Citations

TPS612 Background: The TAILORx and RxPONDER trials demonstrated that RS identifies many postmenopausal pts with node-neg and node-pos BC and RS ≤25, who do not benefit from addition of ACT to endocrine therapy (ET). Both trials also showed that certain subsets of premenopausal pts (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25) benefited from adding ACT to ET. Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, we developed OFSET, a phase III, multicenter clinical trial comparing OFS+ET v ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI). Choice is per investigator discretion; tamoxifen is allowed if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per investigator discretion per protocol guidelines. The HRQOL substudy will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score between arms, as well as increased pain severity (PROMIS). Blood and tumor specimens will be collected for future research. Accrual of 3,960 pts is anticipated to be completed in 7 yrs, 7 mos. Per NSABP B-28 and RxPONDER data, 5yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with one-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur~11 yrs after study initiation. OFSET was activated Aug 2023. Clinical trial information: NCT05879926 .

Abstract Purpose The demographic and radiological risk factors of subchondral insufficiency fractures of the knee (SIFK) continue to be a subject of debate. The purpose of this study was to associate patient‐specific factors with SIFK in a large cohort of patients. Methods Inclusion criteria consisted of patients with SIFK as verified on magnetic resonance imaging (MRI). All radiographs and MRIs were reviewed to assess characteristics such as meniscus tear presence and type, subchondral oedema presence and location, location of SIFK, mechanical limb alignment, osteoarthritis as assessed by Kellgren–Lawrence grade and ligamentous injury. A total of 253 patients (253 knees) were included, with 171 being female. The average body mass index (BMI) was 32.1 ± 7.0 kg/m 2 . Results SIFK was more common in patients with medial meniscus tears (77.1%, 195/253) rather than tears of the lateral meniscus (14.6%, 37/253) ( p < 0.001). Medial meniscus root and radial tears of the posterior horn were present in 71.1% (180/253) of patients. Ninety‐one percent (164/180) of medial meniscus posterior root and radial tears had an extrusion ≥3.0 mm. Eighty‐one percent (119/147) of patients with SIFK on the medial femoral condyle and 86.8% (105/121) of patients with SIFK on the medial tibial plateau had a medial meniscus tear. Varus knees had a significantly increased rate of SIFK on the medial femoral condyle in comparison to valgus knees ( p = 0.016). Conclusion In this large cohort of patients with SIFK, there was a high association with medial meniscus root and radial tears of the posterior horn, meniscus extrusion ≥3.0 mm as well as higher age, female gender and higher BMI. Additionally, there was a particularly strong association of medial compartment SIFK with medial meniscus tears. As SIFK is frequently undiagnosed, identifying patient‐specific demographic and radiological risk factors will help achieve a prompt diagnosis. Level of Evidence Level IV.

Introduction: Immigrants to the United States often experience structural barriers to healthy nutrition and physical activity, which increases their risk of developing obesity, cardiovascular disease (CVD), and other chronic conditions. In our prior work with immigrant communities to co-develop interventions to improve nutrition and physical activity, mood was identified as a possible mediating factor. Hypothesis: We hypothesized that self-reported negative mood would be associated with unhealthy lifestyle behaviors such as poor nutrition and less physical activity. We also evaluated the relationship between mood and sociobehavioral factors such as social support and community belongingness. Methods: The Healthy Immigrant Community (HIC) study, set in Rochester, Minnesota and embedded with the Rochester Healthy Community Partnership, is a randomized, waitlist-controlled obesity and CVD risk reduction intervention. Community-based mentoring and education for health behaviors are delivered by trained health promoters, who are members of the immigrant populations, to their social networks. Baseline self-reported and biometric measures assessed nutrition, physical activity, self-efficacy, and sociobehavioral effects on healthy lifestyle behaviors. On a single-item rating of mood over the past 7 days, responses of poor or fair were considered “negative”, while good, very good, or excellent were considered “positive”. Results: The HIC study enrolled 475 adult participants; 268 Hispanic/Latino and 181 Somali participants completed baseline measures and were included in this analysis. Of the 449 participants, 107 (24%) reported “negative” mood. This group was more likely to be Hispanic/Latino (74%), female (68%), uninsured in the past 12 months (46%), or younger age (mean = 41 years; range = 18-79). Participants who endorsed negative mood at baseline had lower healthy nutrition scores ( p =0.02), lower physical activity scores ( p =0.03), and less confidence in eating healthily ( p =0.001). Those reporting negative mood also reported less support from family and friends to eat healthy ( p =<0.001) and be physically active ( p =0.01), accessed community resources for healthy eating ( p =0.001) and physical activity ( p =<0.01) less often, and reported less sense of belonging to their community ( p =0.01) than those with positive mood. Conclusion: Negative mood was significantly associated with eating a less healthy diet and being sedentary, lower confidence in maintaining a healthy diet, less perceived social support for healthy behaviors, and less sense of belonging to the community among Hispanic/Latino and Somali immigrants. Behavioral interventions designed to support a healthy lifestyle may benefit from incorporating culturally-aligned mood management and sociobehavioral strategies to reduce CVD risk and promote health equity in immigrant populations.

