Citations

Objectives: To assess the feasibility and efficacy of implementing “Family Care Rituals” as a means of engaging family members in the care of patients admitted to the ICU with a high risk of ICU mortality on outcomes including stress-related symptoms in family members. Design: Prospective, before-and-after intervention evaluation. Setting: Two U.S. academic medical ICU’s, and one Italian academic medical/surgical ICU. Subjects: Family members of patients who had an attending predicted ICU mortality of greater than 30% within the first 24 hours of admission. Interventions: A novel intervention titled “Family Care Rituals” during which, following a baseline observation period, family members enrolled in the intervention phase were given an informational booklet outlining opportunities for engagement in care of the patient during their ICU stay. Measurements and Main Results: Primary outcome was symptoms of post-traumatic stress disorder in family members 90 days after patient death or ICU discharge. Secondary outcomes included symptoms of depression, anxiety, and family satisfaction. At 90-day follow-up, 131 of 226 family members (58.0%) responded preintervention and 129 of 226 family members (57.1%) responded postintervention. Symptoms of post-traumatic stress disorder were significantly higher preintervention than postintervention (39.2% vs 27.1%; unadjusted odds ratio, 0.58; p = 0.046). There was no significant difference in symptoms of depression (26.5% vs 25.2%; unadjusted odds ratio, 0.93; p = 0.818), anxiety (41.0% vs 45.5%; unadjusted odds ratio, 1.20; p = 0.234), or mean satisfaction scores (85.1 vs 89.0; unadjusted odds ratio, 3.85; p = 0.052) preintervention versus postintervention 90 days after patient death or ICU discharge. Conclusions: Offering opportunities such as family care rituals for family members to be involved with providing care for family members in the ICU was associated with reduced symptoms of post-traumatic stress disorder. This intervention may lessen the burden of stress-related symptoms in family members of ICU patients.

Reports highlighting the problems with the standard practice of using bar graphs to show continuous data have prompted many journals to adopt new visualization policies. These policies encourage authors to avoid bar graphs and use graphics that show the data distribution; however, they provide little guidance on how to effectively display data. We conducted a systematic review of studies published in top peripheral vascular disease journals to determine what types of figures are used, and to assess the prevalence of suboptimal data visualization practices. Among papers with data figures, 47.7% of papers used bar graphs to present continuous data. This primer provides a detailed overview of strategies for addressing this issue by (1) outlining strategies for selecting the correct type of figure depending on the study design, sample size, and the type of variable; (2) examining techniques for making effective dot plots, box plots, and violin plots; and (3) illustrating how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. We also present solutions to other common problems identified in the systematic review. Resources include a list of free tools and templates that authors can use to create more informative figures and an online simulator that illustrates why summary statistics are meaningful only when there are enough data to summarize. Last, we consider steps that investigators can take to improve figures in the scientific literature.

