Citations

Abstract Introduction: Biomarkers that reflect pathologic processes affecting neuronal function during preclinical and early stages of Alzheimer's disease (AD) are needed to aid drug development. Methods: A targeted, stable isotope, quantitative mass spectrometry‐based investigation of longitudinal changes in concentrations of previously identified candidate biomarkers was performed in cerebrospinal fluid (CSF) of Alzheimer's Disease Neuroimaging Initiative participants who were classified as cognitively normal (CN; n = 76) or with mild cognitive impairment (MCI; n = 111) at baseline. Results: Of the candidate biomarkers, the CSF concentration of neuronal pentraxin 2 (NPTX2), a protein involved in synaptic function, exhibited rates of change that were significantly different between three comparison groups (i.e., CN vs. MCI participants; AD pathology positive vs. negative defined by phosphorylated tau181/amyloid beta1‐42 ratio; and clinical progressors vs. non‐progressors). The rate of change of NPTX2 also significantly correlated with declining cognition. Discussion: CSF NPTX2 concentration is a strong prognostic biomarker candidate of accelerated cognitive decline with potential use as a therapeutic target.

Introduction: The mechanisms linking obesity to increased mortality in patients with coronavirus-disease 2019 (COVID-19) are unclear. Hypothesis: We hypothesised that obesity would be associated with adverse right ventricular (RV) remodelling and function which might be further exacerbated by COVID-19 associated increases in RV afterload/demand. Methods: We used echocardiography and computed tomography to establish links between RV dimensions and function and bodyweight in patients with severe COVID-19. In obese and non-obese participants without COVID-19, we used cardiovascular magnetic resonance to define the effects of obesity upon RV volumes, energetics, systolic function and stress reserve. Results: In patients with severe COVID-19, increasing bodyweight was associated with disproportionate RV dilatation (n=26, echocardiography, R=0.42, P=0.03, CT n=34, R=0.23, P=0.004) and impairment of RV systolic function (fractional area change (FAC) R=-0.45, P=0.04); obesity (BMI >30kg/m2) was associated with a 32% reduction in RV FAC (P=0.03). Similar associations were seen in a validation cohort (n=91, all P<0.05). In participants without COVID-19, class III obesity (n=54, BMI 47±4 kg/m 2 ) was associated with RV remodelling, impaired cardiac energetics (PCr/ATP ratio 23% lower, P<0.001) and reduction in RV systolic function at rest (by 3±1%, P=0.01), which was related to reduced energetics (R=0.3, P=0.04). Participants with class I-II obesity (BMI 35±5 kg/m 2 , n=27) had impaired RV diastolic filling rate at rest (P<0.001) and blunted RV dobutamine stress systolic response (by 68%, P=0.03) and diastolic response (by 78%, P=0.008). Surgical weight loss in patients obesity (n=37, 34±15kg weight loss) was associated with improvement in RV volume (12±26 ml lower, P=0.006) and function (ejection fraction 2±5% higher, P=0.03). Conclusions: Increasing body weight is associated with both significant alterations in RV volumes, systolic function and stress responses which are mitigated with weight loss and also with disproportionate RV dilatation and dysfunction in severe COVID-19. RV dysfunction is a modifiable mechanism which might link obesity to adverse outcomes in patients with COVID-19 and other disorders stressing the right heart.

