Citations

Abstract Background: The kinases ataxia-telangiectasia-mutated-and-Rad3-related (ATR), checkpoint kinase 1 (CHK1) and WEE1 participate in the response to replication stress. Inhibitors of ATR, WEE1 and CHK1 are being tested for antineoplastic activity as monotherapies and in combination with chemotherapy. Although these agents impair cell cycle checkpoints, fork stabilization, origin firing and homologous recombination (HR), little is known about the apoptotic pathways that are engaged and the critical mediators activating cell death mechanisms. The present study utilizes high grade serous ovarian cancer (HGSOC) cell lines and patient derived xenografts (PDXs) to identify the primary mechanism of cell death in ovarian cancer and assess changes involved in the resistance setting after treatment with these inhibitors. Methods: A panel of HGSOC cell lines was examined for responses to ceralasertib (ATRi), prexasertib (CHK1i) or adavosertib (WEE1i) using colony forming assays, immunoblotting and assays for apoptosis. Mechanisms involved in acquired resistance and downstream changes in cell fate were evaluated by generating prexasertib-resistant HGSOC cell lines. Subsequent NGS analysis was performed in the sensitive and resistant pairs. Results: Irrespective of the homologous recombination (HR) status, ovarian cell lines and PDXs underwent cell death during prolonged exposure at clinically achievable concentrations. Treatment of ovarian cancer cell lines with ATRi, CHK1i or WEE1i activated the replication checkpoint, consistent with previously published reports. The subsequent apoptotic response involved PMAIP1 and BCL2L11 upregulation rather than the TNFa-induced death receptor-mediated apoptosis we recently described in acute leukemia (Cancer Res. PMID: 33414171). Additionally, ovarian lines selected for CHK1i resistance failed to die in response to either ATRi or WEE1i. Conclusions: Prexasertib, ceralasertib, and adavosertib exhibit monotherapy activity in both HR deficient and proficient HGSOC cell lines and PDX models. Unlike AML, death receptor mediated apoptosis was not observed; instead, the primary mechanism of cell killing in HGSOC lines involves activation of the mitochondrial apoptotic pathway. Cross-resistance of these DNA damage repair modulators is likely multifactorial and mainly involves diminished replication stress response. Citation Format: Annapoorna Venkatachalam, Kevin L. Peterson, Cristina Correia, Karen S. Flatten, Xianon Hou, Paula A. Schneider, Emily Balczewski, Cordelia McGehee, Rachel M. Hurley, Xue W. Meng, Chance Sine, Rameen Shah, Nicole Vincelettte, Husheng Ding, Hu Li, Saravut (John) Weroha, Scott H. Kaufmann. CHK1 inhibitor prexasertib induces NOXA-dependent apoptosis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1832.

Abstract Background Exosomes are regenerative mediators for skin rejuvenation. Human platelet extract (HPE) is an allogeneic exosome product derived from US-sourced, leukocyte-reduced apheresed platelets with consistent purity and potency. Objectives The authors sought to better characterize the safety and tolerability of novel HPE (plated) Intensive Repair Serum (Rion Aesthetics, Rochester, MN) and its maximal effects on skin rejuvenation at 6 weeks. Methods This prospective, single-arm, non-randomized, longitudinal study investigated the safety and efficacy of HPE. Structured sub-analysis evaluated multifactorial improvement in skin health following standardized skin care regimen to determine the maximal effect. Evaluation at baseline and 6 weeks included participant questionnaires and photo documentation with VISIA-CR Generation 5 3D PRIMOS (Canfield Scientific Inc, Fairfield, NJ). Results VISIA-CR imaging yielded quantifiable and statistically significant improvements in overall skin health (skin health score). A greater score correlated to greater overall skin health, and there was a statistically significant mean delta improvement of 224.2 ± 112.8 (mean ± standard deviation, P ≤ 0.0001) in skin health score at 6 weeks compared with baseline. This correlated to reduction in redness, wrinkles, and melanin production across all cosmetic units (P = 0.005, P = 0.0023, P ≤ 0.0001, respectively) and significant improvements in luminosity and color evenness (P ≤ 0.001). Conclusions A topically applied platelet-derived exosome product, HPE, induced normalization to skin health at 4 to 6 weeks with improved various clinical measures of facial photodamage and cutaneous aging. It is safe, well-tolerated, and well-liked by participants. Level of Evidence: 4