Abstract Abstract 2883 CLL-like monoclonal B-cell lymphocytosis (MBL) shares common immunophenotypic features and cytogenetic abnormalities with CLL and is generally perceived as its premalignant state. The World Health Organization has set a consensus cut-off of 5×109/L circulating B cells to discriminate between what constitutes ‘disease’ and what not. However, the clonal size within MBL is extremely variable. High-count (HC), clinical MBL is associated with absolute lymphocytosis and progresses to CLL requiring treatment at a rate of 1–2% per year, whereas low-count (LC) MBL is found in the general population through high-sensitivity techniques and carries a risk of progression that is limited if any. Given the high frequency of CLL-like MBL in the general population, it is important to understand the underlying mechanisms and also identify biological markers endowing malignant potential that may distinguish between the different forms. To this end, we performed a detailed immunogenetic profiling of 334 CLL-like MBL cases (78 LC and 256 HC) for a total of 355 productive VDJ rearrangements (including double rearrangements), 91 from LC MBL and 264 from HC MBL. We also compared the immunoglobulin (IG) gene repertoires of MBL to 544 CLL Rai Stage 0 (CLL-0) that were part of an IG sequence dataset of 7424 CLL cases previously analyzed by our group. LC and HC MBL had distinct IG gene repertoires, with over-representation of the IGHV1–69 and IGHV4–34 genes in HC and the IGHV4–59/61 genes in LC MBL, respectively (p<0.001). The HC MBL repertoire exhibited clear similarities to CLL-0 in terms of IGHV gene usage (similar frequencies of IGHV1–69 and IGHV4–34). Regarding somatic hypermutation, no differences were identified between LC MBL versus HC MBL versus CLL-0, in that the frequency of mutated rearrangements (<98% identity to the germline) was overall similar (LC MBL: 72.5%, HC MBL: 76.1%, CLL-0: 75%). In this respect, all the aforementioned subgroups differed significantly (p<0.001) from the frequency previously reported by us in CLL where only 55% of rearrangements carried mutated IGHV genes. We finally analyzed the expression of stereotyped B cell receptor (BcR) IGs, identified through a cluster analysis of the MBL sequences together with all CLL sequences from our cohort and 5494 non-CLL IG sequences retrieved from public databases. Overall, only 6/91 (5.5%) LC MBL rearrangements could be clustered with other sequences in subsets with stereotyped BcRs. Two of these six LC MBL cases were clustered together with IG sequences from various entities, including CLL, other lymphomas and autoimmune diseases; thus, they were considered to carry ‘public’ BcR stereotypes. In contrast, HC MBL showed a significantly (p=0.0002) higher frequency of ‘CLL-specific’ BcR stereotypes versus LC MBL, with 60/264 (22.7%) HC MBL cases carrying stereotyped VH CDR3s. This frequency was comparable to the one observed in CLL-0 (20.2%). Notably, a gradation was observed in the frequency of BcR IG stereotypy depending on the absolute count of CLL-like cells, starting with 5.5% in LC MBL, raising to 22.7–20.2% in in HC MBL/CLL-0 and, finally, peaking at 30.4% in the entire CLL cohort as previously reported. Altogether, these findings suggest that rather than a true premalignant condition, LC MBL may merely reflect immune senescence or result from persistent antigen stimulation. On the other hand, HC MBL appears to be a continuum with Rai stage 0 in the evolution to clinically overt CLL, being maybe one step behind where it requires either additional genetic hits or simply extra time to cross the numerical border that discriminates it from CLL. Hence, the identification of molecular genetic markers that may predict progression of HC MBL/CLL-0 into full-fledged CLL is strongly warranted. Disclosures: Shanafelt: Genentech: Research Funding; GlaxoSmith Klein: Research Funding; Teva/Cephalon: Research Funding; Celgene: Research Funding.

INTRODUCTION: Endoscopic surveillance guidelines in Barrett’s esophagus (BE) to detect progression to high grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) are based solely on dysplasia grade. Given low rates of progression, identification of predictors (and scores) of progression may help to focus surveillance or intervention in those at higher risk. We aimed to assess predictors of progression and externally validate the Progression in Barrett’s (PIB) score in an independent multicenter prospective BE and EAC cohort. METHODS: The EA and Barrett’s esophagus (EABE) registry is a prospective cohort of patients recruited from three medical centers. Progressors were defined as those with the development of HGD or EAC more than 12 months after initial diagnosis. Demographic and clinical variables were abstracted. The annual incidence rate and predictors of progression were assessed using univariate and multivariable Cox proportional hazards analysis. The ability of the PIB score (incorporating weighted scores for male gender, smoking (ever versus never), BE length and confirmed LGD) to risk stratify the cohort into low (0-10 points), intermediate (11-20 points) and high risk (> 20 points) groups was assessed. RESULTS: 429 patients were included. 84% were men, with a mean (SD) age of 61.5 (9.9) years. 65% were ever smokers and most (76.7%), had NDBE at diagnosis. Mean (SD) maximal BE segment length was 5.9 (3.2) cm. Eighty-two patients (19.1%) progressed to HGD (n = 65) or EAC (n = 17) over a median (IQR) follow up of 7.5 (3.7, 12.5) years. Annual incidence rates of progression to EAC and EAC/HGD were 0.5% and 2.0% respectively. Univariate and multivariable predictors of progression are displayed in Table 1. The PIB score divided patients into three groups (Table 2) with progressively increasing rates of progression. The risk in the high risk group was three fold higher than the low risk group ( P = 0.024). The risk in the intermediate group was twofold higher but not statistically significantly higher ( P = 0.13). The PIB score had a c-statistic score of 0.76 in the original cohort. In this cohort the c-statistic value was lower at 0.64, suggesting moderate performance. CONCLUSION: Male sex and BE length predicted progression in this independent multicenter cohort. The PIB score was also able to risk-stratify patients in this validation cohort with the high risk cohort being 3x more likely to progress compared to the low risk cohort.