Abstract Background: NET is offered to postmenopausal patients (pts) with clinical stage 2/3 ER+/HER2- BC to promote breast-conserving surgery. Also limited surgical accessibility during the COVID19 pandemic has increased NET utility. Inability to identify ET-resistant disease at diagnosis risks disease progression (PD) and delays more effective treatments. Dowsett et al. recently demonstrated that baseline levels of ER, progesterone receptor (PR), Ki67 (&gt;15% vs ≤15%), and Ki67 (&gt;10% vs ≤10%) 2-4 weeks (wks) after starting NET may improve appropriate patient (pt) selection for NET (PMC7280290). The ER, PR and Ki67-based prediction model divides pts with primary ER+/HER2- BC into 3 groups for appropriateness for NET: (Group 1) NET is likely to be inappropriate (Allred ER &lt;6 or ER 6 and PgR &lt;6), (Group 2) NET may be appropriate and a biopsy for on-treatment Ki67 analysis may be considered after 2-4 wks of NET (2A: ER 7 or 8 and PgR &lt;6 and 2B: ER 6 or 7 and PgR ≥6) given that on-treatment Ki67 &gt;10% has been associated with worse outcome (PMC5455353), or (Group 3) NET is appropriate (ER 8 and PgR ≥6). The ALTERNATE trial (NCT01953588) randomized postmenopausal women with clinical stage II or III, ER+ (Allred score 6-8)/HER2- BC to receive anastrozole (ANA), fulvestrant (FUL), or ANA + FUL for 6 months, unless Ki67 was &gt;10% on wk 4 or 12 biopsy, in which case pts were triaged to receive neoadjuvant chemotherapy (NCT) or surgery. As previously reported, the ET-sensitive disease (mPEPI 0 plus pCR) rates were similar across the treatment arms and overall 22% (286 of 1,299) pts had Ki67 &gt;10% at wk 4 or 12. The ALTERNATE trial therefore provides a large independent data set to evaluate the NET appropriateness model. Results: Among 1,299 eligible pts randomized to receive 6 months of NET, 214 were excluded due to absent HR Allred score (n=41) or absence of pre-treatment and wk 4 Ki67 determinations (n=173). The proportions of the remaining 1,085 pts in Group 1, 2 and 3 were 1% (n=10), 43% (n= 468), and 56% (n=607), respectively. On-study Ki67 &gt;10% prompting conversion from NET to NCT/Surgery occurred in: Group 1 90% (9 of 10), Group 2 30% (141 of 468), and Group 3 17% (104 of 607) (Table 1). Among the 1,075 pts in Groups 2 and 3, 260 (24%) pts had Ki67 ≤15% at baseline (BL), among whom only 14 (5.4%) had Ki67 &gt;10% at wk 4, compared to 231 of the 815 (28.3%) who had BL Ki67 &gt;15% and subsequent Ki67 &gt;10% at wk 4. 2% of pts who remained on NET due to on-treatment Ki67 &lt;10% had PD. Response and PEPI-0 rates by group will be reported. Conclusion: ALTERNATE trial data support a model whereby levels of ER, PR and Ki67 at diagnosis can be used for the identification of postmenopausal pts with primary ER+/HER2- BC who are appropriate for NET. When baseline ER Allred scores are &gt;6 and Ki67 ≤15%, there is a low likelihood of ET-resistant disease. When BL Ki67 is &gt;15%, ET sensitivity is variable, and on-treatment biopsy for Ki67 may assist in triaging regarding NET appropriateness, particularly given the extremely low local PD rates seen in ALTERNATE when on-treatment Ki67 was &lt;10%. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG); NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org; Clinical Trials.gov Identifier: NCT01953588 Table 1 Baseline levels of ER, PR, and Ki67 in Relation to Wk 4 Ki67 (N=1,085)BaselineWeek 4GroupNERAllred ScorePRAllred ScoreKi67Ki67 ≤10%N (%)Ki67 &gt;10%N (%)1N=26&lt;6≤15%0 (0%)2 (100%)9 (90)N=86&lt;6&gt;15%1 (12.5%)7 (87.5%)2AN=647 or 8&lt;6≤15%61 (95.3%)3 (4.7%)90 (30.1)N=2357 or 8&lt;6&gt;15%148 (63%)87 (37%)2BN=466 or 7≥6≤15%42 (91.3%)4 (8.7%)51 (30.2)N=1236 or 7≥6&gt;15%76 (61.8%)47 (38.2%)3N=1508≥6≤15%143 (95.3%)7 (4.7%)104 (17.1)N=4578≥6&gt;15%360 (78.8%)97 (21.2%) Citation Format: Matthew J Ellis, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Mitch Dowsett, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Clifford Hudis, Eric P Winer, Kelly Hunt, Ann H Partridge, Cynthia X Ma, Lisa A Carey. Validation of a predictive model for potential response to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC): An ALTERNATE trial analysis (Alliance A011106) [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 PD2-10.

