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Introduction: Among older adults with cancer receiving chemotherapy, frailty indices predict OS and toxicity. Given the increased use of immunotherapy and targeted therapy for advanced non-small cell lung cancer (aNSCLC), we evaluated frailty and Karnofsky Performance Status (KPS) among older adults with aNSCLC receiving chemotherapy, immunotherapy, and/or targeted therapy., Methods: Patients aged ≥ 65 with aNSCLC starting systemic therapy with non-curative intent underwent geriatric assessments over 6 months. We developed a deficit-accumulation frailty index to categorize patients as robust, pre-frail, or frail. To evaluate associations between frailty and KPS with OS, we used Cox proportional hazards models adjusted for race, insurance, and treatment. We used logistic regression to evaluate hospitalizations, functional decline, and severe toxicity., Results: Among 155 patients (median age 73), 45.8% were robust, 36.1% pre-frail, and 18.2% frail; 34.8% had a KPS ≥ 90, 32.9% had a KPS of 80, and 32.3% had a KPS ≤ 70. The median OS was 17.9 months. Pre-frail/frail patients had worse OS compared to robust patients (adjusted hazard ratio [HR] 2.09, 95% CI, 1.31-3.34) and were more likely to be hospitalized (adjusted odds ratio [OR] 2.21, 95% CI, 1.09-4.48), functionally decline (adjusted OR 2.29, 95% CI, 1.09-4.78), and experience grade ≥ 3 hematologic toxicity (adjusted OR 5.18, 95% CI, 1.02-26.03). KPS was only associated with OS., Conclusions: Our frailty index was associated with OS, hospitalization, functional decline, and hematologic AEs among older adults with aNSCLC receiving systemic therapies, while KPS was only associated with OS. Pretreatment frailty assessment may help identify older adults at risk for poor outcomes to optimize decision-making and supportive care., (© The Author(s) 2024. Published by Oxford University Press.)

Although programmed cell death ligand 1 (PD-L1) is best known for its role in immune suppression, tumor-intrinsic functions are emerging. Here, we report that tumor cells that express PD-L1 are sensitive to ferroptosis inducers such as imidazole ketone erastin (IKE). PD-L1 promotes ferroptosis sensitivity because it suppresses SLC7A11 expression and diminishes glutathione levels. Although the use of anti-PD-L1 antibody drug conjugates (ADCs) could be effective for the delivery of ferroptosis inducers to specific tumor populations, the chemistry of most ferroptosis inducers precludes their incorporation in ADCs. To overcome this challenge, we synthesized an antibody nanogel conjugate (ANC) comprised of an anti-PD-L1 antibody conjugated to a nanogel encapsulated with IKE. This ANC targets PD-L1-expressing cells in vitro and in vivo and induces ferroptosis, resulting in tumor suppression. Importantly, this approach is superior to systemic administration of IKE because it enables enhanced delivery of IKE specifically to tumor cells and it requires lower drug doses for efficacy., Competing Interests: Declaration of interests M.W. and A.M.M are founders and shareholders of RedPoint Oncology, Inc., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The high rate of recurrence after radiation therapy in triple-negative breast cancer (TNBC) indicates that novel approaches and targets are needed to enhance radiosensitivity. Here, we report that neuropilin-2 (NRP2), a receptor for vascular endothelial growth factor (VEGF) that is enriched on subpopulations of TNBC cells with stem cell properties, is an effective therapeutic target for sensitizing TNBC to radiotherapy. Specifically, VEGF/NRP2 signaling induces nitric oxide synthase 2 (NOS2) transcription by a mechanism dependent on Gli1. NRP2-expressing tumor cells serve as a hub to produce nitric oxide (NO), an autocrine and paracrine signaling metabolite, which promotes cysteine-nitrosylation of Kelch-like ECH-associated protein 1 (KEAP1) and, consequently, nuclear factor erythroid 2-related factor 2-mediated (NFE2L2-mediated) transcription of antioxidant response genes. Inhibiting VEGF binding to NRP2, using a humanized mAb, results in NFE2L2 degradation via KEAP1, rendering cell lines and organoids vulnerable to irradiation. Importantly, treatment of patient-derived xenografts with the NRP2 mAb and radiation resulted in significant tumor necrosis and regression compared with radiation alone. Together, these findings reveal a targetable mechanism of radioresistance, and they support the use of NRP2 mAb as an effective radiosensitizer in TNBC.

