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Introduction : General surgery residents often feel unprepared to perform pediatric surgery procedures since case volume and experience may be low. Previously, we successfully implemented a simulation-based training (SBT) module for placement of a silastic silo for gastroschisis. Therefore, we designed a single institution pilot study to assess whether SBT for placement of a percutaneous peritoneal drain for perforated necrotizing enterocolitis (NEC) was feasible and lead to skill acquisition and increased confidence. Methods : Our newly created NEC module within our pediatric surgery SBT curriculum for general surgery residents was used. Residents completed two simulation sessions three months apart with confidence testing before and after each session. Skill acquisition and performance were assessed using a standardized case scenario and procedure checklist. Changes in residents’ confidence and performance were determined using Wilcoxon Signed-Rank Tests. Results : Nine post-graduate-year three general surgery residents completed this curriculum. Following completion, residents reported improved confidence completing each step of the procedure initially (p = 0.005) and at 3 months (p = 0.008) with improved technical scores (p = 0.011). The number of residents deemed proficient significantly improved (p = 0.031). Conclusion : Implementation of SBT module for perforated NEC was feasible and improved residents’ confidence and proficiency completing the procedure.

Gastrostomy tube (GT) placement is a common pediatric procedure with high postoperative resource utilization. We aimed to determine if standardized discharge instructions (SDI) reduced healthcare utilization rates.We performed a retrospective cohort study comparing postoperative hospital utilization of patients who underwent initial GT placement pre- and post-SDI protocol implementation from 2014-2019. Statistical analyses included Chi-square tests, multivariable adjusted logistic regression, adjusted Cox proportion hazard regression, and adjusted Poisson regression models when appropriate.197 patients were included, 102 (51.8%) before and 95 (48.2%) after protocol implementation. On primary analysis, SDI patients did not have significantly different total postoperative hospital utilization events at 30-days (48.0% vs. 38.9%, p = 0.25). On secondary analysis, SDI patients had lower rates of ED (8.4% vs. 19.6%, p = 0.026) and office visits (11.6% vs. 25.5%, p = 0.017) at 30-days. Non-SDIs patients had greater odds of ED visits (OR2.7, 95%CI 1.3-5.9, p = 0.01), office visits (OR3.7, 95%CI 1.7-8.1, p = 0.001) and phone calls (OR2.6, 95%CI 1.2-5.7, p = 0.016) at 1-year. The adjusted hazard ratio was 2.0 (95%CI 1.4-3.0, p 0.001). Incident rate ratio were 1.8 (95%CI 1.2-2.5, p = 0.002) at 30-days and 1.9 (95%CI 1.5-2.4, p 0.001) at 1-year post-discharge.SDIs post-GT placement may reduce multiple aspects of postoperative hospital utilization.

Introduction The disruption score is a new bibliometric tool that has recently been utilized to identify studies that are innovative and shift paradigms. We sought to identify and characterize the top 100 most disruptive publications in pediatric surgery. Methods The 100 most disruptive and cited publications in 17 pediatric surgery journals were identified from a validated dataset and linked with the iCite NIH tool. The top 100 most disruptive publications were reviewed to determine study design, clinical focus, and perceived contribution. Results The publications included in the top 100 list were more disruptive than 99.5% of the entire PubMed universe. Journal of Pediatric Surgery (n = 45) had the most articles included. There was a weak correlation between citation count and disruption score (r = 0.27). Retrospective cohort studies (38%), contributions in clinical outcomes (39%), technical/technological innovations (31%), clinical focus in trauma (18%), and disorders of the gastrointestinal tract (18%) were the most represented. The disruption score identified a unique subset of literature that has created new paradigms with long lasting influence and may be further applied as another tool to measure scientific impact. This wide array of literature highlights both technical and technological innovations as well as key moments in the history of pediatric surgery. Level of evidence V

Clinical and genomic data from patients with early-stage breast cancer suggest more aggressive disease in premenopausal women. However, the association between age, disease course, and molecular profile from liquid biopsy in metastatic breast cancer (MBC) is not well characterized.Patients were classified as premenopausal ( 45 years), perimenopausal (45-55 years), or postmenopausal ( 55 years). Cohort 1 consisted of patients with MBC who consented for prospective serial evaluation of circulating tumor cells (CTCs) using CellSearch™. Cohort 2 included patients who, as part of routine care, had circulating tumor DNA (ctDNA) sequenced by the Guardant360™ assay. Clinicopathologic data were collected from retrospective review to compare disease features between premenopausal and postmenopausal women.Premenopausal women represented 26% of 138 patients in Cohort 1 and 21% of 253 patients in Cohort 2. In Cohort 1, younger patients had a shorter time to metastases and a higher prevalence of lung and brain metastases. Overall, there were similar rates of ≥ 5 CTCs/7.5 mL, HER2 + CTC expression, and CTC clusters between pre- and postmenopausal women. However, for those with triple negative breast cancer, premenopausal women had a higher proportion of ≥ 5 CTCs/7.5 mL. In Cohort 2, premenopausal women had a higher incidence of FGFR1 (OR 2.75, p = 0.022) and CCND2 (OR 6.91, p = 0.024) alterations. There was no difference in the ctDNA mutant allele frequency or the number of detected alterations between these age groups.Our data reveal that premenopausal women diagnosed with MBC have unique clinical, pathologic, and molecular features when compared to their postmenopausal counterparts. Our results highlight FGFR1 inhibitors as potential therapeutics of particular interest among premenopausal women.

BACKGROUND: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. METHODS: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. RESULTS: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. CONCLUSIONS: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.)

ObjectiveSystemic sclerosis (SSc) results in impaired function, disability, and reduced health-related quality of life. We investigated the effect of coping strategies on the patient global assessment of health (PtGA) and Health Assessment Questionnaire–Disability Index (HAQ-DI), after controlling for clinical characteristics and disease activity. We also explored the relationship between coping strategies and the correlation between the PtGA and physician global assessment (PGA) in SSc.MethodsWe undertook posthoc analyses using baseline data obtained from the Raynaud Symptom Study (RSS). The PtGA, Coping Strategies Questionnaire, Pain Catastrophizing Scale, and Scleroderma Health Assessment Questionnaire were collected alongside the PGA, clinical characteristics, and patient demographics. Multivariable linear regression models and correlations were used to evaluate the relationship between coping strategies with the PtGA, HAQ-DI, and PGA.ResultsOf the 107 patients with SSc enrolled in the RSS, there were sufficient data available for the analysis of 91 participants. The mean PtGA was 40/100 (SD 27) and the mean HAQ-DI was 0.87/3.0 (SD 0.73). After controlling for clinical and patient demographics, pain catastrophizing and maladaptive coping skills were significantly associated with the PtGA and HAQ-DI scores (P < 0.05 for both), but not the PGA.ConclusionThe effect of coping strategies on PtGA and HAQ-DI (but not PGA in SSc) could influence the result of composite measures incorporating these outcome measures. Interventions to improve patient coping skills may support increased resilience and improve patient-perceived functional status and PtGA in SSc.

PURPOSE: Right ventricular (RV) capacity to adapt to increased afterload is the main determinant of outcome in pulmonary hypertension (PH), a common morbidity seen in systemic sclerosis (SSc). We hypothesized that supine bicycle echocardiography (SBE), coupled with RV longitudinal systolic strain (RVLSS), improves detection of limitations in RV reserve in SSc. METHODS: 56 SSc patients were prospectively studied during SBE with RV functional parameters compared at rest and peak stress. We further dichotomized patients based on resting RV systolic pressure (RVSP) to determine the effects of load on contractile response. RESULTS: Our pooled cohort analysis revealed reduced global RVLSS at rest (−16.2 ± 3.9%) with normal basal contractility (−25.6 ± 7.7%) and relative hypokinesis of the midventricular (−14.1 ± 6.0%) and apical (−8.9 ± 5.1%) segments. With exercise, global RVLSS increased significantly (p=0.0005), however despite normal basal contractility at rest, there was no further augmentation with exercise. Mid and apical RVLSS increased with exercise suggestive of RV contractile reserve. In patients with resting RVSP < 35 mmHg, global and segmental RVLSS increased with exercise. In patients with resting RVSP ≥35 mmHg, global and segmental RVLSS did not increase with exercise and there was evidence of exertional RV dilation. CONCLUSION: Exercise provocation in conjunction with RVLSS identified differential regional contractile response to exercise in SSc patients. We further demonstrate the effect of increased loading conditions on RV contractile response exercise. These findings suggest subclinical impairments in RV reserve in SSc that may be missed by resting noninvasive 2DE-based assessments alone.

Background: Malrotation is a common congenital anomaly that can lead to bowel obstruction and ischemia if not corrected with a Ladd procedure. Controversy exists between open and laparoscopic appro...

Purpose: Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer. Experimental Design: This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board–approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression. Results: We identified 44 hormone receptor–positive, 20 HER2+, and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were TP53 (P < 0.0075), PIK3CA (P < 0.0126), AR (P < 0.0126), FGFR1 (P < 0.0455), and ESR1 (P < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 (P = 0.0026, and P < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA (P = 0.0042 and P < 0.0001, respectively). Conclusions: Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution.

