recommendations.

Graft failure (GF) after cord blood transplant (CBT) has decreased with improved supportive care and cord selection strategies. We aimed to evaluate cord blood selection and factors associated with retransplantation on the incidence of GF, determine risk factors for GF including host antibodies to Kell antigen and evaluate survival after GF.We retrospectively reviewed 84 patients who underwent CBT at the University of Oklahoma between 2000 and 2016 and compared outcomes in patients with/without engraftment by Day 28. The nonengraftment cohort was further divided into patients who underwent retransplantation. Kaplan-Meier curves with log-rank tests were calculated to assess the association between mortality and engraftment.Engraftment following CBT was high at 81%, with 52% engrafting by Day 28 and an additional 29% engrafting by a median of 36 days. Retransplantation led to 88% engraftment at a median of 53 days. Overall, 75% of the 40 patients who did not engraft by Day 28 died. Female sex and total nucleated cell count 3.5/kg were significantly associated with lack of engraftment and higher mortality. Antibodies to Kell fetal antigen were not identified. Retransplantation by Day 28 for primary GF conferred a survival advantage.This study demonstrates that failure to engraft by 28 days was associated with increased mortality, and risk was mitigated with early retransplantation. Female sex and low total cell dose were associated with increased mortality. Early identification of GF coupled with early retransplantation can reduce mortality in CBT.

Background Despite an increase in our understandings of pathogenesis of thrombotic thrombocytopenic purpura (TTP), the approaches for initial diagnosis and management of TTP vary significantly. Objective The evidence-based guidelines of the International Society on Thrombosis and Haemostasis (ISTH) are intended to support patients, clinicians, and other health care professionals in their decisions about the initial diagnosis and management of acute TTP. Methods In June 2018, ISTH formed a multidisciplinary panel that included hematologists, an intensive care physician, nephrologist, clinical pathologist, biostatistician, and patient representatives, as well as a methodology team from McMaster University. The panel composition was designed to minimize the potential conflicts of interests. The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach and the Population, Intervention, Comparison, Outcome framework to develop and grade their recommendations. Public comments were sought and incorporated in the final document. Results The panel agreed on three recommendations covering the initial diagnosis with emphasis on the importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or inhibitor) and assessment of the pretest probability of TTP by clinical assessment and/or the risk assessment models like the PLASMIC or French score. The panel noted how availability and turnaround time of ADAMTS13 test results might affect early diagnosis and management, in particular the use of caplacizumab. Conclusions There is a lack of high-quality evidence to support strong recommendations for the initial diagnosis and management of a suspected TTP. The panel emphasized the importance of obtaining ADAMTS13 testing in a proper clinical context. Future research should focus on how to monitor and act on ADAMTS13 levels during remission.

Background Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its appropriate treatment. Methods In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to immune-mediated TTP (iTTP) and hereditary or congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations. Results The panel agreed on 11 recommendations based on evidence ranging from very low to moderate certainty. For first acute episode and relapses of iTTP, the panel made a strong recommendation for adding corticosteroids to therapeutic plasma exchange (TPE) and a conditional recommendation for adding rituximab and caplacizumab. For asymptomatic iTTP with low plasma ADAMTS13 activity, the panel made a conditional recommendation for the use of rituximab outside of pregnancy, but prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, and a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy. Conclusions The panel's recommendations are based on all the available evidence for the effects of an individual component of various treatment approaches, including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing the formation of ADAMTS13 autoantibody. There was insufficient evidence for further comparing different treatment approaches (eg, TPE, corticosteroids, rituximab, and caplacizumab, etc.), for which high quality studies are needed.

In this article, Borogovac et al emphasized the burden of stroke and neuropsychiatric symptoms in patients with hereditary thrombotic thrombocytopenic purpura (hTTP) based on an analysis of the International hTTP Registry. Given the rarity of hTTP, patient numbers were small; nevertheless, the prevalence of stroke reached 100% in patients over the age of 50. Nearly all patients also had evidence of neuropsychiatric symptoms. These data confirm the need to diagnose hTTP as early as possible and support the use of prophylaxis to prevent future events.

Background Evidence-based guidelines recommend that von Willebrand factor (VWF) levels be obtained in the third trimester of pregnancy to facilitate peripartum planning for women with von Willebrand disease (VWD). Objectives To identify the frequency of third trimester monitoring in a nationally representative sample of pregnant women with VWD in the United States, as well as the frequency of reproductive bleeding after pregnancy. Patients/methods Patient data were obtained from the Truven Health MarketScan Research Databases. International Classification of Diseases-9 codes were used to identify women with VWD and evidence of infant delivery. We defined third trimester monitoring as a laboratory claim for VWF levels during the 3 months before delivery. Clinical outcomes studied included postpartum hemorrhage (PPH) and heavy menstrual bleeding (HMB). Results We identified 2238 unique pregnant females with VWD. Of these, 32% (n = 714) underwent third-trimester testing of VWF levels. Diagnostic codes consistent with PPH were recorded for 6.5% of women in the 6 weeks after infant delivery. The frequency of PPH in women who underwent VWF monitoring (4.9%) was significantly lower than in those who did not undergo monitoring (7.3%), (risk difference -2.4%, 95% CI -4.4% to -0.3%, P = .023). Diagnostic codes consistent with HMB were recorded for 4.7% of women in the 3 months after infant delivery. Conclusions Third-trimester VWF monitoring was associated with a lower risk of PPH, but testing was performed in only one-third of insured pregnant women with VWD in the United States despite expert recommendations.

