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Abstract Background: Cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) and endocrine therapy (ET) have improved progression-free survival (PFS) and overall survival in hormone-receptor-positive (HR+) metastatic breast cancer (MBC), but endocrine resistance is a major challenge. PROMISE [NCT0281902; n=63] is a multicenter study that enrolled women with HR+ HER2- MBC commencing palbociclib (Pb) with letrozole (1st line [1L]) or fulvestrant (2nd line [2L]), and was designed to perform a comprehensive “omic” assessment of prospectively collected biospecimens (pre-treatment (M1), at 2 months (M2), and at disease progression). The goal is to identify novel genomic variants and pathways associated with resistance to CDK4/6i and ET and PFS outcomes. Here we report the association between the proteomic, metabolomics, and lipidomics data generated from pre-Pb and 2-month serum samples and PFS. Methods: Untargeted mass spectrometry data was generated from Metabolon, assaying 1308 metabolites and 831 lipids. Additionally, 1436 proteins were assayed on the Olink platform. Cox proportional hazard models were used to evaluate the univariate hazard ratio (HR) for all features with respect to PFS. The analyses were performed on samples from 45 patients (N=33 1Lwith 9 progression events and 12 2L with 8 progression events), obtained from M1 and M2 timepoints on Pb + ET. Enrichment analysis p-values are calculated using Fisher’s exact test. Results: Proteomics: In the M1 timepoint, 93 and 43 proteins were associated with PFS in the 1L and 2L settings, respectively; inflammation genes were enriched among the 1L setting (p= 0.034); 33 proteins presented HRs ranging between 0.026 and 0.56. The FABP9 protein (HR of 1.98, 95% CI 1.02-3.83) was associated with worse PFS. Conversely, inflammation genes were not observed to be enriched in 2L. In the M2 timepoint, we observed 60 and 21 proteins significantly associated with PFS, but no biological function was enriched in 1L and 2L. Metabolites: In the M1 timepoint, metabolism of the sulfur-containing amino acids (methionine, cysteine, SAM and taurine) were enriched in the 1L setting (p= 0.035, HR range 0.15-0.33); and the branched-chain amino acids (leucine, isoleucine, and valine) were significantly associated with PFS in the 2L setting (p= 0.028, HR range 0.013-0.33). At the M2 timepoint, the amino acids were no longer enriched, but fatty acid metabolism was significantly enriched for both 1L and 2L (p= 0.048 and 0.067, respectively). Pathways involving lipids, amino acids, and xenobiotics were enriched in metabolites related to PFS (p <0.05) for both treatment lines at M1 and M2. Lipidomics: In the M1 timepoint, 10 and 19 lipids were associated with PFS for 1L and 2L, respectively. The most notable lipid associated with worse PFS in the 1L was an 18 carbon phosphatidylinositol, PI(18:1/18:2), (HR 7.34 (CI 1.27-42.50); 8 triglycerides were associated with improved PFS (HR range 0.39 and 0.55). In 2L, the 19 lipids associated with PFS included 12 phosphatidylcholines (enrichment p = 5.6X10-8). In the M2 timepoint, 15 and 8 lipids were significantly associated with PFS for 1L and 2L. An enrichment of phosphatidylinositols was observed in 1L (p= 1.2X10-5); none were observed in the 2L.Future Directions: Networks are being constructed using the proximity scores of the proteins, lipids, and metabolites associated with PFS in M1 and M2 for 1L and 2L. Network similarities and analyses will be conducted.Conclusion: Distinct multi-omic changes identified in serum samples obtained from PROMISE participants M1 and M2 on Pb correlate with disease progression in both 1L and 2L settings. Additionally, validation studies will determine the significance of these findings. Citation Format: Krishna R. Kalari, Kevin J. Thompson, Jason Sinnwell, Xiaojia Tang, Vera J. Suman, Jun He, Seul Kee Byeon, Akhilesh Pandey, Abe Eyman Casey, Peter T. Vedell, Ann M. Moyer, Alvaro Moreno-Aspitia, Donald W. Northfelt, Minetta C. Liu, Tufia C. Haddad, Saranya Chumsri, Prema Peethambaram, Kathryn J. Ruddy, Karthik V. Giridhar, Roberto A. Leon-Ferre, Richard M. Weinshilboum, Liewei Wang, Ciara C. O’ Sullivan, Matthew P. Goetz. Multiomics data reveal novel biomarkers for CDK4/6 resistance [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-03.

