Pathologic Nodal Staging Before SBRT for Early-stage NSCLC Does Not Impact Overall Survival: A Propensity Score-matched NCDB Analysis.

OBJECTIVE: Stereotactic body radiation therapy (SBRT) for early-stage non-small cell carcinoma of the lung (NSCLC) is increasingly utilized. We sought to assess overall survival (OS) for early-stage NSCLC patients receiving SBRT depending on staging method. METHODS: Early-stage NSCLC patients treated with definitive SBRT were identified in the National Cancer Database (NCDB), and OS was determined based on method of staging. Patient, disease, and treatment characteristics were also analyzed. RESULTS: A total of 12,106 patients were included; 865 (7%) received invasive staging (nodal sampling, NS) and 11,241 (93%) had no nodal sampling (NNS). From this larger dataset, a propensity score matching (1:1 without replacement) was performed, which yielded 839 patients for each group (NNS and NS). With a median follow-up time of 3.12 years, median survival for all patients included in the matched dataset was 2.75 years (95% CI: 2.55-2.93 y), with 2- and 5-year OS estimated at 63.9% and 25.7%, respectively. In a multivariable analysis on matched data, there was no difference in mortality risk between the NNS and NS groups (hazard ratio=1.08, 95% CI: 0.94-1.24, P =0.25). Negative prognostic factors identified in the multivariable analysis of the matched data included: age more than 65, male sex, Charlson-Deyo Score ≥1, and tumor size ≥3 cm. CONCLUSIONS: SBRT use in early-stage NSCLC steadily increased over the study period. Most patients proceeded to SBRT without nodal staging, conflicting with National Comprehensive Cancer Network (NCCN) guidelines which recommend pathologic mediastinal lymph node evaluation for all early-stage NSCLC cases, except stage IA. Our findings suggest similar OS in patients with early-stage NSCLC treated with SBRT irrespective of nodal staging. Furthermore, we highlight patient-related, disease-related, and treatment-related prognostic factors to consider when planning therapy for these patients.

Association between Serum Biomarkers with Postoperative Complications and Delay of Adjuvant Chemotherapy Initiation in Ovarian Cancer Patients Undergoing Primary Cytoreductive Surgery: A Pilot Study.

This study sought to describe and relate the factors associated with complications and delays in adjuvant chemotherapy in patients with ovarian cancer treated with primary cytoreductive surgery. Serum from patients diagnosed with ovarian cancer scheduled for primary cytoreductive surgery were analyzed for prealbumin, 25-OH Vitamin D, intracellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), monocyte chemoattractant protein 2 (MCP-2), macrophage derived chemokine (MDC). Postoperative complications were identified using common terminology criteria for adverse events 4.0 and 30 day after surgery. Delays in adjuvant chemotherapy were defined as >1 week interval between surgery and initiation. Patients with postoperative complications (39.6%) were significantly older, had lower serum prealbumin levels, and higher serum IL-6 and IL-8 than those without. Univariate logistic regression found that age (OR: 1.12, 95%CI: 1.00-1.35) and IL-6 (OR: 1.02, 95%CI: 0.99-1.05) were associated with postoperative complications, whereas age remained significant after multivariate analysis (OR:1.14, 95%CI: 1.00-1.29). Patients with delays in chemotherapy exhibited greater BMI and lower 25-OH Vitamin D than those without. Multivariate analysis found that increasing levels of 25-OH Vitamin D were associated with a lower risk of delayed chemotherapy initiation after controlling for age, body mass index, and tumor grade (OR: 0.93, 95%CI:0.87-0.99). This work suggests that in addition to age being predictive of postoperative complications, serum 25-OH Vitamin D may a provide insight into a patient's risk for postsurgical delays in chemotherapy initiation. These findings should, however, be confirmed in a larger study including robust survival analysis.

In a small cohort, increasing age was associated with postsurgical complications in patients with ovarian cancer following primary cytoreductive surgery.In patients with ovarian cancer following primary cytoreductive surgery delays in adjuvant chemotherapy initiation were inversely associated with serum 25-OH vitamin D status.

Incidence and risk factors for graft failure in the modern era of cord blood transplantation.

BACKGROUND AND OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Youth Assets, Neighborhood Factors, Parental Income, and Tobacco Use: A Longitudinal Study of Health Disparities.

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.