We previously identified gender disparities in academic success during evaluation of the American Society of Hematology (ASH) Clinical Research Training Institute (CRTI) and hypothesized that it may be related to caregiving. The objective was to evaluate the impact of gender and caregiving responsibilities on academic success. A cross-sectional survey that included a question about caregiving responsibilities was distributed to alumni who participated in CRTI from 2003 to 2016 and asked about academic productivity in the previous 3 years. Publications and grants were abstracted from submitted curriculum vitae. Academic success was defined as number of first- or senior-author publications, total publications, grants, and percent effort in research. Of 280 potential respondents, 258 responded (92% response rate), 169 (66%) had caregiving responsibilities, and 110 (43%) were men. Respondents with caregiving responsibilities had fewer first- or senior-author publications (median, 3 vs 5; P = .003) and less percent effort in research (median, 40% vs 50%; P = .006). Men had more first- or senior-author publications (median, 4 vs 3; P = .002) and more total publications (median, 12 vs 6.5; P = .0002) than women. When stratified by those without (P = .0001) or with (P = .042) caregiving responsibilities, men had more publications than women. Among men, caregiving responsibilities significantly reduced all outcomes. However, among women, caregiving did not have an impact. In conclusion, men had more publications than women whether or not they had caregiving responsibilities. However, among men, caregiving reduced academic productivity whereas among women, caregiving did not have impact. The scientific community will need to continue to identify the reasons for disparities and implement changes to address them.

Background Before the advent of radiosurgery, neurosurgical treatment of meningiomas typically involved gross total resection of the mass whenever surgery was deemed possible. Over the past 4 decades, though, Gamma Knife radiosurgery (GKRS) has proved to be an effective, minimally invasive means to control the growth of these tumors. However, the variables associated with treatment failure (regrowth or clinical progression) after GKRS and GKRS-related complications, such as cerebral edema, are less well understood. Methods We retrospectively collected data between 2009 and 2018 for patients who underwent GKRS for meningiomas. After data collection, we performed univariate and multivariable modeling of the factors that predict treatment failure and cerebral edema after GKRS. Hazard ratios (HR) and P values were determined for these variables. Results Fifty-two patients were included our analysis. The majority of patients were female (38/52,73%), and nearly all patients presented with a suspected or confirmed World Health Organization grade 1 meningioma (48/52, 92%). The median tumor volume was 3.49 cc (range, 0.22–20.11 cc). Evidence of meningioma progression after treatment developed in 5 patients (10%), with a median time to continued tumor growth of 5.9 months (range, 2.7–18.3 months). In multivariable analysis, patients in whom treatment failed were more likely to be male (HR = 8.42, P = 0.045) and to present with larger tumor volumes (HR = 1.27, P = 0.011). In addition, 5 patients (10%) experienced treatment-related cerebral edema. On univariate analysis, patients who experienced cerebral edema were more likely present with larger tumors (HR = 1.16, P = 0.028). Conclusions Increasing meningioma size and male gender predispose to meningioma progression after treatment with GKRS. Increasing tumor size also predicts the development of postradiosurgery cerebral edema.

Idelalisib targets PI3Kδ in the BCR pathway generating only a partial response in CLL patients, indicating that the leukemic cells may have evolved escape signals. Indeed, we detected increased activation of AKT accompanied by upregulation of MYC/BCL2 in post-therapy CLL cells from patients treated with idelalisib/ofatumumab. To unravel the mechanism of increased AKT-activation, we studied the impact of idelalisib on a CLL-derived cell line, MEC1, as a model. After an initial inhibition, AKT-activation level was restored in idelalisib-treated MEC1 cells in a time-dependent manner. As BCAP (B-cell adaptor for PI3K) and CD19 recruit PI3Kδ to activate AKT upon BCR-stimulation, we examined if idelalisib-treatment altered PI3Kδ-recruitment. Immunoprecipitation of BCAP/CD19 from idelalisib-treated MEC1 cells showed increased recruitment of PI3Kδ in association with PI3Kβ, but not PI3Kα or PI3Kγ and that, targeting both PI3Kδ with PI3Kβ inhibited AKT-reactivation. We detected similar, patient-specific recruitment pattern of PI3K-isoforms by BCAP/CD19 in post-idelalisib CLL cells with increased AKT-activation. Interestingly, a stronger inhibitory effect of idelalisib on P-AKT (T308) than S473 was discernible in idelalisib-treated cells despite increased recruitment of PI3Kδ/PI3Kβ and accumulation of phosphatidylinositol-3,4,5-triphosphate; which could be attributed to reduced PDK1 activity. Thus, administration of isoform-specific inhibitors may prove more effective strategy for treating CLL patients.