Introduction: Circulating tumor cells (CTCs) are the roots of metastasis which is the main cause for death in metastatic breast cancer (MBC). CTCs enumeration is strongly prognostic in advanced disease and can stratify patients in two distinct disease, Stage IV aggressive and Stage IV indolent. In the former disease, the detection of CTC clusters and HER2-expression increase prognostic and predictive value. The metastatic cascade is a complex, regulated process involving immune cells and endothelial cells for progression and neoangiogenesis. Circulating endothelial cells (CECs) from the inner wall of blood vessels are shed into the blood stream during formation of blood vessels which is considered a sensitive marker of endothelial damage in pathological conditions such as cancer. CECs have been also studied as a biomarker for tumor progression and monitoring anti-angiogenic therapeutic effects in MBC. We evaluated the concomitant detection of CTCs and CECs in MBC patients, along with expression of HER2 in CTCs that may offer an interesting clue to elucidate the metastasis mechanisms. Methods: Whole blood samples (7.5ml/each) were collected from 14 stage IV MBC patients before systemic therapy. CTCs enumeration was performed in FDA approved CELLTRACKS System (Menarini) by using CTC Kit contains specific antibodies targeting the EpCAM for capturing CTCs, anti-CK-PE (for epithelial cells), DAPI (for nucleus), anti-CD45-APC (for leukocytes), and anti-HER-2/neu-FLU. The CTCs were classified as CK+, EpCAM+, DAPI+ and CD45-. Meanwhile, the same patients’ blood samples (4.0ml/each) were processed for CEC analyzed by using CEC kit which immunomagnetically captures CD146+ cells, and then stains the cells for CD105-PE (specific for protein endolgin), CD45-APC, nucleus-DAPI. The positive CECs were classified as CD 146+, CD105+, DAPI+ and CD45-. The associations between CTCs, HER2 expression and CECs were evaluated. Results: The average age of patients was 53.1. Subtypes of Luminal, HER2 positive and TNBC were 64.2% 7.2% and 28.6% respectively. Distant metastasis were found in 13 out of 14 patients, including bone (7), liver (5), Lymph nodes (5) and Pleura (2). CTCs were found positive (≥5, Stage IV aggressive) in 5 patients (range: 5-47, mean=24), and HER expression was identified in all 5 of these cases with a range of numbers between 1 and 7 (mean=4.2). The ratios of HER+ CTC/total ratios were 8.51%, 17.95%, 20%, 30.77%, and 33.33%. HER2 expression were defined officially in our lab according to the percentile of positive HER2 CTCs/Total CTCs and the expression intensity as - ( Citation Format: Qiang Zhang, Paolo D'Amico, Jeannine Donahue, Lorenzo Gerratana, Andrew A. Davis, Saya Liz Jacob, Zheng Cai, Elena Vagia, Wenan Qiang, Ami N. Shah, Katy Kerby, Lisa Flaum, Youbin Zhang, Firas Wehbe, Amir Behdad, William Gradishar, Leonidas Platanias, Massimo Cristofanilli. The detection and enumeration of circulating tumor cells (CTCs) and circulating endothelial cells (CECs) in metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-06.

Background Currently, there are no validated data derived from prospective trials that demonstrate a benefit from anti-HER2 targeted therapy in HER2 negative advanced breast cancer (ABC) patients (pts) bearing HER2 expressing (HER2+) circulating tumor cells (CTCs). Although some retrospective studies suggest that a group of these pts could benefit from a target treatment, a substantial proportion of those will never respond. A better characterization of the HER2+ CTCs could improve the pts selection. We hypothesize that a high correlation between different HER2+ CTCs subgroups and the HER2 status on solid biopsy can predict the likelihood of response of the corresponding subgroup. Here we propose a simple algorithm to identify those HER2+ CTCs subgroups that have demonstrated a higher correlation with HER2+ positivity in the solid biopsy. Methods The IRB-approved study retrospectively analyzed blood samples at two different timepoints (before treatment and at the first evaluation) from 110 ABC pts treated at Northwestern University (Chicago, IL) between 2016 and 2019. CTCs were enumerated through CellSearch™ (Menarini Silicon Biosystems, Bologna, Italy), and characterized for HER2 expression using the CellSearch CXC Kit. HER2 expression in CTCs was defined and categorized in 4 different categories (0,1+,2+,3+) as previously reported (Riethdorf et al., 2010). Four different scores were assessed in their ability to predict a HER2 positive disease (based on metastases HER2 status). Score 0 (negative CTCs), Score 1 (1+ CTCs), Score 2 (2+ CTCs), Score 3 (3+ CTCs) and Score 4 (cHER2 ratio, defined as the sum of 2+ CTCs and 3+ CTCs divided by the total number of CTCs). The performance of these 4 different biomarkers was explored longitudinally through the Wilcoxon test. Results: Out of 110 pts, 49 showed a CTCs count ≥ 5 (stage IV aggressive). Among these pts, Score 0 was associated with a HER2 negative disease with an area under the ROC curve (AUC) of 0.14. No correlation was found between Score 1 and HER2 status (AUC 0.45). A marginally significant association was found in Score 2 and Score 3 (AUC respectively 0.67 and 0.64). A direct correlation was observed between Score 4 and Her2 status (AUC 0.73). The analysis performed on stage IV indolent patients showed a non-significant association among all 4 scores. Significant association was not found among the scores and molecular subtypes, only a numerical increase among HER2+ disease and Score 3 and Score 4 (respectively p=0.06 and p=0.1). The patients were observed longitudinally and a dynamic Score evaluation was performed. No significant changes were found among Score 1 and Score 2 at the two different timepoints (p= 0.35 and p=0.11). Both, Score 0 and Score 4 were significantly decreased among pts at the second timepoint (p=0.0019 and 0.006) Conclusions The data highlighted a strong performance of cHER2 ratio (score4) identifying a HER2 positive disease on tissue biopsy, comparable with the known ability of score0 (presence of only HER2 negative CTCs) to predict a HER2 negative tissue biopsy. Furthermore, the cHER2 ratio has proven to be dependent on the treatment administration, allowing to be considered as a predictive biomarker in future study, to gain a prospective validation. Citation Format: Paolo D'Amico, Lorenzo Gerratana, Ami Shah, Qiang Zhang, Andrew Davis, Youbin Zhang, Saya Jacob, Elena Vagia, Amir Behdad, Carolina Reduzzi, Giuseppe Curigliano, Massimo Cristofanilli. The HER2 circulating ratio to define HER2 expressing circulating tumor cells in advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-15.

Introduction: Previously reported data from our group and others have demonstrated an increase in genomic complexity and number of alterations over the course of treatment in MBC. Our study aims to categorize the pathogenicity of genomic aberrations found on serial ctDNA evaluations in MBC to explore the relevance of emerging mutations. Methods: Patients with MBC and ctDNA next-generation sequencing (NGS) analysis by Guardant360 (Guardant Health, Redwood City, CA) completed from 2015 to 2019 were retrospectively identified with an IRB-approved protocol. Clinical-pathologic features and time point for progression of disease were abstracted from review of the electronic medical record. Among the 255 patients with ctDNA analysis, 85 patients had serial ctDNA analysis from baseline and at subsequent progression of disease (PD1) and 27 had repeat ctDNA analysis at next progression (PD2). Genomic alterations were classified as oncogenic, likely oncogenic, predictive oncogenic, likely benign, inconclusive, unknown significance, and synonymous based on categorization by OncoKB.org (Chakravarty et al, JCO PO 2017). Oncogenic, likely oncogenic, and predicted oncogenic were considered ‘pathogenic’ while the remainder were ‘not known pathogenic’. Two-sample t-tests for difference of means (α = 0.05) was used for analysis of changes in pathogenic proportions and mutant allele frequencies (MAF). Results: The median age was 53.8 years, 41 patients had hormone receptor positive (HR+) HER2-negative, 22 had HER2+, and 22 had triple negative (TN) MBC. The median and interquartile range (IQR) of the time of MBC diagnosis to first ctDNA collection was 10 mo (0.3-23.1 mo), from baseline ctDNA to analysis at the time of disease progression (PD1) was 6.7 mo (3.6-12.5 mo), and from PD1 to second progression (PD2) was 4.6 mo (3.1-8.5 mo). At baseline 66% of alterations were pathogenic (38.4% oncogenic, 27.6% likely oncogenic, 26.5% unknown significance). The proportion of pathogenic variants did not significantly change over time: 62% at PD1 (p=0.41) and 56% at PD2 (p=0.19). The percent of pathogenic alterations by disease subtype at baseline and PD1 was 66% and 60% in HR+ HER2-, 73% and 57% in HER2+, and 62% and 71% in TN. 57% and 70% of patients had a new pathogenic alteration at PD1 and PD2, respectively. The most frequently detected new pathogenic alterations at the time of disease progression were TP53, PIK3CA, ESR1, FGFR1, and MYC, which occurred in 28%, 18%, 15%, 12%, and 11% of patients, respectively. Among genes that were altered in at least 10% of patients, the aberrations were very likely to be pathogenic (>75% of alterations pathogenic) for TP53, PIK3CA, ESR1, MYC, BRAF, FGFR1, often pathogenic (50-75% of alterations pathogenic) for NF1, KIT, GATA3, ERBB2, EGFR, CCNE1, PDGFRA, and often not known pathogenic ( Citation Format: Ami N Shah, Andrew A Davis, Saya Jacob, Lorenzo Gerratana, Brian Finkelman, Shruti Chandra, Neelima Katam, Firas Wehbe, Jeeven Srivastava, Ashwin Sunderraj, Qiang Zhang, Leonidas Platanias, Amir Behdad, William Gradishar, Massimo Cristofanilli. Evaluating the pathogenicity of emerging genomic aberrations detected by circulating tumor DNA over the course of metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-26.

