Citations

Abstract HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.

1562 Background: In Caucasian-predominant populations, overweight or obese NSCLC pts (BMI≥25-kg/m2) have better prognosis while underweight (BMI≤18.5-kg/m2) pts have a worse prognosis. A large pooled sample allowed us to evaluate the role of ethnicity in this BMI-NSCLC OS relationship. Methods: Using individual data, survival analysis was performed on 15 ILCCO studies, assessing the interactions between ethnicity and BMI on overall survival (OS). Adjusted Hazard Ratios (aHR) from Cox models and adjusted penalized smoothing spline plots were generated. Results: Among 13416 (77%) Caucasian, 2975 (17%) Asian, and 935 (5%) Black NSCLC pts analyzed, we confirmed that for all pts, being underweight at NSCLC diagnosis was associated with worse OS (aHR=1.68, CI 1.5-1.8, p<0.001), while overweight/obese pts had improved survival (aHR 0.89, CI 0.8-0.9, p<0.001), when compared to pts with normal BMI. In general, Black pts had poorer OS than Caucasian pts (aHR 1.26 CI 1.1-1.4, p<0.001). However, the BMI-OS relationship differed according to ethnicity (BMI-ethnicity interaction, p=0.009): Caucasian underweight pts had poorer OS (aHR 1.67, CI 1.5-1.8, P<0.001) while overweight/obese pts had improved OS (aHR 0.89, CI 0.8-0.9, P<0.001). In Asian pts, these two associations were aHR 1.15, CI 0.8-1.5, P=0.33, and aHR 0.91, CI 0.7-1.1, P=0.32, respectively. In Black pts, these two associations were aHR 1.06, CI 0.7-1.5, p=0.73 and 0.75, CI 0.6-0.8 p<0.001, respectively. For overweight/obese patients, as BMI rises from 25-kg/m2 through 45-kg/m2, the prognosis worsens for Caucasian pts, remains stable for Asian pts, but improves for Black pts. Conclusions: InCaucasian pts, being underweight had a greater negative impact on OS than for Asian or Black pts, while being obese had a greater beneficial impact in Blacks than in other ethnic groups. These ethnic differences likely reflect genetically-informed muscle/adipose tissue distributions, where Black pts may have less sarcopenic obesity than other ethnicities. In future prognostic studies, BMI relationships must account for ethnic differences.

1514 Background: The prevalence of germline mutations in non-white patients with breast cancer and the germline genetic drivers of breast cancer risk in non-white populations are largely unknown. Methods: The study population included 77,900 women with breast cancer (Non-Hispanic white: 57,003; Black: 6,722; Asian: 4,183; Hispanic: 5,194; Ashkenazi-Jewish: 4,798) who underwent germline multigene panel testing of cancer predisposition genes from March 2012 to December 2016. The prevalence of predisposition gene mutations in racial and ethnic populations relative to non-Hispanic Whites was assessed while accounting for age at diagnosis of breast cancer, family history of breast and ovarian cancer, and estrogen receptor status of breast tumors. Associations between mutations in each gene and breast cancer risk were evaluated using reference controls. Results: The overall frequency of pathogenic mutations in known breast cancer predisposition genes was 9.1% for non-Hispanic Whites, 9.8% for African Americans, 10.2% for Hispanics, 7.6% for Ashkenazi-Jewish, and 7.5% for Asians. BRCA1 mutations were enriched (p < 0.05) and CHEK2 mutations were under-represented in all racial and ethnic populations relative to non-Hispanic Whites. BRCA2 and BARD1 mutations were enriched in African Americans and Hispanics relative to non-Hispanic Whites, whereas PALB2 and RAD51C mutations were enriched in Hispanics. Among genes with mutation counts large enough for assessment, mutations in BARD1, BRCA1, BRCA2, PALB2 and TP53 were significantly associated with clinically relevant increased risks (odds ratio (OR) > 2) of breast cancer across all ethnicities and races. Rates of variants of uncertain significance were highest among Asians (29%), followed by blacks (27%), Hispanics (21%), non-Hispanic whites (16%) and Ashkenazi-Jews (14%). Conclusions: While there is some similarity across ethnic groups, substantial heterogeneity exists in the prevalence of mutations in breast cancer predisposition genes across major racial and ethnic groups in the US population. These findings contribute to our understanding of breast cancer risk and have significant implications for genetic testing, screening, and management of patients with an inherited predisposition to breast cancer, with a need for continued analysis with increased cohort size in ethnic minority groups.

BackgroundEsophageal carcinoma is the eighth most common cancer in the world. Volumetric‐modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small‐spot intensity‐modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small‐spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects.Methods35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small‐spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase‐averaged 4D‐CT's. The dose‐volume‐histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank‐sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose.ResultsIn the nominal scenario, small‐spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE], lung Dmean, heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE], liver V30Gy[RBE], stomach V45Gy[RBE], lung Dmean, V5Gy[RBE], and V20Gy[RBE], cord Dmax and , liver Dmean, heart V20Gy[RBE], and V30Gy[RBE], but IMPT was significantly worse for CTVhigh D95%, , and D5%‐D95%, CTVlow D95%, heart Dmean, and V40Gy[RBE], requiring careful and experienced adjustments during the planning process and robustness considerations. The small‐spot IMPT plans still met the standard clinical requirements after interplay effects were considered.ConclusionsSmall‐spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small‐spot IMPT for the treatment of distal esophageal carcinoma.