This study aimed to assess how the relationship between youth assets and future no-tobacco use among youth might differ according to race/ethnicity, neighborhood factors and socio-economic status. Five waves of annual data were collected from 1111 youth/parent pairs living in Oklahoma, USA who were randomly selected to participate in the Youth Asset Study (YAS). A marginal logistic regression model using all five waves of no-tobacco use, demographics, and their interaction was used to compare the change in tobacco use over time. Among 1111 youth, (Mean age = 14.3; 53% female; 39% White, 28% Hispanic, 24% Black, and 9% other), the percentage of youth tobacco use increased significantly from baseline to wave 5 (4 years after baseline) for all racial/ethnic groups and all parental income groups. Assets were prospectively associated with no tobacco use in the past 30 days for Black, White and Hispanic youth and for youth in all income categories (adjusted odds ratio range = 1.9–2.7). There was one statistically significant association between the neighborhood environment and future no tobacco use. To conclude, the protective effects of youth assets in terms of prevention of tobacco use among youth do not differ by youth race/ethnicity or parental income in the presence of neighborhood environmental factors.

Mitochondrial metabolism is the key source for abundant ROS in chronic lymphocytic leukemia (CLL) cells. Here, we detected significantly lower superoxide anion (O2−) levels with increased accumulation of hydrogen peroxide (H2O2) in CLL cells vs. normal B-cells. Further analysis indicated that mitochondrial superoxide dismutase (SOD)2, which converts O2− into H2O2 remained deacetylated in CLL cells due to SIRT3 overexpression resulting its constitutive activation. In addition, catalase expression was also reduced in CLL cells suggesting impairment of H2O2-conversion into water and O2 which may cause H2O2-accumulation. Importantly, we identified two CpG-islands in the catalase promoter and discovered that while the distal CpG-island (−3619 to −3765) remained methylated in both normal B-cells and CLL cells, variable degrees of methylation were discernible in the proximal CpG-island (−174 to −332) only in CLL cells. Finally, treatment of CLL cells with a demethylating agent increased catalase mRNA levels. Functionally, ROS accumulation in CLL cells activated the AXL survival axis while upregulated SIRT3, suggesting that CLL cells rapidly remove highly reactive O2− to avoid its cytotoxic effect but maintain increased H2O2-level to promote cell survival. Therefore, abrogation of aberrantly activated cell survival pathways using antioxidants can be an effective intervention in CLL therapy in combination with conventional agents.

OBJECTIVES To compare risks of distant-stage colorectal cancer (CRC) diagnosis between whites and American Indian/Alaska Natives (AI/ANs) and to explore effect modification by area-based socioeconomic status (SES). DESIGN Retrospective cohort study using data from the Oklahoma Central Cancer Registry. SETTING Oklahoma. PARTICIPANTS White and AI/AN cases of CRC diagnosed in Oklahoma between 2001 and 2008 (N = 8 438). A subanalysis was performed on the cohort of those aged 50 years and older (N = 7 728). MAIN OUTCOME MEASURE Risk of distant-stage CRC diagnosis stratified by SES score. RESULTS Race and SES were independently associated with distant-stage diagnosis. In SES-stratified analyses, AI/ANs in the 2 lowest SES groups experienced increased risks in the overall cohort and among those aged 50 years and older. In multivariable models, risks remained significant among those aged 50 years and older in the lowest SES groups (Adjusted risk ratio SES score of 2: 1.31, 95% confidence interval: 1.06-1.63 and adjusted risk ratio SES score of 1: 1.21, 95% confidence interval: 1.01-1.44). CONCLUSION Socioeconomic status is an effect modifier in the association between race/ethnicity and stage at CRC diagnosis. Disparities in stage at CRC diagnosis exist between AI/ANs and whites with lower estimated SES. Efforts are needed to increase CRC screening among lower SES AI/ANs.

Background: Despite an increasing incidence of venous thromboembolism (VTE) in pediatric patients in tertiary care settings, relatively few pediatric physicians have experience with antithrombotic interventions. Objective: These guidelines of the American Society of Hematology (ASH), based on the best available evidence, are intended to support patients, clinicians, and other health care professionals in their decisions about management of pediatric VTE. Methods: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews (up to April of 2017). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 30 recommendations, covering symptomatic and asymptomatic deep vein thrombosis, with specific focus on management of central venous access device–associated VTE. The panel also addressed renal and portal vein thrombosis, cerebral sino venous thrombosis, and homozygous protein C deficiency. Conclusions: Although the panel offered many recommendations, additional research is required. Priorities include understanding the natural history of asymptomatic thrombosis, determining subgroup boundaries that enable risk stratification of children for escalation of treatment, and appropriate study of newer anticoagulant agents in children.

The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.

Key Points The proposed guideline manuscript template is the first detailed template for transparent and complete reporting of guidelines.Consistent application of the template may simplify preparing an evidence-based guideline manuscript and facilitate its use., Visual Abstract, Trustworthy health guidelines should provide recommendations, document the development process, and highlight implementation information. Our objective was to develop a guideline manuscript template to help authors write a complete and useful report. The McMaster Grading of Recommendations Assessment, Development and Evaluation Centre collaborated with the American Society of Hematology (ASH) to develop guidelines for the management of venous thromboembolism. A template for reporting the guidelines was developed based on prior approaches and refined using input from other key stakeholders. The proposed guideline manuscript template includes: (1) title for guideline identification, (2) abstract, including a summary of key recommendations, (3) overview of all recommendations (executive summary), and (4) the main text, providing sufficient detail about the entire process, including objectives, background, and methodological decisions from panel selection and conflict-of-interest management to criteria for updating, as well as supporting information, such as links to online (interactive) tables. The template further allows for tailoring to the specific topic, using examples. Initial experience with the ASH guideline manuscript template was positive, and challenges included drafting descriptions of recommendations involving multiple management pathways, tailoring the template for a specific guideline, and choosing key recommendations to highlight. Feedback from a larger group of guideline authors and users will be needed to evaluate its usefulness and refine. The proposed guideline manuscript template is the first detailed template for transparent and complete reporting of guidelines. Consistent application of the template may simplify the preparation of an evidence-based guideline manuscript and facilitate its use.

