Citations

Background The incidence of cervical cancer has decreased by 70% since the 1950s. Preventative measures include vaccination against HPV strains and Papanicolaou tests. Early identification of cervical cancer through routine screening can significantly improve patient outcomes. Materials and methods At our academic institution, Community Internal Medicine (CIM) Clinic, 63% of female patients aged 21–65 were compliant with cervical cancer screening. The opening of the ‘Saturday Pap Smear Clinic’ sought to address barriers by offering non-traditional appointment times on Saturday mornings with an all female staff. Our aim was to increase the cervical cancer screening rate by 1% within 12 weeks. Our team compared CIM (intervention) and family medicine (FM) (control) compliance rates from September 2021 to January 2022. Messages were sent to the patient indicating non-compliance and offering options to complete screening. Results At the start of this study, 5239 CIM patients were cervical cancer screening non-compliant. Postintervention, cervical screening rates among non-compliant women within CIM improved by 1.2%. The intervention cohort, CIM patients, had a significant improvement in compliance compared with the control group, FM patients. White women between the ages of 50 and 65 comprised the majority of patients who used the ‘Saturday Pap Smear Clinic’. Conclusions The availability of Saturday appointments for cervical cancer screening completion can enhance cervical cancer screening compliance among eligible women. Eliminating barriers for women can improve health outcomes.

ABSTRACT Estrogen regulates bone mass in women and men, but the underlying cellular mechanisms of estrogen action on bone remain unclear. Although both estrogen receptor (ER)α and ERβ are expressed in bone cells, ERα is the dominant receptor for skeletal estrogen action. Previous studies using either global or cell‐specific ERα deletion provided important insights, but each of these approaches had limitations. Specifically, either high circulating sex steroid levels in global ERα knockout mice or the effects of deletion of ERα during growth and development in constitutive cell‐specific knockout mice have made it difficult to clearly define the role of ERα in specific cell types in the adult skeleton. We recently generated and characterized mice with tamoxifen‐inducible ERα deletion in osteocytes driven by the 8‐kb Dmp1 promoter (ERαΔOcy mice), revealing detrimental effects of osteocyte‐specific ERα deletion on trabecular bone volume (−20.1%) and bone formation rate (−18.9%) in female, but not male, mice. Here, we developed and characterized analogous mice with inducible ERα deletion in osteoclasts using the Cathepsin K promoter (ERαΔOcl mice). In a study design identical to that with the previously described ERαΔOcy mice, adult female, but not male, ERαΔOcl mice showed a borderline (−10.2%, p = 0.084) reduction in trabecular bone volume, no change in osteoclast numbers, but a significant increase in serum CTx levels, consistent with increased osteoclast activity. These findings in ERαΔOcl mice differ from previous studies of constitutive osteoclast‐specific ERα deletion, which led to clear deficits in trabecular bone and increased osteoclast numbers. Collectively, these data indicate that in adult mice, estrogen action in the osteocyte is likely more important than via the osteoclast and that ERα deletion in osteoclasts from conception onward has more dramatic skeletal effects than inducible osteoclastic ERα deletion in adult mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Introduction: Coronary disease is the most common cause of heart failure (HF). HF is classified as ischemic (IHF) or non-ischemic (NIHF) based on this etiology. IHF and NIHF have distinct mechanisms not accounted for by ejection fraction (EF) and an improved understanding of the differences could drive the discovery of novel therapeutic targets. We therefore sought to identify proteomic signatures between IHF and NIHF. Methods: Proteomic profiling using the SomaScan®1.7K was performed using plasma samples from HF patients in a community cohort (Rochester Epidemiology Project, 2003-2012). IHF was defined by prior myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft, or obstructive disease in at least 1 vessel on coronary angiography. We compared the protein expression levels between IHF and NIHF using t-test and applied the Benjamini-Hochberg false-discovery rate (FDR) procedure for multiple comparisons. We explored pathway analysis for functional annotations using the biological process component of the Gene Ontology Resource (Panther 17v). Results: Among 1,388 patients, there were 518 IHF patients (age: 75±12years, 39.4% female, NYHA Class III/IV: 72.5%, EF:45±15%), and 870 NIHF patients (age: 75±14years, 53.6% female, NYHA Class III/IV: 66.9%, EF:49±17%). Among 7335 plasma proteins quantified, 63 unique proteins (FDR < 0.05) were differentially expressed between IHF and NIHF. Thirty-seven proteins including Troponin-I and T, and Myoglobin showed increased expression in IHF compared to NIHF and 26 including IGFBP-3 showed decreased expression. Pathophysiologic pathways including angiogenesis, coagulation, and lipid metabolism were represented in IHF, while inflammation and remodeling signaling pathways were dominant in relation to NIHF. Conclusions: High-throughput proteomic techniques are able to delineate IHF versus NIHF patients based on distinct biomarkers and pathophysiologic processes.