IntroductionNasal valve compromise is a common issue for patients presenting to an otolaryngologist. Anatomically, the dorsal septal cartilage (DSA) articulates with the upper lateral nasal cartilage (ULC). When the ULC weakens, it is prone to collapse and may result in nasal obstruction. Our objectives were to analyze histological differences between quadrangular and DSA nasal cartilages and compare histological composition of these tissues among patients with diagnosis of nasal valve compromise (NVC) versus those without NVC (no NVC).MethodsProspective cross‐sectional study of nasal cartilages from seventy‐three (73) live donors. Quadrangular cartilage (QC), and DSA from patients undergoing septorhinoplasty were collected. Safranin O histochemical staining was used to observe glycosaminoglycans (GAGs) content and cell count. Masson's Trichrome staining was used to assess collagen content in these nasal cartilages.ResultsMean GAG content was lower in DSA compared with QUAD cartilage (68.18% vs. 87.22%, p < 0.0001), and was lowest in DSA of patients with NVC (59.07%). Mean collagen content was higher in DSA compared with QUAD cartilage, (65.43% vs. 46.65%, p = 0.0002), and was highest in DSA of patients with NVC (74.86%).ConclusionThe DSA showed decreased GAG and increased collagen content compared with quadrangular cartilage. Within the DSA subsite, patients with presurgical NVC had the lowest GAG and highest collagen levels. This observation suggests that the biochemical composition of the DSA may contribute to its weakening, potentially resulting in its inability to withstand minor trauma and/or the effects of aging, ultimately leading to NVC.Level of EvidenceN/A Laryngoscope, 134:4252–4258, 2024

Abstract Background: Identifying pts with HR-positive/HER2-negative breast cancer (BC) who benefit from adjuvant chemotherapy (ACT) has been a major research focus over the past 20 years. Development and clinical application of genomic classifiers such as the 21-gene recurrence score (RS) has contributed to the biologic understanding of BC and has refined pt selection for ACT. The TAILORx and RxPONDER clinical trials demonstrated that RS identifies many postmenopausal pts with node-negative and node-positive BC and RS &lt; 25, who do not benefit from the addition of ACT to endocrine therapy (ET). However, both trials also showed that certain subsets of premenopausal pts (node-negative/high clinical risk/RS 16-20, node-negative/RS 21-25, and node-positive/RS &lt; 25) benefited from the addition of ACT to ET. Most premenopausal pts in these two trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR-positive/HER2-negative BC in the SOFT and TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, OFSET is a Phase III, multicenter clinical trial evaluating the addition of ACT to OFS+ET vs. OFS+ET alone. Methods: We hypothesize that the addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR-positive/HER2-negative tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival (IDFS), overall survival (OS), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and health-related quality of life (HRQOL). Eligible pts must be node-negative with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS &lt; 25. Stratification is by nodal status/RS status (pN0 RS 16-25 vs pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 vs ≥40). Pts are randomized after surgery to either OFS+ET or ACT followed by OFS+ET. ET is an aromatase inhibitor per investigator discretion, but tamoxifen is allowed if pts do not tolerate the AI or if OFS is incomplete. Radiation therapy will be administered per investigator discretion according to protocol guidelines. The HRQOL sub-study will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score, between the arms, as well as increased pain severity (PROMIS) during ACT+OFS+ET compared to OFS+ET. Blood and tumor specimens will be collected for future research. The accrual of 3,960 pts is anticipated to be completed in seven years and seven mos. Based on data from NSABP B-28 and RxPONDER, the 5-year IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on data from TAILORx, the 5-year IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of the pts to be pN0 and 44% pN1, a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET vs. OFS+ET, with one-sided alpha of 0.025 and 80% power will require 380 IBCFS events, which are expected to occur ~11 years after study initiation. The OFSET study is expected to be activated in the third quarter of 2023. Current accrual (06-19-2023) is 0/3,960 Support: U10CA180868, U10CA180822, UG1CA189867, U24CA196067. NCT05879926. Citation Format: Eleftherios Mamounas, Gong Tang, Shannon Puhalla, Sandra Swain, Patricia Ganz, N. Lynn Henry, Reena Cecchini, Sonya Reid, Priya Rastogi, Charles Geyer, Julia White, Amy Clark, Tufia Haddad, Gregory Vidal, Norman Wolmark. NRG-BR009: Phase III Trial Evaluating Addition of Adjuvant Chemotherapy to Ovarian Function Suppression + Endocrine Therapy in Premenopausal Women with pN0-1, HR+/HER2- Breast Cancer and Oncotype Recurrence Score ≤25 (OFSET) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-02.