Objectives: In women with recurrent ovarian cancer (OC), advanced care planning (ACP) such as advanced directives (AD), code status, and timely hospice referral should be addressed. In a high-volume, clinical trial focused cancer center, treatment with novel potentially life-prolonging therapies may alter timing of discussions. Our study compares patterns of ACP between trial and non-trial recurrent OC patients. Methods: All patients ≥18 years who were treated at a single institution for the diagnosis of OC during the year of 2015 and had ever recurred were reviewed. Patients who ever (n=84) versus never (n=41) participated in a therapeutic clinical trial (CT) were compared. Chi-square or Fisher's exact tests and 2 sided t-tests or Wilcoxon Rank-Sum tests compared demographic data and ACP variables of interest using an α = 0.05. Multivariable logistic regression estimated adjusted odds ratios (aOR) adjusted by CT participation, age, and Charlson comorbidity index. Results: A total of 125 patients were identified, and 84 (67%) participated in CTs. Cohorts were similar in age, BMI, insurance status, and histopathologic characteristics. Median time to follow up after first recurrence was 856 days in trial patients vs 308 days in non-trial patients (p Download : Download high-res image (331KB) Download : Download full-size image Conclusions: The time between the recurrence and code status discussions was significantly longer in CT participants, and ACP discussions occurred typically during or after a trial. ACP occurred more frequently when patients were referred to palliative or supportive care referral, independent of participation in either late phase or phase 1 CT. Prioritizing ACP and supportive care referral, especially in CT participants, may improve these rates and optimize end of life care.

Background: Health guideline development requires sequential prioritization of the guideline topic, questions, and health outcomes. In this paper we report on new approaches for prioritizing questions and outcomes in guidelines. Methods: Ten guideline panels on venous thromboembolism rated potential guideline questions on a 9-point scale according to their overall importance and 6 criteria: common in practice, uncertainty in practice, variation in practice, new evidence available, cost consequences, not previously addressed. We randomized panelists to rate one potential question with and without the 6 criteria. Panelists rated importance of outcomes, defined with health outcome descriptors (HODs), using a 9-point scale, and health utility of outcomes on a visual analogue scale. Results: Of 469 potential questions identified, 72.5% were rated as important but not of high priority, and 25.4% as high priority. Each criterion was significantly associated with the overall importance rating. The overall importance rating means were 5.96 (SD 2.38) and 6.53 (SD 2.45) ( P = 0.25) for those randomized to rate questions with and without the criteria, respectively. The mean importance rating for 121 outcomes was 6.01 (SD 1.25), with 35.5% rated as critical for decision-making. Panelists provided health utility ratings for 127 outcomes, with a minimum mean rating of 0.12 (SD 0.10) and maximum of 0.91 (SD 0.15). Conclusion: Our structured process provided information to help explain perspectives of question importance, to facilitate panels' outcome prioritization, and to facilitate decision-making in guideline development. (c) 2021 Published by Elsevier Inc.

Background Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its management. Methods In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to both immune-mediated TTP (iTTP) and hereditary/congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations. Results The panel agreed on eleven recommendations based on evidence ranging from very low to moderate certainty. For first episode and relapses of acute iTTP, the panel made a strong recommendation for the addition of corticosteroids to therapeutic plasma exchange (TPE), and a conditional recommendation for addition of rituximab and caplacizumab. For asymptomatic iTTP with low ADAMTS13, the panel made a conditional recommendation for rituximab outside of pregnancy, and for prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, but a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy. Conclusions The panel's recommendations are based on all the available evidence for the treatment effects of various approaches including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing ADAMTS13 antibody production. There was insufficient evidence for further comparison of different treatment approaches, for which future high-quality studies in iTTP (e.g., rituximab, corticosteroids, recombinant ADAMTS13, and caplacizumab) and in cTTP (eg, recombinant ADAMTS13) are needed.

Background: Randomized comparisons have demonstrated survival benefit of adjuvant immunotherapy in node-positive melanoma patients but have limited power to determine if this benefit persists across various demographic factors. Materials & methods: We assessed the impact of demographic factors on the survival benefit of adjuvant immunotherapy in a database of 38,189 node-positive melanoma patients using the Kaplan–Meier method and Cox proportional hazards models. Results: All assessed demographic factors other than race significantly impacted survival of node-positive melanoma patients in univariate analysis. In multivariable analysis, only the age group interacted with immunotherapy. Conclusion: Analysis of this large database of unselected node-positive melanoma patients demonstrated a positive survival benefit of immunotherapy across all demographic factors assessed and the impact was greater for patients 65 years of age and older., Graphical abstract Stage III melanoma patients who received immunotherapy were at a decreased hazard for death. The protective effect from immunotherapy was greater for those ≥65 years of age compared to those