Background: Circulating tumor DNA (ctDNA) has emerged as a potential tool for detecting disease recurrence, monitoring response to therapy, and identifying resistance mutations in the peripheral blood. With increased frequency of testing, there is an unmet need to recognize putative germline variants in ctDNA, and the probability that these variants are associated with inherited conditions. Here, we evaluated a large cohort of breast cancer patients who underwent ctDNA evaluation to determine the type and frequency of ctDNA mutations identified with confirmed germline testing. Methods: We reviewed ctDNA testing from a single institution (Northwestern University). All breast cancer patients who had next-generation sequencing (NGS) performed by Guardant Health (Redwood City, CA) from 2015-2020 were included in this retrospective study. An allele frequency cutoff of 30% was pre-established as a threshold to review patient charts to determine whether genetic counseling and germline testing were performed, along with the timeframe of this testing (e.g. before or after ctDNA evaluation). Clinical information including demographics, pathology, tissue NGS testing, and germline testing were collected. Descriptive analyses and statistical associations were performed using STATA. Results: The initial cohort consisted of 520 patients with breast cancer who underwent ctDNA testing. From this, we identified 84 patients (16.2%) who had at least one variant with allele frequency ≥30%. The most common variants identified were the following: TP53 (34%), PIK3CA (27%), BRCA1 (9%), BRCA2 (8%), and AKT1 (4%). Guardant360 classified 99% of these variants as pathogenic and 1% as a variant of unknown significance. Germline positivity using a separate CLIA-approved test for this indication was confirmed at the following frequencies: BRCA1 (2 of 8 positive, 25%), BRCA2 (2 of 5 positive, 40%), PIK3CA (0 of 5 positive), and TP53 (0 of 26 positive). In total, 14% of patients with ctDNA allele frequency ≥30% had a confirmed germline mutation. Lower age at breast cancer diagnosis was significantly associated with the probability of germline testing prior to ctDNA evaluation (P=0.0001). For patients who had a variant with allele frequency ≥30%, 24.3% never received genetic counseling or germline testing. Conclusion: High allele frequency ctDNA variants (≥30%) were present in 16% of patients who underwent ctDNA evaluation with 14% of these variants confirmed as true germline variants. Consenting patients for ctDNA testing should include the possibility of identifying putative germline variants, and criteria should be established to refer patients for subsequent genetic counseling and germline testing, given the potential implications for patients and their family members. Citation Format: Andrew A Davis, Michael C Burns, Lorenzo Gerratana, Paolo D'Amico, Saya Jacob, Ami Shah, Neelima Katam, Firas Wehbe, Qiang Zhang, Elena Vagia, Lisa Flaum, Kalliopi P. Siziopikou, Leonidas C Platanias, Amir Behdad, William J Gradishar, Massimo Cristofanilli. Identification of incidental putative germline variants in circulating tumor DNA [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-08.

Introduction: Prognosis of metastatic breast cancer (MBC) is initially predicted by the cancer’s characteristics based on AJCC TNM system, including the size of the cancer tumor, invasion into nearby tissue, lymph nodes and other parts of the body beyond the breast. Although additional information including hormone-receptor status, HER2 status, and possibly Oncotype DX score contributed to improve prognostic evaluation, predicting clinical outcomes and treatment benefit for MBC is still a challenge in clinic because of the clinical and biologically heterogeneous condition. We recently reported that CTCs enumeration can classify MBC in two distinct prognostic groups independently of clinical and molecular characteristics (Crit Rev Oncol Hematol. 2019). Moreover, our group reported that CTCs is associated with HER2 expression in MBC which may indicate more aggressive tumor (2019 AACR #1919). Here we compared CTCs enumeration of Stage III and Stage IV, which would be helpful to evaluate the MBC metastasis capability and treatment in clinic. Methods: The study included 38 specimens prospectively collected under IRB-approved protocol from 38 patients with Stage III MBC, and 254 specimens from 254 patients with stage IV MBC who received standard systemic treatments based on disease subtypes at NMH (2016-2020). Duplicate whole blood samples (7.5ml/each) were collected in EDTA tubes from these patients who were longitudinally characterized for CTCs before therapy (baseline). CTCs enrichment and enumeration were performed in FDA approved semi-automated fluorescence CELLTRACKS ANALYZERII® System (Menarini) by using CELLSEARCH® CXC Kit contains antibodies targeting the Epithelial Cell Adhesion Molecule (EpCAM) antigen for capturing CTCs, anti-CK-PE which is specific for the intracellular protein cytokeratin in epithelial cells, DAPI for staining the cell nucleus, anti-CD45-APC is specific for leukocytes (2019 ASCO #1036). The CTCs were classified based on morphology and correct phenotype as CK+, DAPI+ and CD45-. Kruskal-Wallis test was used for statistics. Results: Patients were classified as Luminal, HER2 positive and TNBC disease subtypes in 46.6%, 46.7% and 6.7% respectively in Stage III patients, and 54%, 18% and 28% respectively in Stage IV patients. The patients at age above 50 were 26.% in Stage III group and 68% in Stage IV group respectively. IBC patients represented 61.5% and 33.5% of Stage III and Stage IV patients respectively. Metastasis in liver, lung and bone were diagnosed in 40.7%, 40.2% and 62.8% in Stage IV patients. CTC negative ( Citation Format: Qiang Zhang, Zheng Cai, Lorenzo Gerratana, Paolo D'Amico, Andrew A. Davis, Saya Liz Jacob, Elena Vagia, Ami N Shah, Lisa Flaum, Youbin Zhang, Wenan Qiang, Firas Wehbe, Amir Behdad, William Gradishar, Leonidas C Platanias, Massimo Cristofanilli. Prognostic value of baseline circulating tumor cells (CTCs) enumerations is for stage III and stage IV breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-20.

Background The enumeration of Circulating Tumor Cells (CTCs) in the peripheral blood of patients (pts) with metastatic breast cancer (MBC) showed prognostic value independent of clinic-pathological characteristics and proposed as a new tool for Stage IV stratification. Molecular characterization of CTCs with analysis of standard HER2 and estrogen-receptor (ER) status provides additional predictive value. The presence of HER2 positive CTCs (CTCs-HER2+) has been documented in pts with HER2 negative MBC and suggestive of tumor heterogeneity. The molecular features associated with the detection of these cells and the clinical significance of CTCs-HER2+ remains of unclear clinical significance. The lack of validated prospective trials limits the use of this immunophenotypic characterization as a prognostic and predictive factor. We conducted an analysis of a large cohort of patients with MBC evaluated for CTCs enumeration (CTCs+), molecular analysis of CTCs (CTCs-HER2+) and ctDNA. Methods The IRB-approved study prospectively analyzed blood samples of pts with MBC enrolled before starting a new line of therapy. Samples were collected from pts treated at Northwestern University (Chicago, IL) between 2016 and 2020. ctDNA was analyzed using the Guardant360 NGS assay (Guardant Health) with a specific focus on the detection of ERBB2 mutations. CTCs were enumerated through CellSearch™ (Menarini Silicon Biosystems, Bologna, Italy), and characterized for HER2 expression using the CellSearch CXC Kit. HER2+ CTCs were divided in 4 different categories (0,1+,2+,3+), leaning on fluorescence intensity, as previously reported by Riethdorf et al. Pts with 0.75 (cHER2high), cHER2 ratio Citation Format: Paolo D'Amico, Qiang Zhang, Lorenzo Gerratana, Youbin Zhang, Ami Shah, Carolina Reduzzi, Andrew Davis, Saya Jacob, Firas Wehbe, Amir Behdad, Giuseppe Curigliano, Massimo Cristofanilli. Ctc-her2+ a novel subset in stage IVaggressive: Molecular correlations, outcome and clinical characteristics in metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-11.