Abstract Background: Ki67 values &gt;10% 2-4 weeks (wks) after starting neoadjuvant ET (NET) indicates persistent cell proliferation, resistance to ET, and is associated with increased risk of recurrence. The ACOSOG Z1031 trial suggested that these tumors are also relatively chemotherapy (chemo) resistant with a low pathologic complete response (pCR) rate to NCT. The ALTERNATE trial (NCT01953588) is a randomized study of neoadjuvant anastrozole (ANA), fulvestrant (FUL), or ANA + FUL in postmenopausal patients (pt) with newly diagnosed clinical stage II or III ER+ (Allred score 6-8)/HER2- BC. Ki67 &gt;10% at wk 4 or 12 after starting NET triggered triage to NCT of physician choice or weekly paclitaxel. Pts who refused protocol-directed therapy, were not candidates for NCT, or decided to undergo immediate surgery are being followed per protocol. Here we report the rates of pCR and residual cancer burden (RCB) following NCT for pts triaged to NCT due to Ki67 &gt;10% at wk 4 or 12. Results: Of the 1,299 eligible pts randomized to receive ANA, FUL, or ANA + FUL, 286 (22%) had Ki67 &gt;10% at wk 4 or 12. 168 of these 286 pts (58.7%) chose to switch to NCT, 32 went to surgery (11.2%), and 86 discontinued further protocol-directed therapy (30.1%). Among the 168 pts who underwent NCT, the presenting clinical T stages were cT2 (n=113; 67.26%), cT3 (n=47; 27.98%) and cT4 (n=8; 4.76%) and N stages were cN0 (n=82; 48.8%), cN1 (n=75; 44.6%), cN2/3 (n=9; 5.4%) and cNx (n=2; 1.2%). Central ER testing was performed on pre-treatment biopsies and confirmed ER Allred score 6-8 in 155 of 168 (92.2%) pts, with the rest being ER Allred score 4-5 (n=5; 3%), ER- (Allred score 0) (n=2; 1.2%), or not tested (n=6; 3.6%). Most (n=139; 82.7%) were ER+/PR+, while 17.3% (n=29) were ER+/PR-, and tumor grades were G1 (n=10; 6%), G2 (n=99; 58.9%), G3 (n=54; 32.1%), not reported (n=5; 3%). Baseline Ki67 levels prior to NET were &gt;10% in 94% (n=158), ≤10% in 3% (n=5), and not done in 3% (n=5). NCT regimens administered included doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T) (n=60; 35.71%); weekly paclitaxel (n=56; 33.33%), docetaxel/cyclophosphamide (TC) (n=33; 19.65%), other doxorubicin and/or taxane containing regimen (n=17; 10.12%), and cyclophosphamide/methotrexate/fluorouracil (CMF) (n=2; 1.19%). 35 (20.8%) pts did not complete planned course of NCT due to toxicity (n=27) or refusal (n=8). 154 NCT pts underwent surgery (mastectomy in 40.3%, and breast conserving surgery in 59.7%). The path ypT stages were Tis/0 (n=10; 6.5%), T1 (n=62; 40.3%), T2 (n=61; 39.6%), and T3/4 (n=21; 13.6%), and the ypN stages were N0 (n=66; 42.9%), N1 (n=57; 37%), N2/3 (n=30; 19.5%), and Nx (n=1; 0.6%). Among the 168 pts who started on NCT (intent to treat population), there were 8 pCRs (no invasive disease in the breast or lymph nodes) (4.8%; 95% CI: 2.1% to 9.2%). Residual Cancer Burden (RCB) categories include RCB 0 (n=8; 4.8%), RCB 1 (n=15; 8.9%), RCB 2 (n=82; 48.8%), RCB 3 (n=42; 25.0%), and not determined (n=21; 12.5%). Correlations of baseline pt and tumor characteristics with pathology response to NCT will also be presented. Conclusion: In pts with NET-resistant ER+/HER2- BC, salvage NCT is not likely to induce a complete or near complete response. More effective treatments are needed for this high-risk ER+/HER2- pt population. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG); NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. Clinical Trials.gov Identifier: NCT01953588 Citation Format: Cynthia X Ma, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Kelly Hunt, Clifford Hudis, Eric P Winer, Matthew J Ellis, Lisa A Carey, Ann H Partridge. Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106) [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 GS4-05.