Background: Immune-related adverse events are associated with efficacy of immune checkpoint inhibitors (ICIs). We hypothesize that immune-mediated thrombocytopenia could be a biomarker for response to ICIs. Materials & methods: This retrospective study included 215 patients with metastatic malignancies treated with ICIs. Patients were stratified by nadir platelet count. Outcomes of interest were progression-free survival and overall survival. Results: On multivariate analysis, grade 1 thrombocytopenia was positively associated with overall survival compared with patients who did not develop thrombocytopenia (hazard ratio [HR]= 0.28 [95% CI: 0.13–0.60]; p = 0.001), while grade 2–4 thrombocytopenia was not (HR= 0.36 [95% CI: 0.13–1.04]; p = 0.060). There was no association between degree of thrombocytopenia and progression-free survival. Conclusion: Follow-up studies are warranted to substantiate the predictive significance of thrombocytopenia in patients receiving ICIs., Lay abstract Immune checkpoint inhibitors (ICIs) are a class of drug that are increasingly being used in different cancers. The extent of response to treatment with ICIs differs among individuals. There is a lack of biomarkers, which would help clinicians predict response to ICIs. In our study, we aimed to explore the development of low platelets as a potential biomarker. Our findings suggest that cancer patients receiving ICIs who develop a mild decrease in platelet count tend to live longer than those who do not. However, this was not true for those who developed a severe decrease in platelet count. The mechanism of how ICIs affect platelets may be related to the interaction between the immune system and platelets. More studies are needed to validate our results and better understand the role of platelets in cancer biology.

OBJECTIVE: The goal of this study was to evaluate differences in levator ani hematoma formation within 3 days of delivery between adult women after their first vaginal delivery and adult women who have had multiple vaginal deliveries. METHODS: This was a cross-sectional study at a single institution from 2013 to 2015 using a high-resolution endovaginal ultrasound transducer to identify postvaginal delivery hematoma formation. Logistic regression was used to examine the association between hematoma formation and vaginal parity while considering potential confounders including induction, vaginal operative delivery, vaginal birth after cesarean, fetal weight, fetal head circumference, race and ethnicity, body mass index, age at delivery, gestational age, and length of second-stage labor. RESULTS: Ninety women (46 vaginal-primiparous; 44 vaginal-multiparous) were included in this study. After adjusting for oxytocin use, length of second-stage labor, and body mass index, the odds of pelvic floor hematoma of 1000 mm(3) or greater were 2.93 (95% confidence interval, 0.78–10.91) times greater in women after their first vaginal delivery compared with women with a history of multiple vaginal deliveries. The adjusted odds of pelvic floor hematoma of 1500 mm(3) or greater were 6.02 (95% confidence interval, 1.09–33.24) times greater in vaginal-primiparous compared with vaginal-multiparous women. CONCLUSIONS: Although the prevalence of pelvic floor hematoma was higher in vaginal-primiparous women than vaginal-multiparous women after vaginal delivery, hematomas were present in both groups. Future prospective studies are needed to evaluate the additive effect of multiple vaginal deliveries on the pelvic floor.

Background:Methods for the development of clinical guidelines have advanced dramatically over the past 2 decades to strive for trustworthiness, transparency, user-friendliness, and rigor. The American Society of Hematology (ASH) guidelines on venous thromboembolism (VTE) have followed these advances, together with application of methodological innovations.Objective:In this article, we describe methods and methodological innovations as a model to inform future guideline enterprises by ASH and others to achieve guideline standards. Methodological innovations introduced in the development of the guidelines aim to address current challenges in guideline development.Methods:We followed ASH policy for guideline development, which is based on the Guideline International Network (GIN)-McMaster Guideline Development Checklist and current best practices. Central coordination, specialist working groups, and expert panels were established for the development of 10 VTE guidelines. Methodological guidance resources were developed to guide the process across guidelines panels. A methods advisory group guided the development and implementation of methodological innovations to address emerging challenges and needs.Results:The complete set of VTE guidelines will include >250 recommendations. Methodological innovations include the use of health-outcome descriptors, online voting with guideline development software, modeling of pathways for diagnostic questions, application of expert evidence, and a template manuscript for publication of ASH guidelines. These methods advance guideline development standards and have already informed other ASH guideline projects.Conclusions:The development of the ASH VTE guidelines followed rigorous methods and introduced methodological innovations during guideline development, striving for the highest possible level of trustworthiness, transparency, user-friendliness, and rigor.