Abstract Background: FGFR dysregulation is observed in multiple cancers and targeting FGFR is an emerging therapeutic strategy with FDA approved treatments in bladder and cholangiocarcinoma. Here we examined the prevalence of FGFR mutations, fusions, and high-level amplifications in breast cancer, stratified by receptor subtype and local/metastatic status, in both Foundation Medicine (FM) and institutional Mayo Clinic (MC) cohorts. Methods: For the FM cohort, comprehensive genomic profiling (CGP) examining at least 324 genes for all classes of alterations, including FGFR1-4 was carried out for 32,048 breast cancers during the course of routine clinical care in a Clinical Laboratory Improvement Amendments (CLIA)-certified lab (Foundation Medicine Inc., Cambridge, MA, USA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb, microsatellite instability high (MSI-High) was determined on up to 114 loci and predicted ancestry from >10,000 SNPs. Estrogen receptor (ER) and HER2 status were available for a subset of FM samples. Additionally, 131 patients with metastatic breast cancer from a subset of patients at three Mayo Clinic sites (MC cohort) with clinical characteristics and cancer-panel DNA sequencing data from a CLIA-certified lab (Tempus, Chicago, IL) were included. Results: In the FM cohort, the prevalence of FGFR1-4 high-level amplification (CN≥10) was 10.1%, while mutations (1.5%) and fusions (0.72%) were rare. Most amplifications occurred in FGFR1 (9.2%); most fusions and mutations occurred in FGFR2 (0.46%, 0.77%). FGFR alteration prevalence was highest in ER+/HER2- subtype (14.4%) and lowest in HER2+ disease (7.7%). FGFR alterations were more common in IDC (11.7%) than ILC (7.7%), p<3E-08. FGFR alterations were more prevalent in the metastatic setting relative to breast-biopsied disease (13.6% v 10.1%; OR = 1.4; p=2E-17), especially in the HER2+ (OR =1.9, p=0.004) and ER-/HER2- (OR = 1.9, p = 0.05) disease; no enrichment was seen in the ER+/HER2- metastases (OR =1.0, p = 1). FGFR amplifications were observed at a higher prevalence in patients with predicted East Asian ancestry, relative to patients with European ancestry (12.1% v 10.0%; p = 0.03). Overall, the most common activating mutations in FGFR were FGFR2 N549K (n=85), FGFR1 N546K (n=78), FGFR4 V510M (n=28), FGFR2 K659E (n=28), FGFR4 V510L (n=20), and FGFR2 Y375C (n=15). The most common recurrent fusions were FGFR3:TACC3 (n=36), FGFR2:TACC2 (n=17), FGFR1:TACC1 (n=9), FGFR1:BAG4 (n=6), and FGFR2:ATE1 (n=5). In patients with FGFR amplifications, the most frequently co-occurring alterations were ZNF703 (78.4%), TP53 (51.5%), CCND1 (36.1%), FGF3/4/19 (32.9 - 34.4%), PIK3CA (30.7%), MYC (29.6%), ESR1 (17.2%), EMSY (16.3%), and PTEN (10.6%). Significant co-occurrence was observed for a number of genes including FGF3/4/19, CDK4, and CDK8 (all OR>2, p<1E-07); mutual exclusivity was observed with PIK3R1, BRCA1, and BRCA2 (all OR <0.5, p<4E-13), among other genes. In the 131 metastatic tumors from MC, the prevalence of FGFR1-4 high-level amplifications was 19.8% [FGFR1 (12.4%), FGFR2 (7.4%), and FGFR3 (0.8%)]. The prevalence of high-level FGFR amplifications did not differ by clinical subtypes: HR-/HER2- (7/31), HR+/HER2- (15/79), and HER2+ (2/11), p=0.68. Conclusions: High-level FGFR amplifications are observed in >11% of breast cancers, especially the ER+/HER2- subtype, while mutations/fusions are rare. These data support the ongoing studies evaluating targeted therapies for FGFR amplified ER + breast cancer. Correlations with clinical information (MC cohort) and associations with actionable alterations are ongoing and may inform potential combination strategies. Citation Format: Karthik V Giridhar, Ethan S Sokol, Peter T Vedell, Jason P Sinnwell, Aakash Desai, Tufia C Haddad, Ciara C O’Sullivan, Roberto A Leon-Ferre, Siddhartha Yadav, Kostandinos Sideras, Brenda Ernst, Minetta C Liu, Abe Eyman Casey, Xiaojia Tang, Zoe Fleischmann, Karthikeyan Murugesan, Krishna R Kalari, Matthew P Goetz. The frequency and somatic mutation landscape of Fibroblast growth factor receptor (FGFR) alterations in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-08-02.