Abstract Overweight [body mass index (BMI) 25.0-29.9 kg/m2] and obesity (BMI ≥30 kg/m2) are risk factors for several malignancies. The Iowa Women's Health Study was examined to determine whether increased BMI was associated with leukemia development. Over 40,000 Iowa women (ages 55-69 years) completed a self-administered lifestyle and health questionnaire in 1986 that included current height and weight. Two hundred women developed leukemia during the period 1986 to 2001 including 74 acute myelogenous leukemia (AML) and 88 chronic lymphocytic leukemia. The risk of AML was increased among women who reported being overweight or obese (relative risk, 1.9; 95% confidence interval, 1.0-3.4; relative risk, 2.4; 95% confidence interval, 1.3-4.5; Ptrend = 0.006) compared with women of normal weight. There was little evidence of a positive association for chronic lymphocytic leukemia (Ptrend = 0.6). Given the prevalence of overweight and obesity in the United States, the population attributable risk of AML due to obesity could approach 30%.

AbstractBackgroundPostoperative management strategies for endoscopic skull base surgery (ESBS) vary widely because of limited evidence‐based guidance.MethodsThe PubMed, EMBASE, and Cochrane databases were systematically reviewed from January 1990 through February 2022 to examine 18 postoperative considerations for ESBS. Nonhuman studies, articles written in a language other than English, and case reports were excluded. Studies were assessed for levels of evidence, and each topic's aggregate grade of evidence was evaluated.ResultsA total of 74 studies reporting on 18 postoperative practices were reviewed. Postoperative pain management, prophylactic antibiotics, and lumbar drain use had the highest grades of evidence (B). The literature currently lacks high quality evidence for a majority of the reviewed ESBS precautions. There were no relevant studies to address postoperative urinary catheter use and medical intracranial pressure reduction.ConclusionThe evidence for postoperative ESBS precautions is heterogeneous, scarce, and generally of low quality. Although this review identified the best evidence available in the literature, it suggests the urgent need for more robust evidence. Therefore, additional high‐quality studies are needed in order to devise optimal postoperative ESBS protocols.

BACKGROUND: The use of high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) for hypoxemic respiratory failure secondary to COVID-19 are recommended by critical-care guidelines; however, apprehension about viral particle aerosolization and patient self-inflicted lung injury may have limited use. We aimed to describe hospital variation in the use and clinical outcomes of HFNC and NIV for the management of COVID-19. METHODS: This was a retrospective observational study of adults hospitalized with COVID-19 who received supplemental oxygen between February 15, 2020, and April 12, 2021, across 102 international and United States hospitals by using the COVID-19 Registry. Associations of HFNC and NIV use with clinical outcomes were evaluated by using multivariable adjusted hierarchical random-effects logistic regression models. Hospital variation was characterized by using intraclass correlation and the median odds ratio. RESULTS: Among 13,454 adults with COVID-19 who received supplemental oxygen, 8,143 (60%) received nasal cannula/face mask only, 2,859 (21%) received HFNC, 878 (7%) received NIV, 1,574 (12%) received both HFNC and NIV, with 3,640 subjects (27%) progressing to invasive ventilation. The hospital of admission contributed to 24% of the risk-adjusted variation in HFNC and 30% of the risk-adjusted variation in NIV. The median odds ratio for hospital variation of HFNC was 2.6 (95% CI 1.4–4.9) and of NIV was 3.1 (95% CI 1.2-8.1). Among 5,311 subjects who received HFNC and/or NIV, 2,772 (52%) did not receive invasive ventilation and survived to hospital discharge. Hospital-level use of HFNC or NIV were not associated with the rates of invasive ventilation or mortality. CONCLUSIONS: Hospital variation in the use of HFNC and NIV for acute respiratory failure secondary to COVID-19 was great but was not associated with intubation or mortality. The wide variation and relatively low use of HFNC/NIV observed within our study signaled that implementation of increased HFNC/NIV use in patients with COVID-19 will require changes to current care delivery practices. (ClinicalTrials.gov registration NCT04323787.)