AbstractBackground and purposePrimary lateral sclerosis (PLS) is a neurodegenerative disorder that primarily affects the central motor system. In rare cases, clinical features of PLS may overlap with those of progressive supranuclear palsy (PSP). We investigate neuroimaging features that can help distinguish PLS with overlapping features of PSP (PLS‐PSP) from PSP.MethodsSix patients with PLS‐PSP were enrolled between 2019 and 2023. We compared their clinical and neuroimaging characteristics with 18 PSP–Richardson syndrome (PSP‐RS) patients and 20 healthy controls. Magnetic resonance imaging, 18F‐flortaucipir positron emission tomography (PET), quantitative susceptibility mapping, and diffusion tensor imaging tractography (DTI) were performed to evaluate eight brain regions of interest. Area under the receiver operating characteristic curve (AUROC) was calculated.ResultsFive of the six PLS‐PSP patients (83.3%) were male. Median age at symptom onset was 61.5 (52.5–63) years, and all had mixed features of PLS and PSP. Volumes of the pallidum, caudate, midbrain, and cerebellar dentate were smaller in PSP‐RS than PLS‐PSP, providing good discrimination (AUROC = 0.75 for all). The susceptibilities in pallidum, midbrain, and cerebellar dentate were greater in PSP‐RS compared to PLS‐PSP, providing excellent discrimination (AUROC ≥ 0.90 for all). On DTI, fractional anisotropy (FA) in the posterior limb of the internal capsule from the corticospinal tract was lower in PLS‐PSP compared to PSP‐RS (AUROC = 0.86), but FA in the superior cerebellar peduncle was lower in PSP‐RS (AUROC = 0.95). Pallidum flortaucipir PET uptake was greater in PSP‐RS compared to PLS‐PSP (AUROC = 0.74).ConclusionsRegional brain volume, tractography, and magnetic susceptibility, but not tau‐PET, are useful in distinguishing PLS‐PSP from PSP.

Pancreatic ductal adenocarcinoma (PDAC) can originate from acinar-to-ductal metaplasia (ADM). Pancreatic acini harboring oncogenic Kras mutations are transdifferentiated to a duct-like phenotype that further progresses to become pancreatic intraepithelial neoplasia (PanIN) lesions, giving rise to PDAC. Although ADM formation is frequently observed in KrasG12D transgenic mouse models of PDAC, the exact mechanisms of how oncogenic KrasG12D regulates this process remain an enigma. Herein, we revealed a new downstream target of oncogenic Kras, cytokine CCL9, during ADM formation. Higher levels of CCL9 and its receptors, CCR1 and CCR3, were detected in ADM regions of the pancreas in p48cre:KrasG12D mice and human PDAC patients. Knockdown of CCL9 in KrasG12D-expressed pancreatic acini reduced KrasG12D-induced ADM in a 3D organoid culture system. Moreover, exogenously added recombinant CCL9 and overexpression of CCL9 in primary pancreatic acini induced pancreatic ADM. We also showed that, functioning as a downstream target of KrasG12D, CCL9 promoted pancreatic ADM through upregulation of the intracellular levels of reactive oxygen species (ROS) and metalloproteinases (MMPs), including MMP14, MMP3 and MMP2. Blockade of MMPs via its generic inhibitor GM6001 or knockdown of specific MMP such as MMP14 and MMP3 decreased CCL9-induced pancreatic ADM. In p48cre:KrasG12D transgenic mice, blockade of CCL9 through its specific neutralizing antibody attenuated pancreatic ADM structures and PanIN lesion formation. Furthermore, it also diminished infiltrating macrophages and expression of MMP14, MMP3 and MMP2 in the ADM areas. Altogether, our results provide novel mechanistic insight into how oncogenic Kras enhances pancreatic ADM through its new downstream target molecule, CCL9, to initiate PDAC.