Background: The Accreditation Council for Graduate Medical Education (ACGME) requires that all graduate medical education (GME) programs provide at least 6 paid weeks off for medical, parental, and caregiver leave to residents. However, it is unclear whether all orthopaedic residency programs have adapted to making specific parental leave policies web-accessible since the ACGME's mandate in 2022. This gap in policy knowledge leaves both prospective and current residents in the dark when it comes to choosing residency programs, and knowing what leave benefits they are entitled to when having children during training via birth, surrogacy, adoption, or legal guardianship., Questions/purposes: (1) What percentage of ACGME-accredited orthopaedic surgery residency programs provide accessible parental leave policies on their program's website, their GME website, and through direct contact with their program's administration? (2) What percentage of programs offer specific parental leave policies, generic leave policies, or defer to the Family and Medical Leave Act (FMLA)?, Methods: As indicated in the American Medical Association's 2022 Freida Specialty Guide, 207 ACGME-accredited orthopaedic residency programs were listed. After further evaluation using previous literature's exclusion criteria, 37 programs were excluded based on osteopathic graduate rates. In all, 170 ACGME-accredited allopathic orthopaedic surgery residency programs were identified and included in this study. Three independent reviewers assessed each program website for the presence of an accessible parental leave policy. Each reviewer accessed the program's public webpage initially, and if no parental leave policy was available, they searched the institution's GME webpage. If no policy was found online, the program administrator was contacted directly via email and phone. Available leave policies were further classified into five categories by reviewers: parental leave, generic leave, deferred to FMLA, combination of parental and FMLA, and combination of parental and generic leave., Results: Our results demonstrated that 6% (10 of 170) of orthopaedic residency programs had policy information available on their program's main orthopaedic web page. Fifty nine-percent (101 of 170) of orthopaedic residency programs had a clearly stated policy on their institution's GME website. The remaining 35% (59 of 170) had no information on their public website and required direct communication with program administration to obtain policy information. After directly contacting program administration, 12% (21 of 170) of programs responded to researchers request with a PDF explicitly outlining their policy. Twenty-two percent (38 of 170) of programs did not have an accessible policy available. Of the programs that had available policies, a total of 53% (70 of 132) of programs were categorized as offering explicit parental leave policies, 9% (12 of 132) were categorized as offering general leave policies, and 27% (36 of 132) deferred to FMLA. Seven percent (9 of 132) offered combined parental leave policies with FMLA, and 4% (5 of 132) offered combined general leave policies with FMLA., Conclusion: Although most ACGME-accredited allopathic orthopaedic surgery residency programs met the ACGME requirement of written parental leave policies in 2023, a small minority of programs have clear, accessible parental leave policies provided on their webpage., Clinical Relevance: Parental leave policies should be easily accessible to prospective and current trainees and should clearly state compensation and length of leave. Ensuring orthopaedic surgery residency programs provide accessible and transparent parental leave policies is important for maintaining diversity in prospective applicants and supporting the work-life balance of current residents., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research ® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2024 by the Association of Bone and Joint Surgeons.)