Background Associations between depression, incident heart failure (HF), and mortality are well documented in predominately White samples. Yet, there are sparse data from racial minorities, including those who are women, and depression is underrecognized and undertreated in the Black population. Thus, we examined associations between baseline depressive symptoms, incident HF, and all‐cause mortality across 10 years. Methods and Results We included Jackson Heart Study (JHS) participants with no history of HF at baseline (n=2651; 63.9% women; median age, 53 years). Cox proportional hazards models tested if the risk of incident HF or mortality differed by clinically significant depressive symptoms at baseline (Center for Epidemiological Studies–Depression scores ≥16 versus <16). Models were conducted in the full sample and by sex, with hierarchical adjustment for demographics, HF risk factors, and lifestyle factors. Overall, 538 adults (20.3%) reported high depressive symptoms (71.0% were women), and there were 181 cases of HF (cumulative incidence, 0.06%). In the unadjusted model, individuals with high depressive symptoms had a 43% greater risk of HF ( P =0.035). The association remained with demographic and HF risk factors but was attenuated by lifestyle factors. All‐cause mortality was similar regardless of depressive symptoms. By sex, the unadjusted association between depressive symptoms and HF remained for women only ( P =0.039). The fully adjusted model showed a 53% greater risk of HF for women with high depressive symptoms ( P =0.043). Conclusions Among Black adults, there were sex‐specific associations between depressive symptoms and incident HF, with greater risk among women. Sex‐specific management of depression may be needed to improve cardiovascular outcomes.

Abstract Background With increasing extracorporeal membrane oxygenation (ECMO) utilization over the last decade, clinicians have developed “hybrid” configurations to meet complex perfusion requirements. In the setting of differential hypoxemia, a veno‐arteriovenous (V‐AV) configuration provides oxygenated cardiac preload and hemodynamic support to satisfy physiologic demands. We aim to further characterize the patient population, indications, and outcomes associated with this hybrid configuration. Methods We retrospectively reviewed all adult patients placed on V‐AV ECMO at our institution from June 2016 to December 2019. Through a review of the electronic medical records, data describing demographic features, comorbidities, and ECMO‐specific information were analyzed systematically. Results 14 patients were placed on V‐AV ECMO during the study period. Our cohort was 79% male with a median age of 54 and BMI of 30.3. These patients had a median SOFA‐0 score of 15 and SAVE score of ‐12. Patients were treated with ECMO support for a median of 144.1 (IQR 98.5 – 183.1) hours, consisting of 0.2 (IQR 0 – 17.7) hours of VA and 92.4 (IQR 53.7 – 115.1) hours of V‐AV followed by 67.4 (IQR 20.3 – 96.6) hours of VV support. Of these 14 patients, 11 survived to decannulation (79%) and 9 survived to hospital discharge (64%). Conclusion ECMO patients with recovering left ventricular function and persistent gas exchange abnormalities are at risk for developing differential hypoxemia. We describe an approach to utilizing V‐AV configuration when the likelihood of differential hypoxemia is extremely high, with a survival rate that compares favorably to Extracorporeal Life Support Organization statistics and published case series.

PURPOSE Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609 ). METHODS Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety. RESULTS High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%). CONCLUSION The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.

Abstract Only recently has the rodent hippocampus been implicated in orexigenic appetitive processing1,2. This function has been found to be mediated at least in part by lateral hypothalamic inputs involving an orexigenic neuropeptide, melanin-concentrating hormone3. This circuit remains elusive in humans. Here, we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues and this modulation was specific to the dorsolateral hippocampus. Lastly, structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behavior revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