Following decades of decline, maternal mortality began to rise in the United States around 1990—a significant departure from the world’s other affluent countries. By 2018, the same could be seen with the maternal mortality rate in the United States at 17.4 maternal deaths per 100 000 live births. When factoring in race/ethnicity, this number was more than double among non-Hispanic Black women who experienced 37.1 maternal deaths per 100 000 live births. More than half of these deaths and near deaths were from preventable causes, with cardiovascular disease being the leading one. In an effort to amplify the magnitude of this epidemic in the United States that disproportionately plagues Black women, on June 13, 2020, the Association of Black Cardiologists hosted the Black Maternal Heart Health Roundtable—a collaborative task force to tackle the maternal health crisis in the Black community. The roundtable brought together diverse stakeholders and champions of maternal health equity to discuss how innovative ideas, solutions and opportunities could be implemented, while exploring additional ways attendees could address maternal health concerns within the health care system. The discussions were intended to lead the charge in reducing maternal morbidity and mortality through advocacy, education, research, and collaborative efforts. The goal of this roundtable was to identify current barriers at the community, patient, and clinician level and expand on the efforts required to coordinate an effective approach to reducing these statistics in the highest risk populations. Collectively, preventable maternal mortality can result from or reflect violations of a variety of human rights—the right to life, the right to freedom from discrimination, and the right to the highest attainable standard of health. This is the first comprehensive statement on this important topic. This position paper will generate further research in disparities of care and promote the interest of others to pursue strategies to mitigate maternal mortality.

MYC gene amplification and somatic mutations are frequent in both adult and pediatric AML although how MYC drives and contributes to the development and maintenance of AML has not been resolved. Transcription factor EB (TFEB) is a master regulator of genes that control autophagy and lysosome biogenesis, a central catabolic recycling pathway that regulates cell survival. Given the oncogenic effects of MYC in AML and that the induction of autophagy compromises AML cell growth and survival, we tested if the oncogenic effect of MYC depends on its suppression of TFEB transcription programs in AML. In support of this hypothesis, inducible MYC expression in K562 and THP-1 leukemia cells was sufficient to suppress expression of TFEB and its target genes. Further and conversely, MYC knockdown in NB4 AML cells provoked increased expression of TFEB mRNA and protein, as well as increased expression of TFEB target genes. Notably, dose response studies demonstrated that expression of TFEBS211A, constitutively nuclear form of TFEB that is refractory to control by mTORC1 signaling, dramatically impairs proliferation of HL60, OCI-AML2 and OCI-AML3 AML cells. In addition, induction of TFEBS211A provoked rampant apoptosis. Of important, overexpression of TFEBS211A in HL-60 and OCI-AML3 cells was also sufficient to promote monocytic and granulocytic differentiation, as judged by morphological changes and the acquisition of mature monocytic and granulocytic markers including CD11b, Gr1, and CD15. To identify TFEB targets that might contribute to myeloid/granulocytic differentiation, we performed RNA-seq analysis of HL60 leukemia cells engineered to inducibly express the TFEBS211A transgene. Using a cut-off of fold change&gt;4 with q&lt;0.01, a total of 1152 genes were differentially regulated following the induction of TFEBS211A in HL60 cells. As expected, this included the robust induction of nearly all TFEB target genes associated with the autophagy-lysosome pathway, but also of STAT1, KLF4, KLF6, CEBPB, CSF1 and GATA2 