Background: Revision total hip arthroplasty (revision THA) occurs for a wide variety of indications and in the United States it is coded under Diagnosis-Related Groups (DRGs) 466, 467, and 468, which do not account for revision etiology, a potentially substantial driver of cost. This study investigates revision THA costs and 30-day complications by indication, both locally and nationally. Methods: Hospitalization costs and complication rates for 1,422 aseptic revision THAs performed at a high-volume center between 2009 and 2014 were retrospectively reviewed. Additionally, charges for 28,133 revision THAs in the National Inpatient Sample (NIS) were converted to costs using the Healthcare Cost and Utilization Project cost-to-charge ratios, and 30-day complication rates for 3,224 revision THAs were obtained with use of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). Costs and complications were compared between revision THAs performed for fracture, wear/loosening, and dislocation/instability with use of simultaneous and pairwise comparisons and a multivariable model accounting for American Society of Anesthesiologists (ASA) score, age, and sex. Results: Local hospitalization costs for fracture (median, $25,672) were significantly higher than those for wear/loosening ($20,228; p < 0.001) or dislocation/instability ($17,911; p < 0.001), with differences remaining significant even after adjusting for patient comorbidities (p < 0.001). NIS costs for fracture (median, $27,596) were higher than those for other aseptic indications (wear/loosening: $21,176, p < 0.001; dislocation/instability: $16,891, p< 0.001). Local 30-day orthopaedic complication rates for fracture (20.7%) were higher those than for dislocation/instability (9.0%; p = 0.007) and similar to those for wear/loosening (17.6%; p = 0.434). Nationally, combined medical and surgical complication rates for fracture (71.3% of patients with ≥1 complication) were significantly higher than those for wear/loosening (35.2%; p < 0.001) or dislocation/instability (35.1%; p < 0.001). Conclusions: Hospitalization costs for revision THA for fracture were 33% to 48% higher than for all other aseptic revision THAs, both locally and nationally. This increased cost persisted even after multivariable comorbidity adjustment, the current DRG basis for stratifying revision THA reimbursement. Additionally, 30-day complication rates suggest that increased resource utilization for fracture patients continues even after discharge. Indication-specific coding and reimbursement systems are necessary to maintain sustainable access to revision THA for all patients. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background: Young women with breast cancer (BC) are increasingly choosing contralateral prophylactic mastectomy (CPM), yet little is known about the impact of surgical choices on quality of life (QOL) and psychological health. Using a large, prospective cohort of young women with BC, we sought to evaluate psychosocial outcomes following surgery. Methods: Among participants of the Young Women's BC Study, a multi-center cohort of women dx'd with BC at age ≤40, we identified women with Stage 0-3 unilateral BC who had surgery and completed surveys that included measures of QOL (CARES) and psychological health (HADS). Linear mixed-effects models were fit to assess changes from 1 to 3 years (yrs) post-dx in anxiety, depression, psychosocial, body image, and sexual scores. Adjusted (stage, hormone receptor status, chemotherapy, age) means were estimated and differences compared (Bonferroni adjusted p-values) between CPM vs breast conserving surgery (BCS) and unilateral mastectomy (UM) at 1, 2, and 3 yrs. Results: Of 863 women, 30% had BCS, 24% UM, 46% CPM. Median age at dx was 37 (range: 22-40). Of women who had UM/CPM, 84% had reconstruction. Among women who had CPM, mean body image (p=.02), psychosocial (p&lt;.0001), sexual (p&lt;.0001), and depression p=.0007) scores decreased, indicating improvement, from yr 1 to 2 but remained stable from yr 2 to 3 (Table). Anxiety decreased from yr 1 to 2 for women who had BCS (p=.0007) and M (p=.03), and from yr 2 to 3 for women who had CPM (p=.003). Body image scores did not change significantly between any time points among women who had M or BCS. Overall change trajectories for sexual (p=.03) and anxiety scores (p=.008) differed by surgery. Compared to BCS and UM, psychosocial scores were higher in women who had CPM at 1 yr (p&lt;.05) and remained higher compared to BCS at 2 yrs (p=.04). Anxiety was higher among women who had CPM vs UM at 1 and 2 yrs (p&lt;.01), vs BCS at 2 yrs (p=.004). Depression was higher among women who had CPM vs UM in yr 1 (p=.05). By yr 3, there were no significant differences in anxiety, depression, and overall psychosocial scores between groups. Compared to BCS, women who had CPM had higher sexual and body image scores (p&lt;.01), indicating worse QOL, at all timepoints. Compared to UM, women who had CPM had higher sexual scores at 1 and 3 yrs (p&lt;.05) and body image scores at 3 yrs (p=.02). Conclusions: While psychosocial health improves over time, differences by surgery persist, with women who have CPM experiencing more sexual and body image issues compared to women who undergo BCS or M in the years following surgery. Given that surgical choices may be affected by distress experienced before or at dx, ensuring young women receive adequate support when making surgical decisions as well as after surgery is warranted. Mean CARES and HADS scores Year 123Psychosocial*CPM.89.78.76 UM.75.69.66 BCS.72.65.66 Sexual*CPM1.641.371.40 UM1.411.291.08 BCS1.181.071.04 Body image*CPM1.331.221.30 UM1.161.131.04 BCS.64.57.56 Anxiety**CPM7.657.406.79 UM6.505.916.39 BCS7.036.226.50 Depression**CPM3.723.213.25 UM3.022.802.70 BCS3.332.823.13**CARES range: 0-4;higher scores=worse QOL **HADS range 0-21;higher scores=more anxiety/depression Citation Format: Rosenberg SM, Hu J, Dominici LS, Poorvu PD, Ruddy KJ, Tamimi RM, Schapira L, Come S, Peppercorn JM, Borges VF, Partridge AH. Longitudinal changes in psychosocial health in young women following breast cancer surgery: Results from a multi-center cohort study [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 P2-14-03.