Citations

Abstract We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Abstract Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that presents with microangiopathic hemolytic anemia and thrombocytopenia, fevers, renal insufficiency and neurologic features. We reviewed clinical, laboratory, and outcome data for TTP cases with severely deficient versus non-severely deficient ADAMTS13 activity levels. Methods: Mean and median data were from the Surveillance, Epidemiology and Risk Factors for TTP (SERF-TTP) study group for idiopathic TTP cases, the Canadian Apheresis Group (CAG), and five published series (Zheng 2004, Raife 2004, Vesely 2003 (Oklahoma TTP-HUS Registry), Matsumoto 2004 (Japan Referral Center), Bennett 2007). Results: Compared to TTP cases with near-normal ADAMTS13 activity levels (n= 282), TTP cases with severe ADAMTS13-deficiency (n=185) were more likely to have severe thrombocytopenia, normal renal function and neutralizing ADAMTS13 antibodies. Severe ADAMTS13 deficient TTP cases have better overall survival after therapeutic plasma exchange (TPE) but are more likely to relapse. TTP patients with severe ADAMTS13 deficiency were primarily categorized as idiopathic or ticlopidine-associated, while TTP patients with non-severely deficient ADAMTS13 activity levels were frequently categorized as idiopathic, secondary to drugs (clopidogrel, quinine), stem cell transplantation, or cancer. Conclusions: Severe ADAMTS13 deficiency is most commonly idiopathic, has better survival following TPE, and a 35–40% spontaneous relapse rate. By contrast, non-ADAMTS13 deficient TTP cases are usually associated with an underlying disorder or external insults. Amongst this cohort, four series have 47–62% survival rates and three series, which contain mostly idiopathic cases, have 83–90% survival rates following TPE. From this, we propose that TTP may occur by three possible mechanism; ADAMTS13-deficient (antibody-mediated), an immunologic mediated pathway independent of ADAMTS13 (i.e. quinine) that is responsive to TPE, and endothelial injury related TTP that is unresponsive to TPE. Platelet count mean (x10^9/L) Creatinine mean (mg/dl) ADAMTS13 neutralizing antibodies (%) Survival % Relapse % * <15% ADAMTS13 activity cutoff Severe ADAMTS13 Deficiency (<10–15%) SERF-TTP (n=30) 19 1.3 83 97 41 Zheng (n=16) 19 1.6 44 81 38 Bennett (n=26) 15 85 Oklahoma (n=18) 12 1.8 94 81 38 Raife (n=50) * 13 1.2 92 35 Japan (n=34) 35 91 Canada (n=11) 16 2.4 82 Not Severely Deficient ADAMTS13 Activity (> 15%) SERF-TTP (n=22) 57 3.9 35 90 0 Raife (n=57) * 44 2.7 83 9 Canada (n=17) 57 4.1 88 Zheng (n=13) 40 3.0 0 54 Bennett (n=13) 62 Japan (n=66) 9 62 Oklahoma (n=94 ) 23 47 3

Background and Aims Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a relapsing–remitting pattern that belongs to autoimmune disease (AID). The JAK inhibitor tofacitinib is a newly (2018.05) FDA approved drug for UC which is a drug previously used to treat another AID, rheumatoid arthritis. A higher dose of tofacitinib has been associated with a safety warning for increased lipid levels as well as serious infections and malignancy. Berberine has proved to be a promising drug candidate for the treatment of UC and shows activity in hyperlipidemia, bacteria; infections and cancer. We hypothesized that a balance between clinical benefit and side effects might be attained by using a combination of tofacitinib and berberine‐‐with reduced doses of both drugs. We first investigated the preclinical activity of reduced doses of tofacitinib plus berberine in experimental colitis in the mouse. Methods Tofacitinib (30 mg/kg/day), berberine (40 mg/kg/day) and reduced doses of tofacitinib (15 mg/kg/day) plus berberine (20 mg/kg/day) were administered orally for 14 and 30 days to C57BL/6 mice with colitis induced by two schedules of three cycles of 2% dextran sulfate sodium (DSS). Disease severity, colon length, colon and spleen swelling and cytokine expression in colon tissue as well as histology of major organs were examined. Results The results showed that compared to the two drugs alone, half reduced doses of tofacitinib plus berberine showed a comparable effect in ameliorating DSS‐induced colitis severity and colon shortening. Co‐treatment showed a greater antagonism of DSS induced colon and spleen swelling when compared to either drug alone. Similar effects were observed in cytokine levels in the colon. In addition, no potential toxicity to major organs was observed with this combination therapy. Conclusions Our studies provide a preclinical rationale for the combination of reduced dosage tofacitinib and berberine as a possible clinical therapeutic strategy for the treatment of UC. Support or Funding Information This work was funded by the Research Foundation of South China University of Technology (x2yxD2182200), the Natural Science Foundation of Guangdong Province (2018A030310388), Guangdong Medical Science Foundation (A2018363), and China Scholarship Council (Grant No. CSC201806155103).