e13538 Background: Breast density is considered a well-established breast cancer risk factor. As quasi-3D, digital breast tomosynthesis (DBT) becomes increasingly utilized for screening, there is an opportunity to routinely estimate volumetric breast density (VBD). However, current methods extrapolate VBD from 2D images acquired with DBT and/or depend on the existence of raw DBT data, which is rarely archived due to cost and storage constraints. Using a racially diverse screening cohort, this study evaluates the potential of deep learning for VBD assessment based solely on 3D reconstructed, “for presentation” DBT images. Methods: We retrospectively analyzed 1,080 negative DBT screening exams obtained between 2011 and 2016 from the Hospital of the University of Pennsylvania (racial makeup, 41.2% White, 54.2% Black, 4.6% Other; mean age ± SD, 57 ± 11 years; mean BMI ± SD, 28.7 ± 7.1 kg/m2), for which both 2D raw and 3D reconstructed DBT images (Selenia Dimensions, Hologic Inc) were available. Corresponding 3D reference-standard tissue segmentations were generated from previously validated software that uses both 3D reconstructed slices and raw 2D DBT data to provide VBD metrics, shown to be strongly correlated with VBD measures from MRI image volumes. We based our deep learning algorithm on the U-Net architecture within the open-source Generally Nuanced Deep Learning Framework (GaNDLF) and created a 3-label image segmentation task (background, dense tissue, and fatty tissue). Our dataset was randomly split into training (70%), validation (15%) and test (15%) sets. We report on the performance of our deep learning algorithm against corresponding reference-standard segmentations for a cranio-caudal (CC) view-only subset. We also stratify our results by the two main racial groups (White and Black). Our evaluation measure was the weighted Dice score (DSC), with 0 signifying no overlap and 1 signifying perfect overlap, overall and separately for each label. Results: Our deep learning algorithm achieved an overall DSC of 0.682 (STD = 0.136). It accurately segmented the three labels of background, fatty tissue, and dense tissue, with DSC scores of 0.995, 0.884, and 0.617, respectively. DSC for White and Black women were 0.688 (STD = 0.127) and 0.680 (STD = 0.146), respectively. Conclusions: Our preliminary analysis suggests that deep learning shows promise in the estimation of VBD using 3D DBT reconstructed, “for presentation” CC view images and does not demonstrate bias among racial groups. Future work involving optimization of performance in other breast views as well as transfer learning based on ground truth masks by clinical radiologists could further enhance this method. In view of rapid clinical conversion to DBT screening, such a tool has the potential to enable large retrospective epidemiological and personalized risk assessment studies of breast density with DBT.