Idelalisib activates AKT via increased recruitment of PI3Kδ/PI3Kß to BCR signalosome while reducing PDK1 in post-therapy CLL cells.

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 PI3Kß, but not PI3Kα or PI3Kγ and that, targeting both PI3Kδ with PI3Kß 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/PI3Kß 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.

SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis.

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.

The Prevalence of Pelvic Floor Hematoma After Vaginal Delivery.

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 mm3 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 mm3 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.

Disparity in outcomes of melanoma adjuvant immunotherapy by demographic profile.

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.

Development of thrombocytopenia is associated with improved survival in patients treated with immunotherapy.

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.

Surgery Versus Surveillance for Well-Differentiated, Nonfunctional Pancreatic Neuroendocrine Tumors: An 11-Year Analysis of the National Cancer Database.

BACKGROUND: Pancreatic neuroendocrine tumors (panNETs) are a rare group of tumors that make up 2%-3% of pancreatic tumors. Recommended treatment for panNETs generally consists of resection for symptomatic or large asymptomatic tumors; however, optimal management for localized disease is still controversial, with conflicting recommendations in established guidelines. Our study aim is to compare surgical intervention versus active surveillance in nonmetastatic panNETs by size of primary tumor. MATERIALS AND METHODS: Using the National Cancer Database, we identified 2,004 patients diagnosed with localized well-differentiated, nonfunctional panNETs (NF-panNETs) between 2004 and 2015. Patients' clinicopathologic characteristics, treatment modalities, and overall survival (OS) were analyzed using frequency statistics, chi-square, and Kaplan-Meier curves. The objective of the study is to assess the outcome of surgical resection versus nonoperative management in patients with panNETs with different tumor sizes. RESULTS: Tumor sizes were divided into three categories: <1 cm, 1-2 cm, and >2 cm. The number of patients with tumor size <1 cm, 1-2 cm, and >2 cm was 220 (11%), 794 (39.6%), and 990 (49.4%), respectively. Overall, 1,781 underwent surgical resection, whereas 223 patients did not. Median follow-up was 25.9 months. After adjusting for covariates, surgical resection was associated with improved OS in patients with tumor size 1-2 cm (hazard ratio [HR] = 0.37) and >2c m (HR = 0.30) but not <1 cm (HR = 2.81). Independent prognostic factors were age at diagnosis, Charlson-Deyo comorbidity score, stage, tumor location, and surgical resection. Higher tumor grade was not associated with worse OS. CONCLUSION: Our findings suggest that active surveillance is potentially a safe approach for NF-panNETs <1 cm. Larger tumors likely need active intervention. Intermediate-grade tumors did not result in worse survival outcome compared with low-grade tumors. Future studies might consider prospective randomized clinical trials to validate our findings. IMPLICATIONS FOR PRACTICE: The present study seeks to address the discrepancy in treatment recommendations in the management of nonfunctional pancreatic neuroendocrine tumors (NF-panNETs) by evaluating whether surgical resection is associated with improved overall survival in different tumor size groups as well as elucidating independent prognostic factors in patients with NF-panNETs. Data from the National Cancer Database were reviewed. This study's findings suggest that active surveillance is potentially a safe approach for NF-panNETs <1 cm. Larger tumors likely need active intervention. Independent prognostic factors include age at diagnosis, Charlson-Deyo comorbidity score, stage, tumor location, and surgical resection. These findings will help guide medical and surgical oncologists when formulating treatment plans for patients with small NF-panNETs.

Predictors of Outcome in Patients With Fibrolamellar Carcinoma: Analysis of the National Cancer Database.

BACKGROUND: Fibrolamellar carcinoma (FLC) is a very rare liver tumor. We aimed to retrospectively analyze the clinicopathological factors and treatment modalities affecting overall survival (OS) in FLC. The objective of the study was to identify predictors of survival in FLC. PATIENTS AND METHODS: Using the National Cancer Database, we identified 496 patients diagnosed with FLC between 2004 and 2015. Clinicopathological, treatment, and survival data were collected. RESULTS: Hepatic resection was performed on 254 (51.2%) patients, liver-directed therapy on 13 (2.6%) patients, and liver transplantation on 15 (3.0%) patients. Median OS by stage were 142.1, 87.2, 32.3, and 14.1 months for stages 1, 2, 3, and 4, respectively. Metastatectomy was not associated with superior median OS (23.4 vs. 10.5 months, p=0.163). Age ≤40, low Charlson-Deyo comorbidity score, early stage and hepatic resection were independently associated with longer OS. CONCLUSION: Our study reports current trends in FLC management, and identifies independent predictors of OS.

