Purpose: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFβ, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGFβ 1/3 trap, reduced TGFβ1-induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PC) with wild-type JAK2 rather than JAK2V617F. Patients and Methods: We conducted an investigator-initiated, multicenter, phase Ib trial of AVID200 monotherapy in 21 patients with advanced MF. Results: No dose-limiting toxicity was identified at the three dose levels tested, and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF-directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGFβ1 levels and pSMAD2 in MF cells. Conclusions: AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of patients with MF and should be evaluated further in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways.

Background: Orthopaedic surgery has the lowest proportion of women surgeons in practice of any specialty in the United States. Preliminary studies suggest that patients who are treated by physicians of the same race, ethnicity, cultural background, or gender feel more comfortable with their care and may have better outcomes. Therefore, understanding the discrepancies in the diversity of the orthopaedic surgeon workforce is crucial to addressing system-wide healthcare inequities. Questions/purposes: (1) Does a difference exist in gender representation among practicing orthopaedic surgeons across geographic distributions and years in practice? (2) Does a difference exist in gender representation among practicing orthopaedic surgeons with regard to rural-urban setting, group practice size, and years in practice? Methods: Orthopaedic surgeons serving Medicare patients in 2017 were identified in the Medicare Physician and Other Supplier Public Use File and Physician Compare national databases. This dataset encompasses more than 64% of practicing orthopaedic surgeons, providing a low proportion of missing data compared with other survey techniques. Group practice size, location, and Rural-urban Commuting Area scores were compared across physician gender and years in practice. Linear and logistic regressions modeled gender and outcomes relationships adjusted by years in practice. Least-square means estimates for outcomes were calculated by gender at the median years in practice (19 years) via regression models. Results: According to the combined Medicare databases used, 5% (1019 of 19,221) of orthopaedic surgeons serving Medicare patients were women; this proportion increased with decreasing years in practice (R² 0.97; p < 0.001). Compared by region, the West region demonstrated the highest proportion of women orthopaedic surgeons overall (7% [259 of 3811]). The Midwest and South regions were below the national mean for proportions of women orthopaedic surgeons, both overall (5% [305 of 6666] and 5% [209 of 4146], respectively) and in the first 5 years of practice (9% [54 of 574] and 9% [74 of 817], respectively). Women worked in larger group practices than men (median [interquartile range] 118 physicians [20 to 636] versus median 56 [12 to 338]; p < 0.001, respectively). Both genders were more likely to practice in an urban setting, and when controlling for years in practice, there was no difference between men and women orthopaedic surgeons practicing in rural or urban settings (respectively, R² = 0.0004 and 0.07; p = 0.89 and 0.09). Conclusion: Among orthopaedic surgeons, there is only one woman for every 20 men caring for Medicare patients in the United States. Although gender representation is increasing longitudinally for women, it trails behind other surgical subspecialties substantially. Longitudinal mentoring programs, among other evidenced initiatives, should focus on the more pronounced underrepresentation identified in Midwestern/Southern regions and smaller group practices. Gender-based equity, inclusion, and diversity efforts should focus on recruitment strategies, and further research is needed to study how inclusion and diversity efforts among orthopaedic surgeons improves patient-centered care. Level of Evidence: Level III, therapeutic study.

Background/Aims: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE ^® ) was developed to capture symptomatic adverse events from the patient perspective. We aim to describe statistical properties of PRO-CTCAE items and summary scores and to provide evidence for recommendations regarding PRO-CTCAE administration and reporting. Methods: Using data from the PRO-CTCAE validation study (NCT02158637), prevalence, means, and standard deviations of PRO-CTCAE items, composite scores, and mean and maximum scores across attributes (frequency, severity, and/or interference) of symptomatic adverse events were calculated. For each adverse event, correlations and agreement between attributes, correlations between attributes and composite scores, and correlations between composite, mean, and maximum scores were estimated. Results: PRO-CTCAE items were completed by 899 patients with various cancer types. Most patients reported experiencing one or more adverse events, with the most prevalent being fatigue (87.7%), sad/unhappy feelings (66.0%), anxiety (63.6%), pain (63.2%), insomnia (61.8%), and dry mouth (60.0%). Attributes were moderately to strongly correlated within an adverse event ( r = 0.53 to 0.77, all p < 0.001) but not fully concordant (κ _weighted = 0.26 to 0.60, all p < 0.001), with interference demonstrating lowest mean scores and prevalence among attributes of the same adverse event. Attributes were moderately to strongly correlated with composite scores ( r = 0.67 to 0.97, all p < 0.001). Composite scores were moderately to strongly correlated with mean and maximum scores for the same adverse event ( r = 0.69 to 0.94, all p < 0.001). Correlations between composite scores of different adverse events varied widely ( r = 0.04 to 0.68) but were moderate to strong for conceptually related adverse events. Conclusions: Results provide evidence for PRO-CTCAE administration and reporting recommendations that the full complement of attributes be administered for each adverse event, and that attributes as well as summary scores be reported.