Background: Readiness for return to sports involves both physical and psychological aspects of recovery; however, the relationship between psychological and physical variables after anterior cruciate ligament (ACL) reconstruction (ACLR) is poorly understood., Hypothesis: ACLR patients with a higher psychological readiness would demonstrate better functional testing results at 6 months., Study Design: Cross-sectional study; Level of evidence, 3., Methods: Participants were evaluated at 6 months after ACLR with various patient-reported outcome metrics: Hospital for Special Surgery Pediatric Functional Activity Brief Scale, pediatric or adult International Knee Documentation Committee Questionnaire (IKDC), Patient-Reported Outcomes Measurement Information System (PROMIS) - Psychological Stress Experience and ACL - Return to Sport After Injury (ACL-RSI) scale. Functional testing included quadriceps, hamstrings, and gluteal strength testing; Y-balance test; single-leg single hop, crossover hop, and triple hop tests; and timed 6-m hop test. Pearson correlation coefficient and multivariable regression were used to determine associations between the limb symmetry index (LSI) on functional testing and patient-reported outcomes. Those with LSI deficits <20% (better performance) were compared with those with deficits >20% (worse performance)., Results: A total of 229 participants (89 male, 140 female) with a median age of 17 years (range, 10.3-30.6 years) were enrolled. IKDC had a moderate negative correlation with PROMIS - Psychological Stress Experience ( r = -0.39; 95% CI = -0.49, -0.27; P < .001) and a moderate positive correlation with ACL-RSI ( r = 0.55; 95% CI = 0.46, 0.64; P < .001). A total of 151 patients completed functional testing. ACL-RSI demonstrated a positive correlation with single-hop LSI ( r = 0.21; 95% CI = 0.05, 0.35; P = .01) and timed 6-m hop ( r = 0.28; 95% CI, 0.42; P = .001). When adjusting for sex, age, and graft type, patients who had <20% deficit on the single-hop test scored 16.6 points higher on ACL-RSI ( P = .001), and those with <20% deficit on crossover hop testing scored a mean 13.9 points higher on ACL-RSI ( P = .04)., Conclusion: Higher psychological readiness for return to sport was associated with better performance and greater symmetry on hop testing 6 months after ACLR, suggesting a potential link between physical and psychological recovery., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: M.D.M. has received royalties from Elsevier and serves on the board of directors for PRiSM. M.A.C. has received royalties from Springer Inc and serves on the board of directors for PRiSM. Y-M.Y. is a consultant for Smith+Nephew and serves on the editorial board for the American Journal of Sports Medicine. E.J.S. has received education payments from Smith+Nephew and hospitality payments from Stryker and Zimmer Biomet Holdings. M.S.K. has received royalties from OrthoPediatrics and education payments from Kairos Surgical. D.E.K. has received education payments from Kairos Surgical and consulting fees from DePuy Synthes Products. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2024.)

Purpose: Patients from diverse racial, ethnic, and socio-economic backgrounds may be particularly vulnerable to experiencing undue social and financial burdens ("collateral damage") from a metastatic breast cancer (mBC) diagnosis; however, these challenges have not been well explored in diverse populations., Methods: From May 2022 to May 2023, English- or Spanish-speaking adults with mBC treated at four New York-Presbyterian (NYP) sites were invited to complete a survey that assessed collateral damage, social determinants of health, physical and psychosocial well-being, and patient-provider communication. Fisher's exact and the Kruskal-Wallis rank-sum tests assessed differences by race and ethnicity., Results: Of 87 respondents, 14% identified as Hispanic, 28% non-Hispanic Black (NHB), 41% non-Hispanic White (NHW), 7% Asian American Pacific Islander (AAPI), and 10% other/multiracial. While 100% of Hispanic, NHW, and AAPI participants reported stable housing, 29% of NHB participants were