Abstract Purpose To report historical patterns of pharmaceutical expenditures, to identify factors that may influence future spending, and to predict growth in drug spending in 2024 in the United States, with a focus on the nonfederal hospital and clinic sectors. Methods Historical patterns were assessed by examining data on drug purchases from manufacturers using the IQVIA National Sales Perspectives database. Factors that may influence drug spending in hospitals and clinics in 2024 were reviewed—including new drug approvals, patent expirations, and potential new policies or legislation. Focused analyses were conducted for biosimilars, cancer drugs, endocrine drugs, generics, and specialty drugs. For nonfederal hospitals, clinics, and overall (all sectors), estimates of growth of pharmaceutical expenditures in 2024 were based on a combination of quantitative analyses and expert opinion. Results In 2023, overall pharmaceutical expenditures in the US grew 13.6% compared to 2022, for a total of $722.5 billion. Utilization (a 6.5% increase), new drugs (a 4.2% increase) and price (a 2.9% increase) drove this increase. Semaglutide was the top drug in 2023, followed by adalimumab and apixaban. Drug expenditures were $37.1 billion (a 1.1% decrease) and $135.7 billion (a 15.0% increase) in nonfederal hospitals and clinics, respectively. In clinics, increased utilization drove growth, with a small impact from price and new products. In nonfederal hospitals, a drop in utilization led the decrease in expenditures, with price and new drugs modestly contributing to growth in spending. Several new drugs that will influence spending are expected to be approved in 2024. Specialty, endocrine, and cancer drugs will continue to drive expenditures. Conclusion For 2024, we expect overall prescription drug spending to rise by 10.0% to 12.0%, whereas in clinics and hospitals we anticipate an 11.0% to 13.0% increase and a 0% to 2.0% increase, respectively, compared to 2023. These national estimates of future pharmaceutical expenditure growth may not be representative of any health system because of the myriad of local factors that influence actual spending.

Background: The extent to which tissue factor pathway inhibitor (TFPI) may regulate the extrinsic clotting cascade, atherogenesis, and MI is uncertain. Reverse genetic studies in the mouse, including deletion of the TFPI Kunitz-1 (K1) domain, have been hindered by intrauterine lethality. We sought to determine the role of TFPI in an alternative animal model, by knocking out the zebrafish ortholog tfpia . Methods and results: High-efficiency transcription activator-like effector nucleases (TALENs), targeting the 5’ region of tfpia, were microinjected into 1-cell zebrafish embryos. Sequence analysis of genomic DNA derived from adult caudal fin tissue revealed indels causing a frameshift mutation and premature stop codon prior to K1. Somatic mutants were outcrossed to WT fish, and the embryos were screened for germline mutations. Founders (F 1 ) were raised and incrossed to produce embryos (F 2 ), including approximately 25% with the desired biallelic null mutation ( tfpia -/- ) that were physically and developmentally indistinguishable, but functionally disparate from heterozygous ( tfpia +/- ) or WT ( tfpia +/+ ) siblings. At 6 days post-fertilization (dpf), F 2 tfpia -/- larvae exhibited a reduction in time to occlusion of the dorsal aorta after exposure to ferric chloride, which was more significant in 6-dpf F 3 tfpia -/- larvae (generated by incrossing F 2 tfpia -/- adults) lacking a possible maternal effect. Furthermore, F 2 tfpia -/- fish had in vivo evidence of increased fatty streaking as late larvae, after receiving a high cholesterol diet, and enhanced cardiac injury as adults, 4 days after cryoinjury-induced MI. Conclusions: Deletion of tfpia does not significantly effect zebrafish development, but leads to hypercoagulability in early larvae, enhanced atherogenesis in late larvae, and increased injury related to MI in adults, indicating a fundamental role for TFPI in the pathogenesis of cardiovascular disease.