OBJECTIVES: Chemotherapy is the standard treatment in stage IVB cervical cancer (CC). However, given that many women have a significant pelvic disease burden, whole pelvic radiation (WPR) in addition to chemotherapy for primary treatment may have utility. The aim of this study was to compare the overall survival (OS) and complication rates between women who received both WPR and chemotherapy (CT) versus CT alone in the management of stage IVB CC. METHODS: A multi-institutional, IRB-approved, retrospective review of patients (pts) with stage IVB CC, diagnosed between 2005 and 2015, was performed. Descriptive statistics of the demographic, oncologic, and treatment characteristics were performed. OS was estimated using the Kaplan Meier method. RESULTS: A total of 126 pts met inclusion criteria. Thirty one patients elected for hospice care at diagnosis and were excluded from further analysis. In the remaining population, median age was 53 yrs. The majority (72%) had squamous cell carcinoma and 82% had FIGO grade 2 or 3 tumors. Thirty four patients (35.8%) received WPR in addition to CT as a part of planned primary therapy and 64.2% (n = 61) received CT alone, with 88.2% and 80.3% receiving a cisplatin-based chemotherapy regimen, respectively. The OS was significantly longer in the WPR with CT group (41.6 vs 17.6 mo, p < 0.01). The rates of ureteral obstruction, vaginal bleeding, pelvic infection, pelvic pain, and fistula were not significantly different between the 2 groups (all p > 0.05). CONCLUSION: This study found WPR in addition to CT gives a significant OS benefit. Further study is warranted to determine which subgroups may benefit the most from this novel treatment strategy.

Even though one of the public health's top achievements of the 20th century involves tobacco cessation, a disproportionate burden of tobacco-related comorbidity still affects those with mental illness (Centers for Disease Control and Prevention, 2017; Cook et al., 2014). There is evidence suggesting that psychiatric disorders are associated with an increased prevalence in cigarette smoking (Tsoi, Porwa, & Webster, 2013). One explanation for this is the potentiating effect of nicotine on dopamine receptors (Mao, Gallagher, & McGehee, 2011). Other explanations include poverty, educational advancement and industry bias in tobacco marketing (MMWR Vital Signs: Current Cigarette, 2016; CDC Morbidity and Mortality, 2013). We know that adults with mental illness smoke at rates twice that of the general population, and are nicotine-dependent at rates up to three times higher than the general population (Cook et al., 2014; Grant, Hasin, Chou, Stinson, & Dawson, 2004). Adults with mental illness comprise about 19% of the population, but smoke approximately one-third of all the cigarettes smoked (MMWR Vital Signs: Current Cigarette, 2016). In the United States, the national tobacco use prevalence is estimated at 19%; however, prevalence among those with bipolar disorder is 51%–70% and 36%–80% among those with major depressive disorder (Grant et al., 2004; King, Dube, & Tynan, 2012; Lasser et al., 2000). Despite these high rates, recent studies suggest that smokers with mental illness are highly motivated to quit (Cook et al., 2014). However, it remains rare for mental and behavioural health professionals to offer tobacco cessation pharmacotherapy and counselling to clients with psychiatric disorders.

Background Platelet counts of less than 150,000 per cubic millimeter during uncomplicated pregnancies are described as gestational thrombocytopenia if no alternative cause is identified. P...

Objectives Age imposes a disparity in the treatment of and outcomes with gynecologic cancer. Older patients are underrepresented in primary treatment trials, but little is known about their ability to withstand trial-based treatment for recurrent or refractory disease. This study sought to examine treatment-related toxicities and outcomes of older versus younger patients participating in phase 1 clinical trials. Methods A retrospective analysis of patients enrolled in phase 1 clinical trials for gynecologic malignancies from 2010 to 2016 was performed. Demographic and clinic-pathologic data was abstracted. Toxicities were defined as either grade III or IV by CTCAE criteria. Best response was calculated using RECIST criteria. Associations between categorical variables were determined using Fisher's exact test and continuous variables using Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. Results 237 patients were included with 22% ( n =51) comprising the older cohort (≥70years). The vast majority (98%) were treated for recurrent disease. Older patients incurred similar grade III/IV hematologic (21% vs 16%, p =0.38) and non-hematologic toxicities (26% vs 29%, p =0.64). Older patients discontinued treatment due to toxicity only 8% of the time. Median survival was 13.0 and 10.3months in the p =0.35). 63% of patients ≥70 achieved clinical benefit. Conclusions Although historically older patients have not been routinely considered for enrollment in phase 1 trials, our data demonstrates similar toxicity profiles to that of younger patients and 63% clinical benefit rate. Thus, with careful selection, patients ≥70 should be considered when facing recurrent or refractory gynecologic cancer.

While patients with immune thrombocytopenia (ITP) and low platelet counts are at risk for bleeding, they are not protected against arterial and venous thrombotic events. Frequently, hematologists are asked to consult on a patient with ITP requiring an antiplatelet (AP) agent or anticoagulant (AC). No direct evidence exists to guide hematologists in weighing the risk of thrombosis against the risk of bleeding in patients with ITP. Therefore, we performed a survey to determine the preferred management of AP/AC therapy in ITP patients. The survey described hypothetical patient scenarios and asked respondents to recommend a minimum platelet count for initiation of AP/AC therapy. We surveyed both hematologists with an international reputation in treatment of ITP (n = 48) and also general hematologist–oncologists in Oklahoma (n = 97). Response rates were 38/48 (79%) for the ITP specialists and 46/97 (47%) for general hematologist–oncologists. Overall, recommended platelet thresholds for antithrombotic therapy were similar between ITP specialists and general hematologist–oncologists. Although both groups recommended a minimum platelet count of 50 × 109/L for AP and AC therapy in most scenarios, there was great variability in individual practice patterns among respondents. This study highlights the need for studies of patients with ITP who require AP/AC therapy to provide high-quality evidence for establishing optimal management strategies.