worried about losing housing (p = 0.002). Forty-two percent of Hispanic and 46% of NHB participants (vs. 8%, NHW and 0%, AAPI, p = 0.005) were food insecure; 18% of Hispanic and 17% of NHB adults indicated lack of reliable transportation in the last year (vs. 0%, NHW/AAPI, p = 0.033). Participants were generally satisfied with the quality of communication that they had with their healthcare providers and overall physical and mental well-being were modestly poorer relative to healthy population norms., Conclusions: In our study, NHB and Hispanic mBC patients reported higher levels of financial concern and were more likely to experience food and transportation insecurity compared to NHW patients. Systematically connecting patients with resources to address unmet needs should be prioritized to identify feasible approaches to support economically vulnerable patients following an mBC diagnosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted and immunotherapies. Whether genetic alterations acquired during the evolution of CRPC impact immune and immunotherapy responses is largely unknown. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which by signaling through VEGFR2 expressed on CD8 + T cells, could directly inhibit T cell activity. Targeting VEGF-VEGFR2 signaling in vivo led to CD8 + T cell-mediated tumor and metastasis growth suppression and significantly increased overall survival in MYC and p53 altered CPRC. VEGFR2 blockade also led to induction of PD-L1, and in combination with PD-L1 immune checkpoint blockade produced anti-tumor efficacy in multiple preclinical CRPC mouse models. Thus, our results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC., Significance: Though immune checkpoint blockade (ICB) therapies can achieve curative responses in many treatment-refractory cancers, they have limited efficacy in CRPC. Here we identify a genetic mechanism by which VEGF contributes to T cell suppression, and demonstrate that VEGFR2 blockade can potentiate the effects of PD-L1 ICB to immunologically treat CRPC., Competing Interests: DECLARATION OF INTERESTS M.R. is a consultant for Boehringer Ingelheim.

Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: J.N.K. has received honoraria from Pfizer. E.G.M. has received support for education from Peerless Surgical and Kairos Surgical. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Purpose: A metastatic breast cancer (mBC) diagnosis can affect physical and emotional well-being. However, racial and ethnic differences in receipt of outpatient psychosocial care and supportive care medications in adults with mBC are not well described., Methods: Adults with mBC were identified in the INSIGHT-Clinical Research Network, a database inclusive of >12 million patients receiving care across six New York City health systems. Outpatient psychosocial care was operationalized using Common Procedure Terminology codes for outpatient psychotherapy or counseling. Psychosocial/supportive care medications were defined using Rx Concept Unique Identifier codes. Associations between race/ethnicity and outpatient care and medication use were evaluated using logistic regression., Results: Among 5,429 adults in the analytic cohort, mean age was 61 years and <1% were male; 53.6% were non-Hispanic White (NHW), 21.4% non-Hispanic Black (NHB), 15.9% Hispanic, 6.1% Asian/Native Hawaiian/Pacific Islander (A/NH/PI), and 3% other or unknown. Overall, 4.1% had ≥one outpatient psychosocial care visit and 63.4% were prescribed ≥one medication. Adjusted for age, compared with NHW, Hispanic patients were more likely (odds ratio [OR], 2.14 [95% CI, 1.55 to 2.92]) and A/NH/PI patients less likely (OR, 0.35 [95% CI, 0.12 to 0.78]) to have an outpatient visit. NHB (OR, 0.59 [95% CI, 0.51 to 0.68]) and Asian (OR, 0.36 [95% CI, 0.29 to 0.46]) patients were less likely to be prescribed medications., Conclusion: Despite the prevalence of depression, anxiety, and distress among patients with mBC, we observed low utilization of psychosocial outpatient care. Supportive medication use was more prevalent, although differences observed by race/ethnicity suggest that unmet needs exist.