Background: As the role of precision medicine in metastatic breast cancer (MBC) expands, there is an increasing emphasis on diagnostic tools to characterize both somatic and germline alterations that drive carcinogenesis. Circulating tumor DNA (ctDNA) has provided an important means for real-time, non-invasive detection and monitoring of tumor somatic alterations without standard paired white blood cell testing. However, its application for the detection of germline mutations remains relatively understudied. Here, we characterize the role of BRCA1&2 ctDNA mutant allele frequency (MAF) to identify underlying putative germline BRCA1&2 mutations. Methods: Patient data were retrospectively obtained under an IRB-approved protocol to review ctDNA data at Northwestern University between 2015 and 2020. All ctDNA samples were analyzed using the Guardant360 next-generation sequencing (NGS) assay (Guardant Health). Patients with ctDNA alterations in the BRCA genes were identified at all mutant allele frequencies (MAF). Clinical data were collected including breast cancer subtype, prior lines of therapy, tissue-based NGS and germline testing information. Separate CLIA-approved testing performed per standard of care was used as the gold standard for germline testing. Statistical analysis was used to test the association of MAF cut-offs with the presence or absence of a germline alteration. Receiver operating characteristic (ROC) analysis was performed. Results: We identified 127 patients with breast cancer who underwent ctDNA collection. There were 69 HR+ HER2-, 24 HER2+, and 34 triple negative breast cancer (TN) patients. Of these, 8 patients had known BRCA1 germline mutations, as confirmed with separate germline testing, and 9 patients had known BRCA2 germline mutations. BRCA1 germline mutations were significantly association with age < 40 (p=0.016) and triple negative subtype (p=0.042). Mean ctDNA BRCA1 MAF was 2.27% (Standard Deviation {SD} 10.19%) and mean BRCA2 MAF was 2.04% (SD 9.51%). BRCA1/2 MAF was analyzed with respect to germline mutations through ROC analysis. For BRCA1 ctDNA MAF cut-off 32.4% was associated with confirmed putative germline mutation. This cutoff demonstrated sensitivity of 1 and specificity of 0.99. Area under the curve (AUC) was 1.00 at this cut-off. For BRCA2, ctDNA MAF cutoff of 28.5% was associated with confirmed putative germline mutations. This cutoff demonstrated sensitivity of 0.86, specificity of 0.99 and AUC of 0.93. Discussion: ctDNA alterations of BRCA1 with MAF>32.4% and BRCA2 with MAF>28.5% in clinical ctDNA testing were useful criterion to identify germline BRCA mutations. The data suggest the potential to utilize ctDNA as a diagnostic tool to predict germline mutations based on MAF thresholds. Future prospective studies are needed to determine how ctDNA testing may be incorporated into existing clinical algorithms to refer patients for germline testing. Citation Format: Saya Jacob, Andrew Davis, Paolo D'Amico, Lorenzo Gerratana, Michael Burns, Ami Shah, Neelima Katam, Firas Wehbe, Qiang Zhang, Elena Vagia, Lisa Flaum, Kalliopi Siziopikou, Leonidas Platanias, Amir Behdad, William Gradishar, Massimo Cristofanilli. Circulating tumor DNA (ctDNA) as a diagnostic tool to identify putative germline BRCA mutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-10.

Background Surgical simulation-based training (SBT) can increase resident confidence and improve performance. SBT in pediatric surgery is in its infancy and often geared toward training pediatric surgery fellows. Since case volume for various pediatric surgery–specific procedures can be low based on the rarity of the pathology involved and the level of care provided by the institution, our aim was to create a pediatric surgery simulation-based curriculum for general surgery residents to address this need. Materials and methods We performed an institutional needs assessment consisting of 4 pediatric surgeons' and 28 general surgery residents’ confidence in resident ability to independently perform pediatric surgery–specific tasks and procedures using a Likert-scaled survey. These included the placement of a silastic silo for gastroschisis, a percutaneous drain for perforated necrotizing enterocolitis, and completion of a laparoscopic pyloromyotomy for pyloric stenosis. Models simulating these pathologies and curriculum for performing each procedure were generated. Results We successfully created a model and SBT curriculum to teach general surgery residents how to place a silastic silo for patients with gastroschisis, a percutaneous drain for patients with perforated necrotizing enterocolitis, and how to complete a laparoscopic pyloromyotomy for patients with pyloric stenosis. These were deemed high fidelity models based on a survey of our pediatric surgeons. Conclusions We created a pediatric surgery SBT curriculum for general surgery residents, which can be used to supplement learning of various high-acuity, low-occurrence procedures. Assessment of residents and validation of scores is underway.

Background Epidemiologic data suggest that patients with systemic lupus erythematosus (SLE) have a lower risk of breast cancer than women in the general population. In light of mechanistic studies suggesting that anti-DNA antibodies have anti-cancer effects, we sought to examine breast cancer risk in autoantibody strata in a well-characterized SLE cohort. Methods SLE patients without a cancer diagnosis prior to entry in the Hopkins Lupus Cohort were studied (N = 2431). Overall and site-specific cancer incidence was calculated in racial strata and compared with the US Surveillance, Epidemiology and End Results (SEER) registry. Breast cancer incidence was further examined in autoantibody subsets. Patients were considered positive for an autoantibody if they were ever positive for a specificity during their disease course. Results Patients with SLE had a 37% lower risk of breast cancer (SIR 0.63, 95% CI 0.39–0.95). The risk of HPV-associated cancers (SIR 4.39, 95% CI 2.87–6.44) and thyroid cancer (SIR 2.27, 95% CI 1.04–4.30) was increased. Cancer risk varied by race, with breast cancer protection occurring in non-African Americans (SIR 0.29, 95% CI 0.11–0.63) and the increased risk of HPV-associated cancers occurring in African Americans (SIR 7.23, 95% CI 4.35–11.3). Breast cancer risk was decreased in patients ever positive for anti-dsDNA (SIR 0.55, 95% CI 0.29–0.96), anti-La (SIR 0.00, 95% CI 0.00–0.78), and lupus anticoagulant (SIR 0.37, 95% CI 0.10–0.94). Patients who were positive for fewer (0–2) SLE autoantibodies did not have a lower risk of breast cancer (SIR 0.84, 95% CI 0.47–1.39), but patients with 3+ autoantibodies had a 59% decreased risk (SIR 0.41, 95% CI 0.16–0.84). Conclusions Positivity for multiple SLE autoantibodies was associated with a lower risk of breast cancer, supporting the hypothesis that a highly diversified immune response may exert an anti-cancer effect against some cancers. Validation of racial differences in cancer risk in SLE is required to determine whether cancer screening strategies should be targeted to racial subgroups.

Mycophenolate is the mainstay of treatment for many organ and life-threatening manifestations of rheumatic and musculoskeletal diseases (RMD). In contrast to most patients with RMD, those taking mycophenolate have an attenuated humoral response to SARS-CoV-2 mRNA vaccination.1 2 The American College of Rheumatology recently recommended withholding mycophenolate for 1 week after vaccination to enhance immunogenicity in this vulnerable population.3 Thus, we sought to analyse the impact of withholding perivaccination mycophenolate in 24 patients with RMD. We leveraged our observational prospective cohort of patients with RMD without prior COVID-19 who underwent SARS-CoV-2 vaccination between 17 December 2020 and 13 May 2021.2 Information on demographics, diagnoses, immunosuppressive regimens and management of perivaccination immunosuppression was collected via electronic questionnaire. One month following vaccination, venipuncture samples were obtained and tested on the semiquantitative Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay which tests for antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein; a consistent correlate of neutralising antibody.4 We compared the percentage of participants with detectable anti-RBD antibody in the group that withheld mycophenolate (n=24) to the group that continued mycophenolate (n=171) using Fisher’s exact test (online supplemental table 1). Crude and adjusted logistic regression analyses were performed to assess associations between antibody response and the primary variable of withholding mycophenolate, as well as after adjusting for clinical characteristics (age, sex, race, vaccine type (mRNA vs adenovirus vector), use of rituximab and glucocorticoids). Wilcoxon rank-sum test was used to compare anti-RBD titers of the …

Objective The aim of this study is to describe 4 of the most common autoantibodies against components of the Th/To complex: human POP1 (hPOP1), RPP25, RPP30, and RPP40. We report their prevalence and clinical characteristics in a systemic sclerosis (SSc) population, and determine whether these specificities are associated with cancer. Methods A case-control study was performed using data from the Johns Hopkins Scleroderma Center Cohort. A total of 804 adult patients with SSc were included; 401 SSc patients with no history of cancer after at least 5 years of disease were compared to 403 SSc patients who ever had a history of cancer. Antibodies against hPOP1, RPP25, RPP30, and RPP40 were assayed by immunoprecipitation of 35 S-methionine-labeled proteins generated by in vitro transcription/translation. Demographic and clinical characteristics were compared between groups. Results Of 804 patients, 67 (8.3%) had antibodies against any component of the Th/To complex. Patients with antibodies to any component were significantly more likely to have limited cutaneous disease, less likely to have tendon friction rubs, and more likely to have findings consistent with interstitial lung disease or pulmonary hypertension. Patients with antibodies against hPOP1, RPP25, RPP30, and/or RPP40 were significantly less likely to develop cancer within 2 years of SSc onset (0% versus 11% of antibody-negative patients; P = 0.009). Conclusion SSc patients who produce autoantibodies to components of the Th/To complex have a clinical phenotype characterized by limited cutaneous disease and pulmonary involvement. Our findings show that the presence of any Th/To autoantibody may have a protective effect against contemporaneous cancer.