11531 Background: Conventional chondrosarcoma (cCS) is the 2nd most common primary bone tumor and is resistant to chemotherapy and radiation. IDH1/2 mutations (m) occur in 50% of cCS. Both IDHm and wild-type (wt) cCS harbor epigenetic dysregulation. In preclinical models of IDHm and wt cCS, combination treatment with HDAC and DNMT inhibitors (i) suppressed growth in vitro and in vivo by reversing the hypermethylated state and inducing tumor suppressors, interferon response genes and apoptosis (Sheikh T, Schwartz G. Mol Cancer Ther 2021;20). Methods: NCI 10330 is a single-arm, multicenter, phase 2 study evaluating the HDACi belinostat (B) with the DNMTi SGI-110 (S) or ASTX727 (A). A replaced S due to drug availability (pts were replaced). Pts had advanced cCS, ECOG PS ≤ 2 and could be treatment naïve. Progression was required for grade 1 cCS. Pts received B 1000mg/m2 IV + S 45mg/m2 SC both days 1-5 or B (same dosing) + A (cedazuridine 100mg/decitabine 35mg) PO both days 1-5, in 28-day cycles. 1° endpoint was objective response. A Simon 2-stage design was used. If ≥ 2/13 responses occurred in stage 1, the study would proceed to full accrual. Design had 85% power with α = 0.05 to test ORR 8% vs 28%. 2° endpoints included safety, PFS and OS. A safety lead-in was performed. Paired biopsies were collected. Results: Stage 1 is complete. 19 pts were treated: 6 on B+S and 13 on B+A. Median age was 50 and 67 years, respectively. All pts had prior surgery. 17% (B+S) and 38% (B+A) had prior radiation. 33% (B+S) and 55% (B+A) were IDHm. 67% (B+S) and 75% (B+A) were histologic grade ≥ 2. There were no objective responses. Best response (at 8 weeks) was stable disease (SD) in 4/6 pts (67%) on B+S and 6/10 pts (60%) on B+A. mPFS was 4.2 mos (95% CI 1.97-NR) for B+S and 3.8 mos (95% CI 2.17-NR) for B+A. mOS has not been reached. For B+A, mPFS for IDHm vs wt pts was 4.7 and 3.1 mos, respectively (p=0.21). One pt with IDHm grade 2 cCS who progressed on FT-2102 (IDH1i) remains on B+A > 1 year. There were no DLTs during either safety lead-in. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17% (B+S) and 69% (B+A). For B+A, the most common grade 3/4 TRAE was neutropenia (54%) and the most common all-grade TRAEs were nausea (69%), leukopenia (61%), neutropenia (54%), anemia (46%) and fatigue (46%). Paired tumor biopsies are being evaluated with whole exome sequencing, RNAseq, methylation array and multiplex IHC with results forthcoming. Conclusions: Combination HDACi + DNMTi was well-tolerated in advanced cCS. There were no objective responses; however, a subset of pts experienced prolonged SD with a trend towards improved mPFS in IDHm pts. Correlative work is ongoing with a focus on differential effects on IDHm tumors and whether modulation of the immune microenvironment might support combinations with immunotherapy. Support: UM1CA186689. Clinical trial information: NCT04340843 .