AbstractBackgroundOral lichen planus confers a 1% risk of transformation to oral squamous cell carcinoma. While prior exome sequencing studies have identified multiple genetic mutations in oral squamous cell carcinoma, mutational analyses of lichen planus‐derived OSCC are lacking. We sought to clarify genomic events associated with oral lichen planus transformation.MethodsUsing rigorous diagnostic criteria, we retrospectively identified patients with non‐transforming oral lichen planus (i.e., known to be non‐transforming with 5 years of clinical follow‐up; n = 17), transforming oral lichen planus (tissue marginal to oral squamous cell carcinoma, n = 9), or oral squamous cell carcinoma arising in lichen planus (n = 17). Gene mutational profiles derived from whole‐exome sequencing on fixed mucosal specimens were compared among the groups.ResultsThe four most frequently mutated genes in transforming oral lichen planus and oral squamous cell carcinoma (TP53, CELSR1, CASP8, and KMT2D) identified 12/17 (71%) of oral squamous cell carcinomas and 5/9 (56%) of transforming oral lichen planus but were absent in non‐transforming oral lichen planus. We identified other known oral squamous cell carcinoma mutations (TRRAP, OBSCN, and LRP2) but also previously unreported mutations (TENM3 and ASH1L) in lichen planus‐associated oral squamous cell carcinomas.ConclusionsThese findings suggest alterations in DNA damage response and apoptosis pathways underlie lichen planus‐related oral squamous cell carcinoma transformation and are supported by mutational signatures indicative of DNA damage. This study characterized patterns of mutational events present in oral lichen planus associated with squamous cell carcinoma and in squamous cell carcinoma associated with oral lichen planus but not in non‐transforming oral lichen planus.

Background: High-frequency (10-kHz) spinal cord stimulation (SCS) continues to be an emerging therapy in chronic pain management. The same complications that plagued earlier SCS systems may affect newer stimulation technologies, although there is limited data on the type of complications and surgical management of these complications. Objective: The aim of this study was to systematically examine real-world complications associated with 10-kHz SCS reported on the Manufacturer and User Facility Device Experience (MAUDE) database. Materials and Methods: The MAUDE database was queried for entries reported between January 1, 2016 and December 31, 2020. Entries were classified into procedural complications, device-related complications, patient complaints, surgically managed complications, serious adverse events, and/or other complications. Primary outcomes included type and frequency of complications, and surgical management of complications. Results: A total of 1651 entries were analyzed. Most entries were categorized as procedural complications (72.6%), followed by serious adverse events (10.5%), device-related complications (10.5%), and patient complaints (9.9%). Most complications were managed surgically with explant (50.9%) rather than revision (5.0%) or incision/drainage (6.6%). Of procedural complications, the most common entries included non-neuraxial infection (52.9%), new neurological symptoms (14.7%), and dural puncture (9.5%). Of device-related complications, the most common entries included lead damage (41.6%), erosion (18.5%), and difficult insertion (11.5%). Conclusion: This retrospective 5-year analysis of complications from10-kHz SCS provides a real-world assessment of safety data unique for this stimulation modality. This analysis may help inform future clinical decisions, lead to device enhancement and optimization, and improve mitigation of risks to provide safe and efficacious use of 10-kHz SCS.

Purpose Integrated plastic surgery residency programs have increased their social media presence to educate and recruit prospective residents. This study aims to understand the impact of integrated plastic surgery residency program social media on the 2020 to 2021 applicants' evaluation of prospective programs, particularly during the coronavirus disease 2019 pandemic. Materials and Methods An optional 20-item online survey was sent to integrated plastic surgery residency applicants applying to the authors' program. Results Surveys were sent to 300 integrated plastic surgery residency applicants with an average of 168 responses (56% response rate). Social media resources included official residency program website (87.1%), Instagram (70.2%), and Doximity (46.8%). The most frequently used resource by applicants was the official residency program website (43.9%); Instagram was the second most frequently used (40.2%) followed by Doximity (8.3%). Most respondents agreed that social media was an effective means to inform applicants (66.1%), and it positively impacted their perception of the program (64.8%). The cited benefits were helping the program exhibit its culture and comradery among residents, faculty, and staff (78.4%). Among applicants, 73.6% noted that it had a significant impact on their perceptions of programs. Most respondents truncated their planned plastic surgery subinternships, completing 1 instead of 3 planned subinternships because of coronavirus disease 2019 limitations. Conclusions During the 2020 to 2021 plastic surgery application cycle, applicants used social media accounts of plastic surgery residency programs to inform and educate themselves about prospective programs. This study suggests that investing resources into a social media residency accounts is a meaningful pursuit for integrated plastic surgery programs and is an important aspect in today's recruitment.