Approximately 12,000 women between 20 and 39 years of age are diagnosed with invasive breast cancer (BC) annually in the USA. We aim to summarize data regarding the impact of BC treatment on fertility and strategies for fertility preservation in young women with BC. Standard curative therapies for breast cancer can lead to subfertility, infertility, and primary ovarian insufficiency by their direct gonadotoxic effects and/or by delaying the age at which a woman can attempt pregnancy. Oocyte and embryo cryopreservation are the preferred options for fertility preservation and, if done efficiently within an established referral system, will not negatively impact long-term outcomes or the ability to receive neoadjuvant therapy in a timely fashion. Gonadotropin-releasing hormone agonists may be included alongside chemotherapy but should not be relied on for fertility preservation. All premenopausal women should be counseled regarding the potential impact of systemic therapies on fertility. A multi-disciplinary approach is needed, including early referral to reproductive endocrinology, to effectively address fertility concerns in young patients with breast cancer.

Many studies have demonstrated an increased risk of cancer in patients with rheumatologic diseases, including systemic sclerosis. Less explored is the role of immunosuppressive therapy as a contributing factor in cancer emergence or detection. This series introduces two cases of patients with systemic sclerosis who demonstrated clinical improvement in their rheumatic disease process with immunosuppression, but both of whom developed neurologic symptoms in the setting of decreasing or discontinuing immunosuppressive therapy, leading to the ultimate diagnosis of Epstein–Barr virus positive diffuse large B-cell lymphoma of the central nervous system. To our knowledge, primary central nervous system lymphoma has not been previously described in systemic sclerosis patients. Immunosuppressive therapies could promote the development of virus-associated malignancies due to decreased viral clearance. We hypothesize that removing immunosuppression could allow the immune system to generate an inflammatory response to an underlying tumor or viral antigen, contributing to development of neurologic symptoms and detection of underlying disease.

The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion rate in a US cohort of early disease. Participants included SSc patients with less than 5 years disease duration consented and enrolled in the Collaborative, National, Quality, and Efficacy Registry (CONQUER) between June 2018 and December 2019. Participants' socio-demographics, hand clinical features (severe modified Rodnan skin score, presence of small joint contractures, acro-osteolysis, calcinosis, and digital ulcers), and completion rates of seven PROMs including a Resource Use Questionnaire were analyzed. Cohort characteristics and baseline PROM completion were evaluated. Multivariable logistic regression assessed the relationship between hand limitations and PROM incompletion at several time points using generalized estimating equations. At the time of data lock, 339 CONQUER subjects had a total of 600 visits available for analysis. Calcinosis (odds ratio [OR] 6.35, confidence interval [CI] 2.41-16.73 and acro-osteolysis OR 3.88 (1.57-9.55) were significantly associated with incomplete PROM. The Resource Use Questionnaire was the PROM most commonly not completed. Increasing age was correlated with resource use questionnaire incompletion rate. Acro-osteolysis and calcinosis were associated with lower PROM completion rates in a US SSc cohort, independent of the length of the questionnaires or the modality of administration (electronic or paper). Resource Use Questionnaires are important for understanding the economic impact and burden of chronic disease; however, in this study, it had lower completion rates than PROMs devoted to clinical variables. Key points •Multiple strategies are needed to ensure optimal completion of PROM in longitudinal cohort studies. Even if patients request electronic surveys, we have found it is important to follow up incomplete surveys with paper forms provided at the time of a clinical visit. •The Resource Utilization Questionnaire was lengthy and prone to non-completion in the younger population. •Acro-osteolysis and calcinosis were associated with reduced PROM completion rates.

Advancements in the care for patients with early stage HER2-positive breast cancer is a story of incremental successes aimed at optimizing efficacy and reducing the toxicities of administered therapies. HER2 drives an aggressive breast cancer subtype that represents 15%-20% of breast cancers, for which HER2-targeted therapy is very active. In addition to trastuzumab, pertuzumab, neratinib, and ado-trastuzumab emtansine have been approved in recent years for the treatment of high-risk early stage HER2-positive breast cancer. As a result of both a high response rate to neoadjuvant therapy and the opportunity for response-adapted adjuvant therapy, the treatment paradigm has evolved so that most patients with stage II and III disease now receive neoadjuvant therapy. Additionally, the efficacy of HER2-therapy allows for de-escalation of treatment in many patients with stage I disease. As a result, multidisciplinary evaluation is essential for the optimal care of patients with HER2-positive breast cancer. Important areas of further research include tailoring the duration and intensity of therapy based on disease risk and response to neoadjuvant therapy. This article will review the evaluation of patients with early stage HER2-positive breast cancer and provide an evidence- and guideline-based summary of risk-based treatment strategies.

Objective: To directly observe the in vitro real-time effects of intense pulsed light (IPL) on a Demodex mite extracted from an eyelash of a patient with ocular rosacea. Background: Demodex is a ri...

Breast cancer is the most common malignancy in young women worldwide, accounting for an estimated 30% of new cancer diagnoses and 25% of cancer deaths. Approximately two thirds of young women with breast cancer have hormone receptor–positive (HR+)/human epidermal growth receptor 2–negative (HER2−) tumors. Numerous studies, primarily in early‐stage breast cancer, have demonstrated that young age is an independent risk factor for more aggressive disease and worse outcomes. Although more limited data are available regarding outcomes in young patients with advanced disease, these age‐related disparities suggest that breast cancer in premenopausal women has distinct clinicopathologic and molecular features that can impact treatment outcomes. Until recently, limited data were available on the intrinsic molecular subtypes and genetics of young patients with HR+/HER2− metastatic breast cancer (mBC). In this review, we explore insights into the clinical and pathologic features of HR+/HER2− mBC in younger women derived from recent clinical trials of the cyclin‐dependent kinase 4/6 inhibitors palbociclib (PALOMA‐3), ribociclib (MONALEESA‐7), and abemaciclib (MONARCH 2) and the implications of these findings for clinical practice, guideline development, and future research. Implications for Practice This review provides clinicians with an overview of emerging data on the unique clinicopathologic and molecular features of hormone receptor–positive/human epidermal growth receptor 2–negative metastatic breast cancer (mBC) in premenopausal women, summarizes findings from the most recent clinical trials of endocrine‐based treatment in this patient population, and explores the implications of these findings for clinical practice, guideline development, and future research. Improved understanding of the key factors influencing disease course and treatment response in premenopausal patients with mBC may lead to more timely incorporation of evidence‐based treatment approaches, thereby improving patient care and outcomes., Age‐related disparities in breast cancer care suggest that breast cancer in premenopausal women has distinct features that can affect treatment outcomes. On the basis of results of recent related clinical trials, this review explores insights into the clinical and pathologic features of HR+/HER2− breast cancer in younger women.

Background: Advanced triple negative breast cancer (TNBC) has a poor prognosis, with a median survival of approximately 12 months. Due to a lack of receptor targets, chemotherapy remains the mainstay of treatment. A subset of TNBC has defects in homologous recombination (HR) DNA repair due to germline BRCA mutations. Poly(ADP-ribose) polymerase (PARP) inhibitors have been shown to be an effective therapy in this subgroup. The phosphoinositide-3-kinase (PI3K) pathway inhibitors are also active in some breast cancers, lowering nucleotide pools required for DNA synthesis and S-phase progression. Preclinical studies suggest that PI3K stabilizes and preserves double strand break repair by interacting with the HR complex. Inhibition of PI3K/mTOR could impede PI3K interaction with the HR complex, thereby increasing dependency on PARP enzymes for DNA repair, and making this dual inhibition a rational combination. This trial is studying the safety and efficacy of combining the PI3K/mTOR inhibitor, gedatolisib, and the PARP inhibitor, talazoparib. Single-agent talazoparib is currently approved in advanced HER2 negative breast cancer with a germline BRCA 1/2 mutation. Trial design: This trial is designed with a safety run-in to determine the recommended phase 2 doses (RP2D) of the talazoparib and gedatolisib combination. The safety run-in will be followed by a phase II single-arm study of the combination, with 2 patient cohorts. Cohort A will be comprised of patients with advanced TNBC with negative or unknown germline BRCA1/2 status. Cohort B will be used for an exploratory analysis, comprised of patients with advanced HER2 negative breast cancer and a germline BRCA1/2 mutation. Eligibility Criteria: For the safety run-in phase, patients ≥18 of age with advanced breast cancer (defined as metastatic or unresectable) are eligible if they meet criteria for either cohort A or cohort B. For cohort A, all patients are required to have at least one line of prior systemic therapy for advanced breast cancer but no more than 2 lines of prior chemotherapy are allowed. For cohort B, no more than 2 lines of prior chemotherapy are allowed, with no limit on prior endocrine or targeted therapies. Patients with type I or poorly controlled diabetes are excluded due to the common side effect of hyperglycemia with gedatolisib. Specific aims: Primary objective of the safety run-in: Determine the RP2D of talazoparib in combination with gedatolisib in patients with advanced HER2 negative (triple negative or BRCA1/2 deficient) breast cancer. Primary objective of the phase II study: Estimate the objective response rate (ORR) in patients with BRCA1/2 negative, or unknown, advanced TNBC - Cohort A. Correlative analysis will include correlating the HR deficiency (HRD) score with clinical response in patients with TNBC. Statistical Methods: In the safety run-in, a 3+3 design will be used for dose escalation. Maximum tolerated dose (MTD) is decided when 6 patients are treated at a dose level with < 2 DLTs. The MTD will be the RP2D. The safety run-in (dose escalation) component will require 9-18 subjects. In the Phase II study, the primary endpoint for sample size justification is ORR for cohort A (TNBC). The null response rate of 5% will be compared to the alternative hypothesis of 20% ORR with a 1-sided alpha level of 0.1. Based on the exact binomial test, we propose 21 subjects to target a power level of 80%. ORR in cohort B is a secondary endpoint. Target Accrual: Our target accrual for the safety run-in is 9-18 participants. Assuming 10% of subjects will be not be evaluable for the primary outcomes, then the number of patients accrued to cohort A will be 24. Cohort B will remain at 12 since it is exploratory. Contact information: The study is being administered through the Big Ten Cancer Research Consortium and can be identified as BTCRC-BRE18-337. Citation Format: Sneha Phadke, Menggang Yu, Kathy Miller, Ami Shah, Oana Danciu, Kari Wisinski. Phase 2 trial with safety-run in of gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive HER2 negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-06-02.