AimsChondroblastomas (CB) are rare bone tumours that typically arise in the epiphysis/apophysis of long bones in skeletally immature patients. We explore the clinicopathological features of CB presenting in adults.Methods and resultsCB in patients ≥20 years of age were retrieved from our institutional archives. Thirty‐nine CB were identified (29 male/10 female; aged 20–54 years). Twenty (51%) cases occurred in long tubular bones, 10 (26%) in small bones of the feet, five (13%) in flat bones and four (10%) in the patella. All cases showed classic cytological features of CB, and chondroid matrix was universally present. Calcification was identified in 10 cases (26%), including various combinations of serpiginous (n = 7), punctate (n = 6), classic chicken‐wire (n = 4) and psammomatous (n = 2) patterns. Haemosiderin (n = 19), woven bone (n = 13), secondary aneurysmal bone cyst formation (n = 8), foamy macrophages (n = 4), hyalinised vascular spaces (n = 2) and cholesterol clefts (n = 2) were noted. Follow‐up information (n = 32, 1–452 months) revealed local recurrence in three patients, all >40 years of age with flat bone origin, one of which developed pulmonary metastases 132 months after initial diagnosis.ConclusionsCB in patients >20 years of age more frequently involves the short bones of the hands/feet and flat bones compared to those arising in their younger counterparts. A subset may harbour extensive serpiginous or psammomatous calcification rather than the classic chicken‐wire pattern. Although the overall local recurrence rate in adulthood is approximately 10%, all three patients with recurrent disease had tumours involving flat bones, suggesting that tumours arising in these sites may behave more aggressively.

Abstract Background: I-SPY2 is a multicenter, Phase II trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk at least T2N0 breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify regimens that have ≥ 85% Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR) and HER2 status, and MammaPrint (MP). Regimens may leave the trial for futility (&lt; 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and &lt; 85%), or as recommended by the independent DSMB. For HER2- subjects the control arm is weekly paclitaxel x12 then doxorubicin & cyclophosphamide (AC) q2-3 weeks x4. For this arm, paclitaxel was omitted and replaced with maximum tolerated dose PARPi talazoparib with synergy dosed irinotecan (25mg/m2). Paclitaxel could be given adjuvantly for these subjects and non-responding subjects could be taken off of experimental therapy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 cycles after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Talazoparib was given at 1mg daily with 25mg/m2 irinotecan q2wks. Analysis was intention to treat. Subjects who switched to non-protocol therapy count as non-pCR. Subjects on experimental therapy at time of arm closure are non-evaluable. Talazoparib/irinotecan (TI) was open only to HER2- tumors and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-/HER2-. Results: TI did not meet criteria for graduation and was stopped at the recommendation of the DSMB based on expectations of limited activity beyond that seen with standard treatment. Maximum sample size had been reached at the time of this recommendation and subjects currently receiving TI were allowed to continue or change to standard therapy. Exploratory “as treated” analysis for response in gBRCA mutation carriers showed 6/10 gBRCA carriers attained a pCR in the TI arm. Except for 1 patient these gBRCA pCR subjects had &gt;90% tumor reduction by MRI after TI and prior to AC (range: 68-96%). In the TI arm pCR rates were also higher in subjects with a PARPi7-High/MP2 gene expression signature (0.344 vs 0.146). Expected differences in toxicity were seen between arms including g3/4 peripheral neuropathy on control therapy which included paclitaxel (2.6% vs none) and g3/4 neutropenia with TI (30.2% vs 8.2%). Notably gBRCA mutation carriers receiving TI had higher rates of g3/4 neutropenia (60% vs 25.9%). Conclusion: The I-SPY2 study finds the probability that investigational regimens will be successful in a Phase III neoadjuvant trial; TI did not reach the efficacy threshold of 85% probability of success in Phase III in any of the 3 signatures. However by adding talazoparib with synergy dosed irinotecan we were able to omit paclitaxel and observe similar estimated pCR rates. This informs current work to evolve the I-SPY2 trial design to reduce toxicity without compromising outcomes and develop successful combinations targeted to biology, including DNA repair deficiency. Citation Format: Richard Schwab, Amy S. Clark, Christina Yau, Nola Hylton, Wen Li, Denise Wolfe, A Jo Chien, Anne M. Wallace, Andres Forero-Torres, Erica Stringer-Reasor, Rita Nanda, Nora Jaskowiak, Judy Boughey, Tufia Haddad, Heather S. Han, Catherine Lee, Kathy Albain, Claudine Isaacs, Anthony D. Elias, Erin D. Ellis, Payal Shah, Julie E. Lang, Janice Lu, Debasish Tripathy, Kathleen Kemmer, Douglas Yee, Barbara Haley, Melanie Majure, Erin Roesch, Christos Vaklavas, Cheryl Ewing, Teresa Helsten, W Fraser Symmans, Jane Perlmutter, Hope S. Rugo, Michelle Melisko, Amy Wilson, Ruby Singhrao, Laura van 't Veer, Angela DeMichele, Smita Asare, Don Berry, Laura J. Esserman. Evaluation of talazoparib in combination with irinotecan in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT136.