Introduction: Our previous qualitative studies of immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors revealed that patients did not communicate to their hematologists about residual cognitive and fatigue issues. A way to overcome this communication barrier is implementation of patient-reported outcomes (PROs) in routine care. Integration of PROs into the clinical care of other diseases has resulted in improved patient-provider communication, symptom management, quality of life and overall patient satisfaction. However, decisions about the mode of administration are challenging. Although 92% of the United States population has access to the internet, studies have shown minorities prefer alternative modes of administration. Given that iTTP disproportionately affects Black women, understanding patient preference is critical for integrating PRO instruments into routine care. The primary study goal was to determine the preferred mode of administration of PRO instruments in iTTP. Furthermore, many individuals use the internet as a source of medical information/advice. A study of iTTP literacy reported that only 34% of survivors correctly identified disease relapse risk factors suggesting a critical knowledge gap. A secondary goal was to describe iTTP survivors' behaviors regarding using the internet for medical information or support. Methods: We utilized a cross-sectional study design. iTTP survivors were recruited from August 2019 until present. Eligibility included: 1) age >18 years, 2) documented ADAMTS13 deficiency (< 10% activity) at diagnosis or during a relapse and 3) > 1-year clinical remission. Multi-center recruitment of survivors included: Oklahoma University, Ohio State University, University of Minnesota, Johns Hopkins University, University of Rochester, University of Pennsylvania, University of Alabama at Birmingham, University of Utah and the University of Vermont. Following informed consent, survivors were administered the PROMIS ® cognitive function ability, anxiety and fatigue instruments via their preferred mode (online, telephone, or self-administered). Typical internet usage, behaviors regarding searching for health information online and demographics were also obtained. Results: To date, 94 survivors have completed the study (83% female; 54% White; 34% Black; median age 49 years [range 26-85 years]). A majority (54%) preferred completing PROMIS ® surveys online vs. self-administered or telephone administered. However, among Black survivors, only 38% preferred online administration and among survivors aged ≥65 years only 22% preferred online administration. Interestingly, there was an overall shift in a preference toward online administration following the onset of the COVID-19 pandemic (45% (21/47) preferred online pre vs 66% (31/47) preferred online post). Ninety-one percent (86/94) of survivors reported at least occasional internet use vs 8 (9%) reported none. Similarly, 82% (70/85) had searched the internet for health/medical information for themselves in the past year. Also 62% (53/86) of the survivors selected 'strongly agree' or 'agree' to the statement that the internet helps them determine if symptoms are important enough to see a doctor. Likewise, 62% used the internet to interpret doctor's recommendations. Additionally, 47% (40/86) 'strongly agree/agree' the internet helped determine if they would take a medication/seek alternative treatment. Moreover, 64% (55/86) agreed the internet was a good way to find others experiencing similar health problems. However, when asked about behaviors over the past year, only 42% (36/85) used online social networking sites like Facebook to look for health information or find others with iTTP and only 36% (31/85) had actually participated in online iTTP support groups. Conclusions: Overall iTTP survivors preferred online PRO administration; however, Black and older survivors preferred other methods. Recognizing these preferences is a vital step toward integrating PROs into routine care. Furthermore, iTTP survivors are using the internet as a source of medical support and information. Therefore, it is critical to not only educate iTTP survivors about credible online resources but also to create additional content. Also, future studies are needed to further explore the impact of the COVID-19 pandemic on online health behaviors. Disclosures Terrell: Sanofi: Consultancy; Takeda: Consultancy. Journeycake: HEMA Biologics: Honoraria; LFB: Honoraria. Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. Cuker: Spark Therapeutics: Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Synergy: Consultancy. Chaturvedi: Dova: Other: Advisory board member; UCB: Other: Advisory board participation; Argenx: Other: Advisory board member; Alexion: Other: Advisory board member; Sanofi Genzyme: Other: Advisory board member. Lim: Hema Biologics: Honoraria; Sanofi Genzyme: Honoraria; Dova Pharmaceuticals: Honoraria. Gangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy. Cataland: Alexion: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Ablynx/Sanofi: Consultancy, Research Funding; Takeda: Consultancy.