Background : Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies, such as prostate, penile, and testicular cancer. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. Objective : Here, we provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Study Design : We utilized systematic review methodology to summarize incidence, risk factors, screening, prevention and treatment of these complications and provide consensus evidence-based recommendations for clinical practice and future research. Results : Most of the evidence regarding male GvHD is still based on limited data, precluding strong therapeutic recommendations. We therefore recommend to systematically screen for male genital GvHD regularly and report it to large registries to allow for a better understanding. Future research should also address treatment since little published evidence is available to date. Male-specific endocrine consequences of HCT include hypogonadism which may also affect bone health. Since the evidence is scarce, current recommendations for hormone substitution and/or bone health treatment are based on similar principles as for the general population. Following HCT, sexual health decreases and this topic should be addressed at regular intervals. Future studies should focus on interventional strategies to address sexual dysfunction. Infertility remains prevalent in patients having undergone myeloablative conditioning, which warrants offering sperm preservation in all HCT candidates. Most studies on fertility rely on descriptive registry analysis and surveys, hence the importance of reporting post-HCT conception data to large registries. Although the quality of evidence is low, the development of cancer in male genital organs does not seem more prevalent than in the general population; however, subsequent malignancies in general seem to be more prevalent in males than females, and special attention should be given to skin and oral mucosa. Conclusion : Male-specific late effects, probably more under-reported than female-specific complications, should be systematically considered during the regular follow-up visits of male survivors who have undergone HCT. Care of patients with male-specific late effects warrants close collaboration between transplant physicians and specialists from other involved disciplines. Future research should be directed towards better data collection on male-specific late effects and on studies about the interrelationship between these late effects, to allow the development of evidence based effective management practices.

Background Scleroderma is a serious chronic autoimmune disease in which a patient’s disease state manifests in several irregularly spaced longitudinal measures of lung, heart, skin, and other organ systems. Threshold crossings of pulmonary and cardiac measures indicate potentially life-threatening key clinical events including interstitial lung disease (ILD), cardiomyopathy, and pulmonary hypertension (PH). The statistical challenge is to accurately and precisely predict these events by using all of the clinical history for the patient at hand and for a reference population of patients. Methods We use a Bayesian mixed model approach to simultaneously characterize each individual’s future trajectories for several biomarkers. We estimate this model using a large population of patients from the Johns Hopkins Scleroderma Center Research Registry. The joint probabilities of critical lung and heart events are then calculated as a byproduct of the mixed model. Results The performance of this approach is substantially better than standard, more common alternatives. In order to predict an individual’s risks in a clinical setting, we also develop a cross-validated, sequential prediction (CVSP) algorithm. As additional data are observed during a patient’s visit, the algorithm sequentially produces updated predictions for the future longitudinal trajectories and for ILD, cardiomyopathy, and PH. The updated prediction distributions with little additional computing, for example within an electronic health record (EHR). Conclusions This method that generates real-time personalized risk estimates has been implemented within the electronic health record system for clinical testing. To our knowledge, this work represents the first approach to compute personalized risk estimates for multiple scleroderma complications.

AIM Interstitial lung disease (ILD) is the leading cause of disease-related death in systemic sclerosis (SSc). Here, we assess baseline characteristics of SSc subjects with and without restrictive lung disease (RLD) in a multi-center, US-based registry. METHODS SSc patients within 5 years of disease onset were enrolled in the Collaborative National Quality and Efficacy Registry (CONQUER), a multi-center US-based registry of SSc study participants (age ≥ 18 years) enrolled at 13 expert centers. All subjects met 2013 American College of Rheumatology / European League Against Rheumatism criteria. Subjects with a pulmonary function test (PFT) at baseline before April 1, 2020 were included. High-resolution computed tomography scan of the chest was not available to characterize ILD for all subjects. RLD was defined as forced vital capacity (FVC)

ObjectivePatients with inflammatory arthritis (IA) associated with immune checkpoint inhibitor (ICI) treatment for cancer are typically seronegative for anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor, but little is known about the presence of other autoantibodies in this patient population. We investigated the prevalence and characteristics of anti-RA33 antibodies in patients with ICI-induced IA.MethodsAnti-RA33 ELISAs were performed on sera from four groups of patients: 79 with ICI-induced IA, 52 with rheumatoid arthritis (RA), 35 treated with ICIs without IA during follow-up and 50 healthy controls. Anti-RA33 positivity and level, clinical and demographic data were compared across groups.ResultsAnti-RA33 antibodies were found in 9/79 (11.4%) patients with ICI-induced IA but in 0/35 patients treated with ICIs who did not develop IA (0%; p=0.04). Of the patients positive for anti-RA33, two had sera available from before ICI treatment; anti-RA33 antibodies were present in both pre-ICI treatments. In patients with RA, 7.7% were positive for anti-RA33 antibodies as were 2% of healthy controls. In ICI-induced IA, anti-RA33 antibodies were associated with anti-CCP antibodies (p=0.001). We found no statistically significant differences in other clinical characteristics in those with and without anti-RA33 antibodies.ConclusionsAnti-RA33 antibodies are present in a subset of patients with ICI-induced IA, absent in other ICI-treated patients and may be a biomarker for developing IA. Additional studies evaluating serial samples before and after ICI treatment will further establish the temporal relationship of these antibodies to IA development.

BackgroundRuxolitinib, a Janus kinase (JAK)-1/JAK-2 inhibitor that reduces T-cell activation and proliferation leading to a potent anti-inflammatory effect, was recently approved to treat steroid-refractory acute graft-versus-host disease (aGvHD) and is under study for chronic GvHD (cGvHD). However, there are few reports on its use in pediatric and young adult patients with GvHD.MethodsWe retrospectively report our single center experience with ruxolitinib in 15 patients aged 11-29 years: 5 patients with steroid refractory/steroid dependent aGvHD and 10 patients with cGvHD who had failed at least one systemic therapy.ResultsIn the aGvHD group, ruxolitinib led to an overall response rate (ORR) of 40% at day 28 and 80% with longer follow-up (complete response, CR 60%), with a median of 21 days (5-74) to achieve a response. In the cGvHD group (9 evaluable patients), we observed an ORR of 67% and a CR of 22%, with a median of 78 days (35-180) to achieve a response. Adverse events included cytopenias, gastrointestinal symptoms, infections, and an allergic reaction attributable to ruxolitinib.ConclusionsOverall, our results show that ruxolitinib is an effective salvage therapy for severe GvHD in pediatric and young adult patients. The toxicities noted warrant adequate antimicrobial prophylaxis and close monitoring of blood counts.

Purpose of review The COVID-19 pandemic has been an unprecedented challenge for healthcare delivery, disrupting normal workflows and demanding re-allocation of resources. In the setting of breast imaging, this entailed an initial marked reduction of services during the acute phase of the pandemic followed by a gradual reopening with modified protocols to minimize potential virus exposure. Recent findings Protocols were devised for providing limited breast imaging services during the acute phase of the pandemic and for safely reopening during the post acute phase. Example cases of breast cancers diagnosed during the acute phase of the pandemic are provided to illustrate the modified workflow. Summary This manuscript reviews practical strategies for restructuring breast imaging workflow, onsite policies, and staffing at a multi-site academic center in New York City during the COVID-19 pandemic. By sharing our experience, we hope to provide others with a roadmap for managing breast imaging services during future unforseen crises.