OBJECTIVE The development of new endovascular technologies and techniques for mechanical thrombectomy in stroke has greatly relied on benchtop simulators. This paper presents an affordable, versatile, and realistic benchtop simulation model for stroke. METHODS A test bed for embolic occlusion of cerebrovascular arteries and mechanical thrombectomy was developed with 3D-printed and commercially available cerebrovascular phantoms, a customized hydraulic system to generate physiological flow rate and pressure, and 2 types of embolus analogs (elastic and fragment-prone) capable of causing embolic occlusions under physiological flow. RESULTS The test bed was highly versatile and allowed realistic, radiation-free mechanical thrombectomy for stroke due to large-vessel occlusion with rapid exchange of geometries and phantom types. Of the transparent cerebrovascular phantoms tested, the 3D-printed phantom was the easiest to manufacture, the glass model offered the best visibility of the interaction between embolus and thrombectomy device, and the flexible model most accurately mimicked the endovascular system during device navigation. None of the phantoms modeled branches smaller than 1 mm or perforating arteries, and none underwent realistic deformation or luminal collapse from device manipulation or vacuum. The hydraulic system created physiological flow rate and pressure leading to iatrogenic embolization during thrombectomy in all phantoms. Embolus analogs with known fabrication technique, structure, and tensile strength were introduced and consistently occluded the middle cerebral artery bifurcation under physiological flow, and their interaction with the device was accurately visualized. CONCLUSIONS The test bed presented in this study is a low-cost, comprehensive, realistic, and versatile platform that enabled high-quality analysis of embolus–device interaction in multiple cerebrovascular phantoms and embolus analogs.

BackgroundAlcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. AH patients have intense hepatic infiltration of leukocytes. Up‐regulation of cell adhesion molecules (CAMs) upon endothelial cell (EC) activation plays an important role in leukocyte transendothelial migration. CAMs can shed from EC surface and accumulate in the blood, serving as soluble markers for EC activation. In this study, we examined the impact of heavy drinking on expression of soluble forms of EC activation markers (CD146, ICAM‐1, VCAM‐1, and VEGF‐A) and the effect of alcohol abstinence on the reversal of these abnormalities in heavy drinkers with and without AH.MethodsELISA and multiplex immunoassays were used to measure soluble EC activation markers in plasma samples from 79 AH patients, 66 heavy drinkers without overt liver disease (HDC), and 44 healthy controls (HC) at baseline, 31 AH patients and 30 HDC at 6‐month follow‐up, and 18 AH patients and 25 HDC at 12‐month follow‐up.ResultsAt baseline, the 4 soluble markers were significantly up‐regulated in AH patients compared with HDC and HC, whereas only sVCAM‐1 was elevated in HDC relative to HC. At follow‐ups, plasma levels of CD146, VCAM‐1, and VEGF‐A remained higher in AH patients, even for those who stopped drinking. These dysregulated markers correlated with AH disease severity, clinical parameters, and several soluble inflammatory factors.ConclusionsThe levels of soluble CD146, ICAM‐1, VCAM‐1, and VEGF‐A were highly elevated in AH patients, and alcohol abstinence did not completely reverse these abnormalities.