genes that are necessary and/or sufficient to provoke terminal monocytic and granulocytic differentiation of AML cells. Surprisingly, among genes induced by TFEB in HL60 cells is IDH1, which catalyzes the production of α-ketoglutarate (α-KG), a required substrate of the TET family of dioxygenases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In particular, TFEBS211A expression provoked increases in levels of α-KG and significant increases in global levels of 5hmC in genomic DNA of HL60 leukemia cells both ex vivo and in vivo. Furthermore, TFEB-mediated induction of IDH1/2 mRNA and protein, and of IDH1 promoter activity, was antagonized by inducible expression of MYC. To assess the global effects of TFEB on 5mC/5hmC landscapes, we performed paired reduced representation bisulfite (BS)- and oxidation bisulfite (oxBS)-sequencing. As predicted, TFEBS211A induced both loss and gains of 5mC, but there were more losses (n = 722) than gains (n = 459) across all 22 chromosomes. Quite remarkably, and consistent with TFEB-provoked increases of 5hmC signals, TFEBS211A exclusively induced 5hmC gains (in a total of 863 genes), and 37% and 36% of these 5hmC gains occurred in promoter regions and CpG islands, and across all 22 chromosomes. Comparison of BS- and oxBS-seq versus RNA-seq analyses of HL60 cells expressing TFEB revealed significant changes in mRNA levels and concomitant differential changes in 5mC and 5hmC marks in KLF4, KLF6, STAT3, TP73, andFOXO1 that have pivotal roles in controlling myeloid cell differentiation and death. Collectively, these findings demonstrate that MYC suppresses TFEB expression and function in AML cells, and that TFEB functions as a tumor suppressor that provokes AML cell differentiation and death. Strikingly, these responses rely on epigenetic control, where TFEB directly induces the transcription of IDH1 and IDH2 to provoke global hydroxylation of 5-methylcytosine and the expression of genes that drive terminal differentiation and apoptosis. Thus, a MYC-TFEB-IDH1/2-TET2 circuit controls AML cell fate. Disclosures Murphy: Merck: Research Funding; Puma Biotech: Research Funding. Ballabio:CASMA Therapeutics: Other: Co-Founder. Kaufmann:Takeda Pharmaceuticals: Research Funding.

Abstract Objective To describe headache characteristics, medication use, disability, and quality of life in a large patient cohort from the United States who have chronic migraine (CM) and medication overuse headache (MOH). Methods In all, 610 adult patients were enrolled into the Medication Overuse Treatment Strategy trial from 34 healthcare clinics, including headache specialty, general neurology, and primary care clinics. Descriptive statistics characterize baseline demographics, headache characteristics, medication use, disability (Headache Impact Test 6 [HIT‐6] and Migraine Functional Impact Questionnaire [MFIQ]), pain interference (PROMIS Pain Interference), and quality of life (EQ‐5D‐5L). Relationships with headache frequency were assessed. Results Mean age was 45 years (SD 13) and 531/608 (87.3%) were females. Mean headache days per 30 was 24.3 (SD 5.5), including 13.6 (SD 7.1) with moderate to severe headache. Daily headaches were reported by 36.1% (219/607) of patients. Acute headache medications were used on 21.5 (SD 7.5) per 30 days. The most commonly overused medications were simple analgesics (378/607, 62% of patients), combination analgesics (246/607, 41%), and triptans (128/607, 21%). HIT‐6, MFIQ, PROMIS Pain Interference, and EQ‐5D‐5L scores demonstrated substantial negative impact from CM with MOH on patient functioning and quality of life. Higher headache frequency was associated with more moderate–severe headache days, more frequent acute headache medication use, greater headache‐related disability, and lower quality of life. Only 272/606 (44.9%) were taking migraine preventive medication. Conclusions CM with MOH is associated with a large burden on patients in the United States. Higher headache frequency is associated with greater impact on functioning, pain interference, and quality of life.