Numerous studies have identified autoantibody status as an important biomarker of cancer risk around the time of systemic sclerosis (SSc) onset. For example, anti-RNA polymerase III antibody positivity associates with increased cancer risk near SSc onset, while the presence of anticentromere or anti-Th/To antibodies may be protective.1–4 In this context, we selected serum from a well-characterised patient with SSc with squamous cell skin cancer and a short cancer–scleroderma interval to discover cancer-associated autoantibodies. Immunoprecipitations performed with this serum using 624 melanoma cell lysates were subjected to on bead digestion and liquid chromatography tandem mass spectrometry peptide sequencing. This identified antibodies targeting the tumour suppressor gene, acidic leucine-rich nuclear phosphoprotein (ANP32A), which migrates on SDS-polyacrylamide gels at ~28.5 kDa. Antibodies against ANP32A were validated in this serum by immunoprecipitation using 35S-methionine labelled ANP32A generated by in vitro transcription/translation from DNA (Origene) as described.5 To further explore the association between anti-ANP32A antibodies and cancer in patients with SSc, sera from patients with (n=213) and without cancer (n=190) were randomly selected from the Johns Hopkins Scleroderma Center Research Registry for anti-ANP32A antibody testing. The Registry prospectively collects demographic information, cancer diagnoses and longitudinal disease metrics. …

Mesenteric cysts are benign congenital cysts typically discovered incidentally during abdominal explorations for other reasons. When feasible, they should be excised to prevent recurrence, bowel obstruction or volvulus, and resulting complications. We present a unique case of an infant, diagnosed prenatally by ultrasound with possible bowel obstruction, found to have micro and macro chylous mesenteric cysts. Although initially asymptomatic with normal abdominal x-ray and discharged on day of life 2, the parents were taught how to recognize symptoms of bowel obstruction. He presented at 1 month with obstructive symptoms, was confirmed to have large mesenteric cystic structures on ultrasound, and was immediately taken to the operating room. Due to the extensive number of cysts and intimate involvement of the largest cyst with the superior mesenteric artery, he was treated with partial excision and observation since resection may have resulted in short gut syndrome. Given a prenatal ultrasound suggestive of mesenteric cysts, we recommend abdominal imaging at birth with close follow-up until the appropriate time for elective resection. When disease is extensive precluding full enucleation and resection, we advocate for enucleation in combination with unroofing of as many cysts as possible followed by postoperative surveillance ultrasounds and family counseling.

Objective To determine if mother’s own milk (MOM) dose after gastroschisis repair is associated with time from feeding initiation to discharge. Secondary outcomes included parenteral nutrition (PN) duration and length of stay (LOS). Study design Retrospective study of 44 infants with gastroschisis examined demographics, gastroschisis type, PN days, timing of nutrition milestones, feeding composition, and LOS. Results MOM dose was significantly associated with shorter time to discharge from feeding initiation (adjusted hazard ratio [HR] for discharge per 10% increase in MOM dose, 1.111; 95% CI, 1.011–1.220, p = 0.029). MOM dose was also significantly associated with shorter LOS (adjusted HR for discharge per 10% increase in MOM dose, 1.130; 95% CI, 1.028–1.242, p = 0.011). Conclusions MOM dose was significantly associated with a decrease in time to discharge from feeding initiation and LOS in a dose-dependent manner. Mothers of gastroschisis patients should receive education and proactive lactation support to optimize MOM volume for feedings.

Although there is abundant evidence of vascular perturbation from studies of peripheral blood in systemic sclerosis (SSc), there are few data about the ability to use biomarkers of vascular injury and growth factors to predict vascular outcomes and response to therapy. We sought to explore the association between candidate vascular biomarkers and digital ulcerations (DU) in a clinical trial context.We examined 19 circulating vascular, angiogenic, and inflammatory biomarkers in 124 patients with scleroderma and DU who participated in a randomized controlled trial of oral treprostinil diolamine (ClinicalTrials.gov identifier NCT00775463). Correlation, regression, and random forest analyses were conducted to assess biomarker relationships in response to drug treatment.Over the 20-week trial, 82 (66%) patients had their cardinal ulcer completely heal, 54 (44%) developed new ulcers, and 72 (58%) had complete healing of all ulcers; mean change in ulcer burden comparing week 20 with baseline was - 0.36 ± 1.70. Nineteen biomarkers were analyzed for their association and ability to predict clinical DU outcomes. After adjusting for multiple comparisons, no individual biomarker (baseline level, week 20 level, or change over time) was significantly associated with any of the clinical outcomes, suggesting that traditional vascular, angiogenic or inflammatory drivers are not predictive of ulcer fate.The lack of strong response to any of the vascular, angiogenic, or inflammatory markers suggest that these pathways are not primary drivers in the development of DU clinical outcomes in a SSc population with prevalent DU.• Currently we lack robust biomarkers to predict vascular outcomes or response to therapy in scleroderma patients with Raynaud's phenomenon.• Longitudinal assessment of vascular biomarkers in a clinical trial setting provides a unique opportunity to define biomarkers that predict vascular outcomes.• In a randomized controlled trial of oral treprostinil diolamine for treatment of scleroderma-associated digital ulcers, biomarkers involved in several vascular, inflammatory, and angiogenic pathways did not predict short-term clinical response to therapy or digital ulcer outcomes.• Further study of these and other biomarkers should be considered in Raynaud's clinical trials in scleroderma patients without prevalent digital ulcers.

The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud’s symptom. The data collection methodology incorporates successful models from other SSc registries. The cohort is designed to provide linked bio-specimen and clinical outcomes data on a longitudinal cohort of SSc patients for validation of hypothesis-driven research and to provide a platform for studying patient-reported outcomes in scleroderma. The CONQUER registry was developed using the guidelines of the International Society for Biological Repositories, and was an iterative process between physicians with an expertise in SSc, patient stakeholders, and information technology experts. Enrollment commenced in June 2018. During the first 6 months of the CONQUER Scleroderma study, 151 SSc patients with less than 5 years of disease duration (from first non-Raynaud’s symptom) have been recruited. The mean age is 51 ± 14 years, 83% are female, and 60% of patients have diffuse disease. Survey completion rates are above 88% for all patient-reported outcome surveys. Bio-specimen collection rates are over 97%, and disease severity score completion rates are over 98%. Pulmonary function test data is available on 91% of patients, and echocardiography is available 80%. The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud’s symptom. • The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • CONQUER is innovative in its design in that it is focused on prospective collection of paired clinical and patient outcome data with bio-specimens.

BackgroundWe undertook a study to determine the impact of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) and their therapies upon the health-related quality of life (HRQOL) of patients and their families.Materials and methodsWe undertook a survey of patients and their families, who self-identified as having either WAS or XLT. We assessed the PedsQL™ 4.0, the parent proxy form, and the family impact module. These results were compared with normative data from previously published reports.ResultsSixty-eight patients (29 patients completed both the PedsQL™ 4.0 and the parent proxy form; 21 completed only the PedsQL™ 4.0; and 18 completed only the parent proxy form) were included. In contrast to patient-reported outcomes, parents of patients who had a bone marrow transplant (BMT) reported that their children had better QOL scores compared with those who did not (82.6 vs. 73.3, p = 0.023). The QOL of patients vs. previously published normative data showed decreases in patient scores for psychosocial health (72.62 vs. 86.58, p =

PurposeThe purpose of this study is to understand how young consumers engage in the multi-category context. To that end, engagement on the focal product (dating platforms) and the other product (matrimony platforms) were studied. The objective is to find an answer to the following research question: Why do consumers tend to engage more with the focal product, yet are likely to purchase its complement or substitute?Design/methodology/approachSemi-structured depth interviews and Straussian grounded theory method were used to collect, analyze and interpret the data.FindingsSelf-determination theory provides an answer to the research question. This study suggests: young consumers experience different levels of need fulfilment when they evaluate the focal product in the single-category and in the multi-category contexts; young consumers’ motivational orientation (controlled motivation, autonomous motivation and intrinsic motivation) results into high-level behavior and engagement (pleasure-seeking, platform abandonment, goal-oriented pleasure-seeking, goal-oriented problem-solving, anxious and outsourcing) with the focal product and the other product.Originality/valueValue of the paper lies in developing a grounded theory framework for engagement in the multi-category context. This study can help practitioners in making important business decisions, especially in the dating and matrimony e-business categories.

OBJECTIVE To examine the association of anti-RNPC-3 antibodies in patients with systemic sclerosis (scleroderma or SSc) with selected gastrointestinal (GI) tract complications. METHODS Sera from patients with SSc with or without severe GI dysfunction (total parenteral nutrition dependence) from the Johns Hopkins Scleroderma Center were screened for anti-RNPC-3 antibodies. We then examined anti-RNPC-3-positive cases and negative SSc controls from the University of Pittsburgh and the University of Pittsburgh Medical Center (UPMC) scleroderma cohort to confirm our findings and to examine whether specific GI features were associated with anti-RNPC-3 antibodies. RESULTS In the discovery cohort, patients with SSc with severe GI dysfunction (n = 37) and without GI dysfunction (n = 38) were screened for anti-RNPC-3 antibodies. The former were more likely to have anti-RNPC-3 antibodies (14% versus 3%; P = 0.11). In the Pittsburgh cohort, moderate-to-severe GI dysfunction (Medsger GI score ≥2) was present in 36% of anti-RNPC-3-positive patients versus 15% of anti-RNPC-3-negative patients (P ≤ 0.01). Anti-RNPC-3-positive patients were more likely to be male (31% versus 15%; P = 0.04), African American (18% versus 6%; P = 0.02), have esophageal dysmotility (93% versus 62%; P < 0.01), and interstitial lung disease (ILD) (77% versus 35%; P < 0.01). After adjusting for relevant covariates and potential confounders, moderate-to-severe GI disease was associated with anti-RNPC-3 antibodies (odds ratio [OR] 3.8 [95% confidence interval (95% CI) 1.0-14.3]), and ILD trended toward significance (OR 2.8 [95% CI 1.0-8.2]). CONCLUSION Patients with SSc and anti-RNPC-3 antibodies are more likely to be male and African American and to have moderate-to-severe GI disease and ILD. Further studies on larger patient cohorts may be helpful in further defining subsets of patients with SSc at risk for severe GI involvement.