Abstract Background: Pembrolizumab (Pembro), an anti-PD-1 immune checkpoint inhibitor, has been approved for the treatment of a variety of cancers. Pembro was recently evaluated in HER2- breast cancer patients in the neoadjuvant I-SPY 2 TRIAL and graduated in the triple negative (TN), HR+HER2-, and HER2- signatures. TN breast cancers tend to have high numbers of immune infiltrates, including T cells and tumor associated macrophages (TAMs). We utilized multiplex multispectral imaging to evaluate the presence and spatial proximity of various immune cell populations as specific predictors of response to Pembro. Methods: Pre-treatment biopsies were available from 54 patients. FFPE sections were immunostained using Opal fluorescence reagent kits on a fully automated Ventana Discovery platform and imaged with a Vectra automated imaging system. Image analyses were performed with a variety of software packages. Immune biomarkers included CD3, CD8, FoxP3, CD68, PD-1, PD-L1, and cytokeratins. Cell densities were determined per area of tissue. Spatial analyses were performed to quantitate proximity of cell types. We used logistic regression with the likelihood ratio test to evaluate associations between pathologic complete response (pCR) with immune cell counts, ratios, and spatial proximity measurements. This analysis was also performed adjusting for HR status, and within receptor subsets, sample size permitting. Our statistics are descriptive rather than inferential and do not adjust for multiple hypothesis testing or multiplicities of other biomarkers outside this study. Results: Densities of CD3+ T cells ranged from 193-5155 cells/mm2, with CD8+ cytotoxic T cells (Tc) ranging from 103 to 3774 cells/mm2 and FoxP3+ Tregs from 0-416 cells/mm2. Densities of PD-1+ T cells and PD-1+ Tc cells ranged from 0-1341 cells/mm2 and 0-698 cells/mm2, respectively. Macrophage cell densities ranged from 84-2644 cells/mm2. PD-L1+ tumor cell densities ranged from 0-2981 cells/mm2. High PD-L1 expression (&gt;=10% of tumor cells positive for PD-L1) was observed in 12% of the cases. Overall T cell density was positively associated with pathological complete response (pCR), as were Treg cell density and PD-1+ T cell density. The ratio of macrophages to Tc cells was negatively associated with response. Finally, the spatial distribution of CD3+ T cells in proximity to cancer cells correlated positively with pCR. Conclusion: Cell density, immune cell ratios and spatial resolution provide insight to response and resistance. We confirmed the observation that T cell density predicts pCR, but more specifically that Treg and PD1+ T cell densities increase the chance of pCR. An increase in macrophages relative to cytotoxic T cells predicts resistance. The closer the T cells are to the tumor, the better the response. These results demonstrate the utility of characterizing the immune microenvironment, in the context of therapy with immuno-oncology agents, not only to predict response, but to gain insight and learn now to potentiate agents and combinations. Citation Format: Michael J. Campbell, Christina Yau, Jennifer Bolen, Scott Vandenberg, Clifford Hoyt, Lamorna Brown-Swigart, Gillian Hirst, Rita Nanda, Minetta Liu, Smita Asare, Laura van'tVeer, Douglas Yee, Angie DeMichele, Don Berry, Laura Esserman, I SPY 2 TRIAL Investigators. Analysis of immune cell infiltrates as predictors of response to the checkpoint inhibitor pembrolizumab in the neoadjuvant I-SPY 2 TRIAL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT003.