Abstract BACKGROUND Fertility can be diminished by adjuvant chemotherapy or by age-related decline in ovarian reserve in young women with breast cancer (BC). We sought to better understand the burden of concern about fertility, utilization of fertility preservation strategies, and the impact of fertility concerns on treatment decision-making among young women newly diagnosed with BC enrolled in a large multi-site study. METHODS The Young and Strong study was a cluster-randomized study that tested the effect of an educational and supportive care intervention for young women with BC (≤45) and their oncologists, at community and academic sites across the US. Patients were surveyed following diagnosis at enrollment (within 3 months of diagnosis), and at 3, 6 and 12 months thereafter. The surveys included sociodemographic and psychosocial measures (HADS anxiety and depression; Perceived Stress Scale), as well as a modified Fertility Issues Survey, which assessed fertility concerns and preservation. Treatment and tumor pathology data were abstracted from the medical record. Logistic regression was used to identify sociodemographic, clinical, and psychosocial factors that were associated with fertility concern. Variables with p ≤ 0.20 in univariable analyses were evaluated in the multivariable model using stepwise selection; variables achieving significance at p < 0.05 were included in the final model. RESULTS Of 467 women enrolled from 54 sites (14 academic, 40 community), 419 had evaluable data regarding treatment decision-making. Median age of participants at diagnosis was 40 yrs (range 22-45), 11% were African American, 80% were married/lived with a partner, and 75% had children. 35% of tumors were stage I, 51% stage II, and 14% stage III; 82% of women were treated with chemotherapy. At the time of treatment decision-making, 133 (32%) were concerned about fertility, varying by age, with fertility concern reported by 73%, 28% and 13% of those age ≤35, 36-40 and >40 (p<.01), respectively. 67 (16%) said their treatment decisions had been affected by fertility concerns, including 62 of the 133 (47%) with fertility concern. 12/419 (3%) chose one chemotherapy regimen over another, 4 (1%) chose not to take hormonal medication, and 32 (8%) chose or may choose to take it for less than 5 years. 251 (60%) reported having discussed fertility issues with their physician before starting therapy, including 117/133 (88%) of women with fertility concern. 29 (7%), including 27/133 (20%) of the concerned, took special steps to lessen the chance of infertility: 14 underwent cryopreservation of embryos, 14 cryopreservation of eggs and 12 took GnRH agonist or pursued other strategies. In the multivariable model, history of difficulty becoming pregnant (versus none, OR=3.86, 95%CI: 1.84-8.1) was associated with greater concern about fertility. Older age (OR=.75 per 1-year increase, 95%CI: 0.69-0.81) and having more than one child at diagnosis (versus never delivered, OR=0.14, 95%CI: 0.05-0.40) were associated with less concern about fertility. Race, being partnered, high-education, income, symptoms of depression, stress or anxiety at diagnosis, tumor stage, hormone receptor status and receipt of chemotherapy were not independently associated with concern about fertility in the multivariable model. CONCLUSION In a geographically and ethnically diverse study of young women with newly diagnosed BC in the U.S., many were concerned about fertility, with potential impact on their treatment decisions. For the majority of women, these concerns were discussed with their providers, though only a minority underwent fertility preservation strategies prior to treatment. Citation Format: Elisabeth Etaix, Yue Zheng, Shoshana Rosenberg, Kathryn J Ruddy, J Russel Hoverman, Karen M Emmons, Ann H Partridge. Fertility concerns and treatment decision-making among young women with 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 P2-13-17.