11507 Background: Single agent or combination chemotherapy, typically Dox- or gemcitabine-based, are standard 1st- and 2nd-line therapies in patients (pts) with metastatic LMS; however, objective response rates (ORR), progression-free, and overall survival (PFS/OS) remain inadequate. Lurbi (PharmaMar S.A. / Jazz Pharmaceuticals) binds to DNA inhibiting transcription and inducing double strand breaks leading to apoptosis and delaying S/G2 progression. In a prior pilot study, we showed Lurbi+Dox is well-tolerated, with signs of activity, particularly in LMS. We designed this phase 1b to optimize dosing to lead into a randomized (1:1) phase 2 trial of Dox+/-Lurbi in anthracycline-naïve LMS. Herein we provide updated efficacy and tolerability data for this Phase 1b cohort. Methods: Pts > 18 yrs with locally advanced/metastatic, unresectable non-GIST STS (Phase 1b only) w/o prior anthracycline or Lurbi/trabectedin, ECOG PS < 3, RECIST 1.1 measurable, and normal organ function were eligible. The phase 1b followed a 3+3 design. Dosing included fixed Lurbi (3.2 mg/m2 d1) with two Dox dose levels (DL; DL1: 25 mg/m2 d1; DL2 25 mg/m2 d1+8). All pts received GCSF prophylaxis. Tumor assessments were every 2 cycles. DL1 was chosen as RP2D and the phase 2 trial began accrual in Aug 2022 aiming to enroll 50 LMS pts randomized 1:1 (stratified by uterine LMS [uLMS]] v. other LMS) with PFS as primary endpoint. Pts progressing on Dox are allowed to cross to Lurbi monotherapy. Results: 10 patients were enrolled in Phase 1b. Histologies included 5 LMS (4 uLMS) and 1 each of myxofibrosarcoma (myxFS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), endometrial stromal sarcoma (ESS), and solitary fibrous tumor (SFT). With a median follow-up of 344 days, 5/10 pts remain on treatment with median PFS of 357 days (95%CI 175-ND). 6 pts demonstrated partial response (PR; 5 confirmed), 3 with stable disease (SD), and 1 with progressive disease (PD, Table). Median time to PR was 81 days (range 46-207). Duration of response was over 132 days in all responders with 3 still on treatment. Treatment-related AEs were typical for Dox/Lurbi, including nausea, fatigue, and reversible LFT elevations/cytopenias. Updated safety and response data will be provided at the time of the meeting. Conclusions: Lurbi+Dox is well-tolerated with efficacy in STS including 6/10 pts achieving PR, 9/10 pts staying on treatment for >120d, and 6/10 pts >200d. The randomized phase 2 study is currently enrolling. Clinical trial information: NCT05099666 . [Table: see text]

11505 Background: Potentiation of chemotherapy, without increased toxicity, to improve outcome is an area of interest. Preclinical and clinical evidence shows simultaneous utilization of antiangiogenic agents and chemotherapy have a synergistic effect. We hypothesized that the dual targeting of VEGF and c-MET pathways with cabozantinib (CAB) would result in clinical benefit for patients with soft tissue sarcoma (STS) when combined with temozolomide (TMZ), an alkylating agent. Utilization of CAB/TMZ is anticipated to produce a synergistic antitumor effect worthwhile to explore in STS. Methods: A multicenter phase II study of CAB/TMZ in patients with unresectable/metastatic leiomyosarcoma (LMS) and other STS was conducted by the Midwest Sarcoma Trials Partnership. Age ≥ 18, adequate performance status, organ function, measurable disease (RECIST 1.1), and 0-5 prior chemotherapy regimens were required. CAB 40 mg PO daily plus TMZ 150-200 mg/m2 PO 1-5 days were given in 28-day cycles until disease progression or unacceptable toxicity. Patients enrolled in 2 cohorts: 1. Uterine and non-uterine LMS 2. Other STS. The first 14 subjects to be enrolled in the study in either cohort served as a safety lead in. The primary endpoint was progression-free rate (PFR) at 12 weeks for cohort 1. Secondary endpoints include overall response rate (ORR), clinical benefit rate, median progression-free survival (PFS), overall survival, and safety and tolerability. The exploratory endpoint was to estimate the correlation of PFR and OS to expression levels of VEGF, amongst others. A Simon 2-stage design was used. Results: A total of 42 patients were enrolled in Cohort 1, and 30 in Cohort 2, across 5 sites. For Cohort 1, median age was 59 years (range 35-86), 85.7% were non-Hispanic, 73.8% were female, 61.9% had ECOG of 0. The PFR at 12 weeks was 45.9% (for 37 evaluable patient) with a median PFS of 6.4 months (95% CI 4.6-6.7). Five PR were observed for an ORR of 13.5%. For Cohort 2, median age was 63 (20-86), 83.3% were non-Hispanic, 36.7% were female, 53.3% had ECOG of 0. The PFR at 12 weeks was 50% (for 28 evaluable patients) with a median PFS of 3.2 months (95% CI 1.4-4.6). One PR was observed. Reported grade 3-4 adverse events attributed to one or both intervention drugs affecting ≥10% of patients (n = 70) included hypertension (10%), decreased neutrophils (18.7%), decreased platelets (31%). Conclusions: The combination therapy of CAB/TMZ in patients with unresectable or metastatic LMS exceeded its primary endpoint with a PFR at 12 weeks > 39%. The PFS of 6.4 months in Cohort 1 exceeds rates achieved with second line tyrosine kinase inhibitors (TKIs) and alkylators in LMS patients. Treatment was feasible and did not reveal any previously unreported toxicities. The combination with CAB with TMZ demonstrated meaningful clinical benefit and is worth further exploration in LMS. Clinical trial information: NCT04200443 .