Introduction: Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) describe cognitive concerns years after acute episodes. However, these concerns are not routinely addressed during hematology visits. The Patient-Reported Outcomes Measurement Information System (PROMIS) cognitive function abilities survey is an easy to administer, valid, reliable, generic instrument that has not been evaluated in iTTP patients from the United States (US). Therefore, the first aim of this study was to compare PROMIS scores of iTTP patients in remission to the normative US population. Also, research in other disorders reported that a barrier to integrating PROMIS into routine care was physician uncertainty related to interpreting results. PROMIS instruments utilize normative scoring, which lacks clinical meaning. Therefore, creation of clinical severity cut-points ('mild', 'moderate', 'severe') is critical to facilitate clinical interpretation. The second aim was to create clinical severity thresholds for the PROMIS instrument. Methods: iTTP patients were recruited from 9 US centers (8/2019 to present). Eligibility included: 1) age >18 years, 2) documented ADAMTS13 deficiency (< 10% activity) at diagnosis or during a relapse and 3) > 1-year clinical remission. Following informed consent, patients were administered the PROMIScognitive survey via their preferred mode (online, telephone, or self-administered). The instrument focused on cognitive function over the last 7 days. Responses were a 5-point Likert scale ranging from 'not at all' (indicating poor function) to 'very much' (no current problem). Demographics and the PROMIS global health question ('In general, would you say your health is') were also obtained. Descriptive statistics summarized patient scores relative to the US population (mean 50, SD 10) with lower scores indicating worse function. Additionally, we determined the T-score ranges for patients who reported 'not at all/a little bit' on all cognitive items and for those who reported 'quite a bit/very much' on all cognitive items. The upper end of the T-score range for patients reporting 'not at all/a little bit' determined the threshold for 'Severe' impairment and the lower end of the T-score range for those reporting 'quite a bit/very much' determined the threshold for 'No/Mild' impairment. Scores greater than the threshold for 'Severe' but lower than the threshold for 'No/Mild' were considered 'Moderate' cognitive impairment. Patients were then classified into a severity category based on their T-scores. As a descriptive validity check, we compared the proportion of patients reporting 'excellent/very good' on the global health question between the 'Severe' and 'No/Mild' impairment classifications. Results: To date, 94 patients have completed the study (83% female; 54% White; 34% Black; median age 49 years [range 26-85 years]). Overall the mean cognitive score was 45 (SD 9) compared to the US mean 50 (SD 10). Patients who preferred online administration had a mean score of 47 (SD 9) vs patients who preferred telephone or self-administered (mean score of 43 [SD 9]). T-scores for patients reporting 'not at all/a little bit' on all items ranged from 23.4-35.1. Based on T-scores, 14 patients (15%) were then classified as having 'Severe' cognitive impairment with T-scores < 35.1 (Figure 1). Only 14% of patients classified as having 'Severe' cognitive impairment reported their general health as 'excellent/very good'. T-scores for patients reporting 'quite a bit/very much' on all items ranged from 49.2-68.9. Thirty-one (33%) patients were classified as 'No/Mild' impairment with T-scores >49.2 (Figure 1) and 52% of these patients classified their health as 'excellent/very good'. Conclusion: iTTP patients in remission have descriptively lower cognitive scores versus the US population. Our results are similar to those reported from a cohort of iTTP patients from the United Kingdom (PROMIS cognitive mean 40, SD 8). Further, results showed that patients with cognitive T- scores 49, who have no/mild cognitive impairment. This is the first study to create clinical severity thresholds for the PROMIS cognitive function abilities instrument. Our data provide clinical meaning for PROMIS which should facilitate clinical use in iTTP by identifying patients with severe impairment who need referral to specialists. Figure 1 Figure 1. Disclosures Terrell: Sanofi: Consultancy; Takeda: Consultancy. Journeycake: LFB: Honoraria; HEMA Biologics: Honoraria. Mazepa: Sanofi Aventis: Other; Answering TTP Foundation: Research Funding. Cuker: Novartis: Research Funding; Bayer: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Synergy: Consultancy; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Takeda: Research Funding. Chaturvedi: Sanofi Genzyme: Other: Advisory board member; Alexion: Other: Advisory board member; Dova: Other: Advisory board member; Argenx: Other: Advisory board member; UCB: Other: Advisory board participation. Lim: Hema Biologics: Honoraria; Dova Pharmaceuticals: Honoraria; Sanofi Genzyme: Honoraria. Gangaraju: Sanofi Genzyme: Consultancy; Alexion: Consultancy. Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Takeda: Consultancy; Alexion: Consultancy, Research Funding.

BACKGROUND Chordomas are rare tumors arising from the embryonal notochord presenting at the base of skull, spine, or sacrum. Pediatric chordomas (PC) comprise less than 5% of all chordomas and are more likely to be atypical or dedifferentiated. Evidence for management is limited to single institution series with 5-year overall survival (OS) between 60-100%. METHODS Using the NCDB Participant User File, a retrospective observational cohort study was performed. The cohort was defined using the bone-soft-tissue, brain, and central nervous system databases selecting for cases with chordoma ICD-03 codes and age ≤ 25 years. Kaplan Meier method, log-rank test, and Cox proportional hazards regression were performed. RESULTS 297 patients from 2004-2017 met inclusion criteria for descriptive analysis with 269 cases included for survival analysis. Mean age was 16.9 years, with 10% less than age 5. The cohort was 55% female, 8% Black, and 79% White. Primary sites included bones of the skull (70%), spine (22%), and pelvis (6%). Regarding treatment, 7% had no resection, 49% sub-total resection (STR), 33% gross-total resection (GTR), and 11% unspecified resection. 51% received radiation therapy with 46% of those receiving proton therapy. 7% received chemotherapy. The 1, 3, 5, and 10-year OS was 95%, 86%, 77%, and 72%. Selected prognostic factors from univariable OS model for OS analysis included: age > 5 (HR 0.30 (95% CI 0.16-0.57) p = 0.0002), surgical resection [GTR (HR 0.28 (95% CI 0.12-0.63) p = 0.0023) and STR (HR 0.27 (95% CI 0.12-0.59) p = 0.0011)], and radiation dose ≥ 7200cGy (HR 0.40 (95% CI 0.16-0.99) p = 0.047). CONCLUSION In the largest cohort reported for PC, 3 and 10-year OS was 86% and 72%. Age, surgery, and radiation dose are important prognostic factors. Propensity score analysis to gauge effect of treatment, tumor, and patient characteristics on OS is forthcoming.