Abstract Background: Fear of cancer recurrence (FCR) is prevalent among breast cancer survivors and more intense in younger women. Given that FCR is a powerful determinant of quality of life and is associated with healthcare utilization, identifying who may be at risk for experiencing elevated FCR without resolution can inform the timing and targeting of interventions. Methods: Participants included women diagnosed (dx’d) at age ≤40 enrolled in the Young Women’s Breast Cancer Study, a multi-site prospective cohort surveyed at baseline and regularly in follow-up. Surveys include the 3-item Lasry Fear of Recurrence Index which measures the degree of concern about recurrence and current health using 4-point Likert response options that provide a score ranging from 3-12; higher scores indicate greater concern. Group-based trajectory modeling was used to classify distinct FCR patterns from baseline (median of 5 months from dx) through 3 years post-dx. Multinomial logistic regression was used to identify the associated patient (socio-demographics and BRCA status), disease (stage, ER/PR/HER2) and treatment (surgery, chemotherapy) characteristics associated with each trajectory. Variables significant at p<0.05 in univariable models were entered into the final multivariable model. Results: 965 women with Stages 0-III breast cancer were included in the analysis, with a median age at dx of 37. Participants were predominantly non-Hispanic White (85%), partnered (76%) and had completed college (84%). There was a significant decrease in median FCR scores from baseline to year 3 (9 vs. 8, Wilcoxon signed-rank test P<0.01). Five FCR trajectories (Table) were identified: 1) 10.5% of participants reported low/stable FCR from baseline over follow-up; 2) 33.1% had moderate FCR that improved over time; 3) 5.5% had moderate FCR scores at baseline that worsened over time; 4) 30% had high FCR scores at baseline that improved over time; 5) 20.8% had high FCR at baseline that remained high at all time points. In the fully adjusted multinomial model, younger age at dx and Stage 3 and 2 (vs. 1) disease were associated with higher odds of being in the high/stable trajectory. Having a lumpectomy (vs. mastectomy) was associated with higher odds of being in a high/stable as well as moderate/improving trajectory while White (vs. non-White) women had higher odds of being in a trajectory of improving FCR. Receipt of chemotherapy and financial discomfort were significantly associated with assignment to specific FCR trajectories in univariate analyses, however did not remain significant in the adjusted model. Being partnered, BRCA mutation status, and ER/PR/HER2 status were not significantly associated with any FCR trajectory classification in univariate or multivariate analyses. Conclusion: While FCR improves over time for many young women with breast cancer, a substantial minority (26%) had FCR that was severe and did not improve or worsened over time. Younger women with higher stage disease who are at risk for high levels of unresolved FCR may benefit from intervention including early referral to mental health professionals. Ongoing monitoring of women at risk for developing FCR following active treatment is warranted. Table Mean FCR score for each trajectoryBaselineYear 1Year 2Year 3TrajectoriesLow/Stable (N=103)5.725.605.545.45Moderate/Improving (N=331)7.907.487.287.09Moderate/Worsening (N=34)6.748.329.6410.54High/Improving (N=294)9.889.419.088.67High/Stable (N=203)11.0211.0811.0310.88 Citation Format: Lidia Schapira, Yue Zheng, Shari Gelber, Philip Poorvu, Kathryn J Ruddy, Rulla Tamini, Jeffrey Peppercorn, Steve Come, Virginia Borges, Ann Partridge, Shoshana Rosenberg. Trajectories of fear of cancer recurrence in young breast cancer survivors [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 P2-13-09.

OBJECTIVE This study’s purpose was to improve understanding of the forces driving the complex mechanical interaction between embolic material and current stroke thrombectomy devices by analyzing the histological composition and strength of emboli retrieved from patients and by evaluating the mechanical forces necessary for retrieval of such emboli in a middle cerebral artery (MCA) bifurcation model. METHODS Embolus analogs (EAs) were generated and embolized under physiological pressure and flow conditions in a glass tube model of the MCA. The forces involved in EA removal using conventional endovascular techniques were described, analyzed, and categorized. Then, 16 embolic specimens were retrieved from 11 stroke patients with large-vessel occlusions, and the tensile strength and response to stress were measured with a quasi-static uniaxial tensile test using a custom-made platform. Embolus compositions were analyzed and quantified by histology. RESULTS Uniaxial tension on the EAs led to deformation, elongation, thinning, fracture, and embolization. Uniaxial tensile testing of patients’ emboli revealed similar soft-material behavior, including elongation under tension and differential fracture patterns. At the final fracture of the embolus (or dissociation), the amount of elongation, quantified as strain, ranged from 1.05 to 4.89 (2.41 ± 1.04 [mean ± SD]) and the embolus-generated force, quantified as stress, ranged from 63 to 2396 kPa (569 ± 695 kPa). The ultimate tensile strain of the emboli increased with a higher platelet percentage, and the ultimate tensile stress increased with a higher fibrin percentage and decreased with a higher red blood cell percentage. CONCLUSIONS Current thrombectomy devices remove emboli mostly by applying linear tensile forces, under which emboli elongate until dissociation. Embolus resistance to dissociation is determined by embolus strength, which significantly correlates with composition and varies within and among patients and within the same thrombus. The dynamic intravascular weakening of emboli during removal may lead to iatrogenic embolization.