Objective Immune checkpoint inhibitors (ICI) are transforming the field of oncology, leading to tumor regression in multiple advanced cancers. With this case series, we review the ultrasound imaging findings in a series of patients with ICI-induced inflammatory arthritis (IA), a novel rheumatic disease that is caused by cancer immunotherapy. Methods We identified patients with rheumatologist-diagnosed, ICI-induced IA who had musculoskeletal ultrasound performed for clinical care. A retrospective chart review was done to obtain demographics, oncologic history, clinical presentation, imaging, and synovial fluid results. Ultrasound images were reviewed and scored for synovial and tendon pathology, presence of Doppler, and bony erosion. Results Nine patients were included in this study with a total of 18 joint regions assessed. The knees were the most commonly imaged joint followed by the hands, wrists, feet, and ankles. Synovitis was seen in 12 of the 18 joints with active Doppler in 50% of the cases. Tendon involvement was also frequently seen (13 of 18 joints) with tenosynovitis, tendinitis, and enthesophytes. Erosions were less frequent and seen in only three cases but were also an early finding. Conclusion Patients with ICI-induced IA had a wide range of pathology affecting the synovium, tendons, and bones on musculoskeletal ultrasound. Further systematic study with imaging is needed for this group of diseases.

Background: Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (irAEs). Methods to obtain real-time multidisciplinary input for irAEs that require subspecialist care are unknown. This study aimed to determine whether a virtual multidisciplinary immune-related toxicity (IR-tox) team of oncology and medicine subspecialists would be feasible to implement, be used by oncology providers, and identify patients for whom multidisciplinary input is sought. Patients and Methods: Patients treated with ICIs and referred to the IR-tox team in August 2017 through March 2018 were identified. Feasibility was defined as receipt of electronic referrals and provision of recommendations within 24 hours of referral. Use was defined as the proportion of referring providers who used the team’s recommendations, which was determined through a postpilot survey. Demographics and tumor, treatment, and referral data were collected. Patient features and irAE associations were analyzed. Results: The IR-tox team was found to be feasible and used: 117 referrals from 102 patients were received in 8 months, all providers received recommendations within 24 hours, 100% of surveyed providers used the recommendations, and 74% changed patient management based on IR-tox team recommendations. Referrals were for suspected irAEs (n=106; 91%) and suitability to treat with ICIs (n=11; 10%). In referred patients, median age was 64 years, 54% were men, 13% had prior autoimmunity, and 46% received ICI combinations versus monotherapy (54%). The most commonly referred toxicities were pneumonitis (23%), arthritis (16%), and dermatitis (15%); 15% of patients had multisystem toxicities. Multiple referrals were more common in those treated with combination ICIs (odds ratio [OR], 6.0; P=.035) or with multisystem toxicities (OR, 8.1; P=.005). The IR-tox team provided a new multidisciplinary forum to assist providers in diagnosing and managing complex irAEs. This model identifies educational and service needs, and patients with irAEs for whom multidisciplinary care is most sought. Conclusions: A virtual multidisciplinary toxicity team for irAEs was a feasible and used service, and facilitated toxicity identification and management.

We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy–requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen–mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation–based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.

Ocular graft-versus-host disease (GVHD) occurs in more than one-half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity that affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed. Ocular GVHD involves at least 3 biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have identified several novel pathogenic mechanisms, including the renin angiotensin system and endoplasmic reticulum stress signaling, which can be targeted by therapeutic agents. Numerous studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. The efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important that all health professionals caring for HCT recipients have adequate knowledge of ocular GVHD to provide optimal care.

Tissue marker placement after image-guided breast biopsy has become a routine component of clinical practice. Marker placement distinguishes multiple biopsied lesions within the same breast, prevents re-biopsy of benign lesions, enables multi-modality correlation, guides pre-operative localization and helps confirm surgical target removal. Numerous breast tissue markers are currently available, with varied shapes, composition, and associated bio-absorbable components. This review serves to familiarize the breast interventionalist with the tissue markers most widely available in the United States today and to provide guidance regarding selection of appropriate markers for various clinical settings.

Objective To compare the effects of high concentration to titrated oxygen therapy (HCOT) on transcutaneous carbon dioxide (PtCO2 ) level in pediatric asthma exacerbation. Titrated oxygen therapy (TOT) in acute asthma will avoid a rise in PtCO 2 in the pediatric population. Method The study design is a prospective, randomized, clinical trial comparing HCOT (maintain SpO2 92-95%) while being treated for asthma exacerbation in the emergency department (ED). Inclusion criteria 2 to 18 years, previously diagnosed asthma with acute exacerbation (asthma score >5). PtCO2 and asthma scores were measured at 0, 20, 40, 60 minutes and then every 30 minutes until disposition decision. The primary outcome was a change in PtCO 2 . Secondary outcomes were admission rate and change in asthma score. Results A total of 96 patients were enrolled in the study with a mean age of 8.27 years; 49 in HCOT and 47 in the TOT group. The 0 minute PtCO2 was similar (35.33 + 3.88 HCOT vs 36.66 + 4.69 TOT, P = 0.13); whereas, the 60 minutes PtCO 2 was higher in the HCOT (38.08 + 5.11 HCOT vs 35.51 + 4.57 TOT, P = 0.01). The asthma score was similar at 0 minute (7.55 + 1.34 HCOT vs 7.30 + 1.18 TOT, P = 0.33); whereas, the 60 minutes asthma score was lower in the TOT (4.71 + 1.38 HCOT vs 3.57 + 1.25 TOT, P = 0.0001). The rate of admission to the hospital was 40.5% in HCOT vs 25.5% in the TOT (P = 0.088). Conclusions HCOT in pediatric asthma exacerbation leads to significantly higher carbon dioxide levels, which increases asthma scores and trends towards the increasing rate of admission. Larger studies are needed to explore this association.

Background: Since IBC is rare and burdened by a particularly unfavorable prognosis, biomarkers able to enhance diagnosis and risk assessment are of pivotal importance and a current unmet need. The aim of this study is to integrate standard clinico-pathological features with CTCs-based biomarkers for a more objective and detailed characterization of IBC. Methods: This study analyzed retrospectively 251 Advanced Breast Cancer (BC) patients (pts) longitudinally characterized for CTCs and CTCs-based biomarkers at Thomas Jefferson University (Philadephia, PA) and Northwestern University (Chicago. IL). CTCs were enumerated through the CellSearch system (Menarini Silicon Biosystems), and characterized for HER2 expression using the CellSearch CXC Kit. Pts were defined as stage IV aggressive based on the previously reported ≥5 CTCs cut-off (Davis et al. 2018). Associations between clinical features, CTC-derived biomarkers and IBC were tested through uni and multivariate logistic regression. Survival was tested though log-rank test. Results: Within the analyzed cases, 46% were diagnosed with IBC and among them, 38% was stage IV aggressive. CTC clusters (CTC_CL) were detectable in 12.5% of pts and HER2 positive CTCs (HER2_CTC) in 29.5%. Notably, IBC patients (pts) had a significantly lower CTC count with respect to non-IBC (median 2.5 vs 0 respectively for non-IBC and IBC; P=0.019). BC subtype (HER2 positive BC: OR 2.97; Triple negative BC: OR 2.13), liver and bone involvement (liver: OR 0.46; bone involvement: OR 0.31) were the only significant clinico-pathological features associated with IBC at univariate logistic regression. Interestingly, a marginal significance was observed for soft tissue involvement (OR 1.65, 95%CI 0.95 - 2.87, P=0.07). Stage IV aggressive and presence of HER2_CTC at baseline were moreover inversely associated with IBC. The multivariate model confirmed the significant association between IBC and HER2 positive BC subtype (OR 2.64, 95%CI 1.08 - 6.48, P=0.034), absence of bone involvement (OR 0.31, 95%CI 0.14 - 0.68, P=0.003) and absence of HER2_CTC (OR 0.38, 95%CI 0.15 - 0.98, P=0.045). The baseline detection of CTC_CL was a strong predictor of prognosis for OS in IBC pts (median OS (mOS) 7.6 months (mts) vs not reached (NR) respectively for detectable vs non-detectable CTC_CL; P Conclusion: HER2_CTC and in particular CTC_CL are promising prognostic predictors in IBC. Stage IV aggressive IBC pts could benefit from a longitudinal CTCs assessment, being more prone to develop CTC_CL and therefore at higher risk of rapid disease progression. Probably due to the tropism for soft tissue, IBC is characterized by a lower number of HER2_CTC. Citation Format: Gerratana L, Zhang Q, Wang C, Shah A, Davis AA, Ye Z, Zhang Y, Abu-Khalaf M, Flaum L, Strickland K, Rossi G, Behdad A, Gradishar W, Platanias L, Yang H, Cristofanilli M. How is inflammatory breast cancer (IBC) different? Integration of clinico-pathological features and circulating tumor cells (CTCs)-based biomarkers for disease and prognostic assessment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-17-03.