BACKGROUND: Long-term post-treatment surveillance imaging algorithms for head and neck squamous cell carcinoma are not standardized due to debates over optimal surveillance strategy and efficacy. Consequently, current guidelines do not provide long-term surveillance imaging recommendations beyond 6 months. PURPOSE: We performed a systematic review to evaluate the impact of long-term imaging surveillance (i.e., imaging beyond 6 months following treatment completion) on survival in patients treated definitively for head and neck squamous cell carcinoma. DATA SOURCES: A search was conducted on PubMed, Embase, Scopus, the Cochrane Central Register of Controlled Trials, and Web of Science for English literature published between 2003 and 2024 evaluating the impact of long-term surveillance imaging on survival in patients with head and neck squamous cell carcinoma. STUDY SELECTION: 718 abstracts were screened and 95 underwent full-text review, with 2 articles meeting inclusion criteria. The Risk of Bias in Non-randomized Studies of Interventions assessment tool was used. DATA ANALYSIS: A qualitative assessment without a pooled analysis was performed for the two studies meeting inclusion criteria. DATA SYNTHESIS: No randomized prospective controlled trials were identified. Two retrospective two-arm studies were included comparing long-term surveillance imaging with clinical surveillance and were each rated as having moderate risk of bias. Each study included heterogeneous populations with variable risk profiles and imaging surveillance protocols. Both studies investigated the impact of long-term surveillance imaging on overall survival and came to a different conclusion with one study reporting a survival benefit for long-term surveillance imaging with FDG PET/CT in patients with stage III or IV disease or an oropharyngeal primary tumor and the other study demonstrating no survival benefit. LIMITATIONS: Limited heterogeneous retrospective data available precludes definitive conclusions on the impact of long-term surveillance imaging in head and neck squamous cell carcinoma. CONCLUSIONS: There is insufficient quality evidence regarding the impact of long-term surveillance imaging on survival in patients treated definitively for head and neck squamous cell carcinoma. There is a lack of standardized definition of long-term surveillance, variable surveillance protocols, and inconsistencies in results reporting, underscoring the need for a prospective multi-center registry assessing outcomes. ABBREVIATIONS: HNSCC = Head and Neck Squamous Cell Carcinoma; RT= radiotherapy; NCCN = National Comprehensive Cancer Network; MPC = metachronous primary cancer; CR = complete response; OS = overall survival; CRT = chemoradiotherapy; HPV = human papillomavirus; PFS = progression-free survival; CFU = clinical follow up; NI-RADS = Neck Imaging Reporting and Data System.

Summary: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder with limited therapeutic options. Insufficient understanding of driver mutations and poor fidelity of currently available animal models has limited the development of effective therapies. Since GATA1 deficient megakaryocytes sustain myelofibrosis, we hypothesized that they may also induce fibrosis in lungs. We discovered that lungs from IPF patients and Gata1 ^low mice contain numerous GATA1negative immune-poised megakaryocytes that, in mice, have defective RNA-seq profiling and increased TGF-β1, CXCL1 and P-selectin content. With age, Gata1 ^low mice develop fibrosis in lungs. Development of lung fibrosis in this model is prevented by P-selectin deletion and rescued by P-selectin, TGF-β1 or CXCL1 inhibition. Mechanistically, P-selectin inhibition decreases TGF-β1 and CXCL1 content and increases GATA1positive megakaryocytes while TGF-β1 or CXCL1 inhibition decreased CXCL1 only. In conclusion, Gata1 ^low mice are a novel genetic-driven model for IPF and provide a link between abnormal immune-megakaryocytes and lung fibrosis.