Incorporation of whole pelvic radiation into treatment of stage IVB cervical cancer: A novel treatment strategy.

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.

Effect Modification of the Association Between Race and Stage at Colorectal Cancer Diagnosis by Socioeconomic Status.

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.

Factors Associated with Treatment Failure and Radiosurgery-Related Edema in WHO Grade 1 and 2 Meningioma Patients Receiving Gamma Knife Radiosurgery.

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.

Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade.

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.

Prospective Evaluation of Multinational Association of Supportive Care in Cancer Risk Index Score for Gynecologic Oncology Patients With Febrile Neutropenia.

BACKGROUND: The Multinational Association of Supportive Care of Cancer (MASCC) risk-index score has been validated as a stratification tool for febrile neutropenia (FN) risk in a heterogeneous group of cancer patients; recently, it has been deemed a suitable tool in gynecologic oncology patients in a retrospective study. This is a prospective multi-institutional study wherein we sought to validate MASCC score for stratifying FN morbidity in gynecologic oncology patients. METHODS: IRB approval was obtained at 4 institutions for prospective data collection of gynecologic cancer patients admitted with FN from 3/1/2013 to 9/1/2014. Participating institutions have a policy of inpatient management of FN patients receiving chemotherapy. Deidentified data was compiled and processed at the leading institution. RESULTS: In total, 31 patients met inclusion criteria. Most had advanced stage disease (67%). 100% of patients were receiving chemotherapy (57% for primary, 43% for recurrent disease). 55% had a positive culture. Median MASCC score was 21 (range, 10 to 26); 58% of patients were considered low risk. High risk patients more often had one (11% vs. 38%, P=0.09) or multiple (6% vs. 23%, P=0.28) severe complications, ICU admission (0% vs. 15%, P=0.17), and delay in next chemotherapy cycle (33% vs. 54%, P=0.25). No patients died from FN during the study period. CONCLUSIONS: This pilot data suggests that MASCC score may be a promising tool for determining suitability of outpatient management of FN in gynecologic oncology patients. Larger studies are warranted to achieve statistically significant results, which may enable us to effectively utilize this risk stratification tool for cost containment and avoidance of nosocomial infections.

Patterns of von Willebrand Disease Screening in Girls and Adolescents With Heavy Menstrual Bleeding.

OBJECTIVE: To estimate the frequency of von Willebrand disease screening and factors that affect screening frequency in a national sample of girls and adolescents with heavy menstrual bleeding. METHODS: In this retrospective cohort study, we used a national claims database for privately and publicly insured patients between 2011 and 2013 for girls aged 10-17 years. Diagnostic criteria of heavy menstrual bleeding were the presence of one inpatient or two outpatient International Classification of Diseases, 9th Revision codes for heavy menstrual bleeding. We defined severe heavy menstrual bleeding as heavy menstrual bleeding plus an inpatient stay for menstrual bleeding, iron deficiency anemia, or blood transfusion. To assess whether patient- or facility-level characteristics affected screening, we performed logistic regression analysis including patient age, health care provider type seen at first visit for menorrhagia, patient residence in a metropolitan statistical area (proxy for urban vs rural inhabitance), and approximate travel time to the nearest hemophilia treatment center. RESULTS: We identified 23,888 postpubertal girls and adolescents with heavy menstrual bleeding (986 with severe heavy menstrual bleeding). Von Willebrand disease screening was performed in 8% of females with heavy menstrual bleeding and 16% with severe heavy menstrual bleeding. Younger age at diagnosis, commercial insurance, and living within a metropolitan statistical area were associated with higher screening rates. Patients who underwent testing for iron deficiency anemia had the highest likelihood of undergoing screening (odds ratio 7.08, 95% CI 6.32-7.93). Among patients living in a metropolitan statistical area, those 60 minutes or more from a hemophilia treatment center were less likely to undergo screening. CONCLUSION: Despite recommendations by the American College of Obstetricians and Gynecologists for more than 15 years, fewer than 20% of postpubertal girls and adolescents with heavy menstrual bleeding underwent screening for von Willebrand disease in this cohort. Increased clinician awareness and adherence to recommended screening recommendations may increase diagnosis of von Willebrand disease.