3079 Background: Elraglusib (9-ING-41), a novel inhibitor of GSK-3β, has been evaluated in >230 patients (pts) with advanced malignancies including metastatic melanoma in the 1801 phase 1/2 trial (NCT03678883). Pts with melanoma treated with single agent elraglusib demonstrated clinical benefit including a durable complete response despite multiple prior lines of therapy including checkpoint inhibitors (CPI). Methods: We collected data from numerous -omic modalities in the 1801 trial to characterize markers of elraglusib response with bioinformatics and machine learning (ML). Genomic panels were collected on 105 pts. The most frequent tumor types included colorectal cancer (n=35), pancreas (n=31), lung (n=15) and metastatic melanoma (n=12). Pts were treated with elraglusib as a single agent or in combination with chemotherapy. Pathway based features were generated by quantifying the percent of each Reactome pathway that was mutated. These pathway features were iteratively evaluated for their performance in shallow neural networks predicting patient RECIST with each model using 5-15 randomly selected features at a time. Publicly available genomic data from an anti-PD-1 trial in patients with metastatic melanoma (Hugo et al., 2017) was transformed into pathway-based features and input into the final model to predict elraglusib response in this population. Results: Our final pathway based genomic model for elraglusib response performed with a training accuracy of 93% and a test accuracy of 88% on the 1801 patients. We then tested the model on metastatic melanoma patients who were treated with anti-PD-1 therapy. We found that patients from Hugo et al. were predicted to respond to elraglusib (22/26). In addition, most patients with tumors resistant to anti-PD-1 therapy were also predicted to respond to elraglusib (10/12). Finally, we tested the model on metastatic melanoma patients treated with elraglusib in the 1801 study that had failed CPI and for whom -omic data was available. The model correctly identified 5/5 patients that demonstrated clinical benefit (1 CR, ongoing>1400 days; 4 prolonged OS of 107, 256, 357, and 556 days). Conclusions: We applied robust in-silico modeling developed using 1801 trial data to develop a rationale for the development of elraglusib in the treatment of metastatic melanoma including patients that failed or were refractory to anti-PD-1 treatment. This model correctly identified metastatic melanoma patients in 1801 with good clinical outcomes that had failed prior CPI treatment. Further, we present this in silico approach as a robust way to repurpose prior clinical study genomics and ML modeling for population enrichment during the clinical development of novel drugs. Clinical trial information: NCT03678883 .