e13041 Background: PIK3CA mutations occur in about 40% of patients with HR+/HER2- breast cancer. The phase III SOLAR-1 trial demonstrated prolonged progression-free survival with alpelisib and fulvestrant compared to fulvestrant alone among patients with HR+/HER2-/ PIK3CA mutant advanced breast cancer previously treated with endocrine therapy. Hyperglycemia was seen in 64% of patients treated with alpelisib and fulvestrant and was treated with metformin. Inhibition of PI3Kα leads to an on-target effect of hyperglycemia and a secondary hyperinsulinemia. This rebound hyperinsulinemia may lead to escape PI3K pathway activation in breast cancer progression via the insulin and IGF1pathways. Concurrent administration of SGLT2 inhibitors may abrogate the PI3K pathway activation effect and delay disease progression. This study reports time on treatment with alpelisib and PFS among patients who received an SGLT2 inhibitor with alpelisib. Methods: A retrospective review of all metastatic breast cancer patients treated with alpelisib was completed from 8/2019 to 5/2021 at the Saint Luke’s Koontz Center for Advanced Breast Cancer. Results: This review included 22 female patients, 11 received an SGLT2 inhibitor for treatment related hyperglycemia (A+SGLT group) and 11 who received metformin/other diabetic agents (A group). Baseline characteristics were not significantly different between the two groups: median age 63, BMI of 29.1, hemoglobin A1C of 6.3 and fasting blood glucose of 119.1mg/dl. PIK3CA mutations included H1047X (40.9%), E545X (31.8%), E542K (13.6%), other (13.6%). The median number of prior treatments for MBC was 3 (range 1-5). Prior treatments included aromatase inhibitors: 100%, fulvestrant: 77%, CDK 4/6 inhibitors: 82%, everolimus: 32% and chemotherapy: 68%. Hyperglycemia grade 2+ was seen in 72.7% of patients. There were no significant differences between the two groups for emergency room visits, hospitalizations, or endocrinology referrals related to hyperglycemia. Median time to initiation of an SGLT2 inhibitor was 13 days following the first dose of alpelisib. PFS was longer in the A+SGLT compared with the A group with a median time to progression of 6.1 months and 3.9 months respectively (HR 0.51; 95% CI 0.16 to 1.63; p = 0.39). Time on treatment was significantly longer for A+SGLT group compared with the A group, with a median time on treatment of 5.8 months, compared with 3.0 months (HR 0.32; 95% CI 0.11 to 0.92; p = 0.03). The primary reason for discontinuation of alpelisb was disease progression in 73%, with no statistically significant difference in the reason for discontinuation between the groups. Conclusions: This study supports a potential clinical benefit of an SGLT inhibitor along with alpelisib in allowing for a longer time on treatment, without significant adverse events. It also suggests a possible favorable impact on PFS for the combination.

Abstract Background The COVID-19 pandemic produced unprecedented demands and rapidly changing evidence and practices within critical care settings. The purpose of this study was to identify factors and strategies that hindered and facilitated effective implementation of new critical care practices and policies in response to the pandemic. Methods We used a cross-sectional, qualitative study design to conduct semi-structured in-depth interviews with critical care leaders across the United States. The interviews were audio-taped and professionally transcribed verbatim. Guided by the Consolidated Framework for Implementation Research (CFIR), three qualitative researchers used rapid analysis methods to develop relevant codes and identify salient themes. Results: Among the 17 hospitals that agreed to participate in this study, 31 clinical leaders were interviewed. The CFIR-driven rapid analysis of the interview transcripts generated 12 major themes, which included six implementation facilitators (i.e., factors that promoted the implementation of new critical care practices) and six implementation barriers (i.e., factors that hindered the implementation of new critical care practices). These themes spanned the five CFIR domains (Intervention Characteristics, Outer Setting, Inner Setting, Characteristics of Individuals, and Process) and 11 distinct CFIR constructs. Salient facilitators to implementation efforts included staff resilience, commitment, and innovation, which were supported through collaborative feedback and decision-making mechanisms between leadership and frontline staff. Major identified barriers included lack of access to reliable and transferable information, available resources, uncollaborative leadership and communication styles. Conclusions: Through applying the CFIR to organize and synthesize our qualitative data, this study revealed important insights into implementation determinants that influenced the uptake of new critical care practices during COVID-19. As the pandemic continues to burden critical care units, clinical leaders should consider emulating the effective change management strategies identified. The cultivation of streamlined, engaging, and collaborative leadership and communication mechanisms not only supported implementation of new care practices across sites, but it also helped reduce salient implementation barriers, particularly resource and staffing shortages. Future critical care implementation studies should seek to capitalize on identified facilitators and reduce barriers.