Abstract Introduction Introduction: Rapid eye movement (REM) sleep behavior disorder (RBD) is strongly associated with progressive phenoconversion to an overt synucleinopathy (e.g., parkinsonism). Neurotrauma [i.e., traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)], increases the odds of RBD diagnosis by ~2.5-fold and is associated with an increased later diagnosis of Parkinson’s Disease (PD), a service-connected illness in Veterans. Thus, RBD and neurotrauma are both independently associated with parkinsonism; however, it is unclear how neurotrauma influences neurological symptoms and exam findings in patients with RBD. Methods Methods: Participants ≥18 years of age with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 as part of the North American Prodromal Synucleinopathy (NAPS) Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory and autonomic function were completed. This sub-study applied a cross-sectional, case-control (1:4 ratio) analysis comparing cases (n=24; RBD+TBI+PTSD) to controls (n=96; RBD) matched for age (±2 years), sex, and years of education (±2 years). Results Results: Participants with neurotrauma reported an earlier age of RBD symptom onset and more severe RBD phenotype, more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to participants without neurotrauma. Conclusion Conclusion: This cross-sectional, matched case:control study showed that individuals with comorbid neurotrauma and RBD have significantly worse neurological outcomes related to common features of early parkinsonism. Although confirmatory longitudinal studies are still ongoing, these results may be a sign of further/faster progression of synucleinopathy in those with comorbid neurotrauma and RBD. Support (if any) Support: NIH R34 AG056639, NIH U19 AG071754, VA RRD 1K2 RX002947, Parkinsons Center of Oregon

Abstract Purpose: To evaluate the impact of trimodality treatment versus monotherapy or dual therapy for radiation-associated angiosarcoma of the breast (RAASB) after prior breast cancer treatment. Experimental Design: With Institutional Review Board approval, we identified patients diagnosed with RAASB and abstracted data on disease presentation, treatment, and oncologic outcomes. Trimodality therapy included (i) taxane induction, (ii) concurrent taxane/radiation, and then (iii) surgical resection with wide margins. Results: A total of 38 patients (median age 69 years) met inclusion criteria. Sixteen received trimodality therapy and 22 monotherapy/dual therapy. Skin involvement and disease extent were similar in both groups. All trimodality patients required reconstructive procedures for wound closure/coverage, compared with 48% of monotherapy/dual therapy patients (P &lt; 0.001). Twelve of 16 (75%) patients receiving trimodality therapy had a pathologic complete response (pCR). With median follow-up of 5.6 years, none had local recurrence, 1 patient (6%) had distant recurrence, and no patients died. Among 22 patients in the monotherapy/dual therapy group, 10 (45%) had local recurrence, 8 (36%) had distant recurrence, and 7 (32%) died of disease. Trimodality therapy demonstrated significantly better 5-year recurrence-free survival [RFS; 93.8% vs. 42.9%; P = 0.004; HR, 7.6 (95% confidence interval, CI: 1.3–44.2)]. Combining all patients with RAASB regardless of treatment, local recurrence was associated with subsequent distant recurrence (HR, 9.0; P = 0.002); distant recurrence developed in 3 of 28 (11%) patients without local recurrence compared with 6 of 10 (60%) with local recurrence. The trimodality group had more surgical complications that required reoperation or prolonged healing. Conclusions: Trimodality therapy for RAASB was more toxic but is promising, with a high rate of pCR, durable local control, and improved RFS.

ObjectiveTo compare improvement in patient‐reported outcomes (PROM) in persons undergoing endoscopic and open surgical management of Zenker diverticula (ZD).MethodologyProspective, multicenter cohort study of all individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative who underwent surgery for ZD. Patient survey, radiography reports, and the 10‐item Eating Assessment Tool (EAT‐10) pre‐ and post‐procedure were abstracted from a REDCap database, which summarized means, medians, percentages, and frequencies of. Outcome based on operative intervention (endoscopic vs. open) was compared using t‐test, Wilcoxon rank sum test or chi‐square test, as appropriate.ResultsOne hundred and forty‐seven persons were prospectively followed. The mean age (SD) of the cohort was 68.7 (11.0). Overall, 66% of patients reported 100% improvement in EAT‐10; 81% of patients had greater than 75% improvement; and 88% had greater than 50% improvement. Endoscopic was used for n = 109 patients, and open surgical intervention was used for n = 38. The median [interquartile range, IQR] EAT‐10 percent improvement for endoscopic treatment was 93.3% [72, 100], and open was 100% [92.3, 100] (p = 0.05). The incidence of intraoperative complications was 3.7% for endoscopic and 7.9% for open surgical management. The median [IQR] in follow‐up was 86 and 97.5 days, respectively.ConclusionBoth endoscopic and open surgical management of ZD provide significant improvement in patient‐reported outcomes. The data suggest that open diverticulectomy may provide a modest advantage in symptomatic improvement compared to endoscopic management. The data suggest that the postoperative complication rate is higher in the open surgical group.Level of Evidence3 Laryngoscope, 134:97–102, 2024