Background: Shoulder instability in pediatric and adolescent patients can be treated operatively via arthroscopic or open procedures, but there a paucity of evidence to support the incidence of these treatment modalities over time. It is hypothesized that the overall rate of arthroscopic shoulder stabilization procedures will increase over time. Given advances in open stabilization techniques, we also hypothesized that the rate of open procedures may be increasing., Methods: The Pediatric Health Information System database was queried for patients 19 years or younger who underwent arthroscopic or open surgery for shoulder instability and pediatric orthopedic surgeries between 2009 and 2019. Data from 37 of the 52 pediatric hospitals with Pediatric Health Information System data was included in the analysis. Annual and overall incidence rates were estimated for arthroscopic and open procedures, along with 95% confidence intervals. The yearly incidence for secondary (homolateral revisions) or primary contralateral arthroscopic and open procedures was also examined., Results: 4747 patients underwent primary arthroscopic procedures and 384 patients had primary open procedures. There were 8.2 primary open shoulder stabilization procedures per 10,000 orthopedic surgical patients in 2009, which decreased by 19% to 6.7 per 10,000 orthopedic surgical patients in 2019. There was an increase seen in both arthroscopic and open secondary stabilization procedures. In 2009, there were 0.97 secondary arthroscopic procedures per 10,000 orthopedic surgical patients. This increased by 672% to 7.5 per 10,000 orthopedic surgical patients in 2019. No secondary open procedures were recorded in 2009; however, an increase to 2.6 secondary open procedures per 10,000 orthopedic surgical patients was seen by 2019., Conclusion: This study shows a rise in primary arthroscopic pediatric shoulder stabilization surgeries across the U.S. over the last decade. There was a slight decrease in the rate of primary open shoulder stabilization surgeries and an increase in both arthroscopic and open secondary (homolateral revisions or primary contralateral) shoulder stabilization surgeries, implying an increasing revision burden in this population., (© 2024 The Author(s).)

We are interested in the contribution of integrins and the extracellular matrix to epithelial differentiation in carcinomas. This study was motivated by our finding that the Hippo effectors YAP and TAZ can sustain the expression of laminin 332 (LM332), the predominant ECM ligand for the integrin β4, in breast carcinoma cells with epithelial differentiation. More specifically, we observed that YAP and TAZ regulate the transcription of the LAMC2 subunit of LM332. Given that the β4-LM332 axis is associated with epithelial differentiation and YAP/TAZ have been implicated in carcinoma de-differentiation, we sought to resolve this paradox. Here, we observed that the β4 integrin sustains the expression of miR-200s that target the transcription factor ZEB1 and that ZEB1 has a pivotal role in determining the nature of YAP/TAZ-mediated transcription. In the presence of β4, ZEB1 expression is repressed enabling YAP/TAZ/TEAD-mediated transcription of LAMC2. The absence of β4, however, induces ZEB1, and ZEB1 binds to the LAMC2 promoter to inhibit LAMC2 transcription. YAP/TAZ-mediated regulation of LAMC2 has important functional consequences because we provide evidence that LM332 enables carcinoma cells to resist ferroptosis in concert with the β4 integrin., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Preoperative risk factors contributing to poor outcomes after arthroscopic partial meniscectomy (APM) have not yet been consolidated and codified into an index scoring system used to predict APM success., Purpose: To create an index score using available preoperative factors to predict the likelihood of favorable postoperative outcomes after APM., Study Design: Case-control study; Level of evidence, 3., Methods: A consecutive cohort of patients undergoing primary APM were enrolled in this study. Patients completed pre- and postoperative patient-reported outcome measure (PROM) questionnaires that included the Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog scale (VAS) for pain, Veterans RAND 12-Item Health Survey (VR-12 Physical and Mental), and Marx Activity Rating Scale (MARS). Multivariable logistic regression models were performed to evaluate independent predictors of KOOS Pain, Symptoms, and Activities of Daily Living scores and achievement of the minimal clinically important difference (MCID) and substantial clinical benefit (SCB). The authors assigned points to each variable proportional to its odds ratio, rounded to the nearest integer, to generate the index score., Results: In total, 468 patients (mean age, 49 years [SD, 10.4 years; range, 19-81 years]) were included in this study. In the univariate analysis, shorter symptom duration, lower Kellgren-Lawrence (KL) grade, lower preoperative KOOS Pain value, and lower VR-12 Physical score were associated with a higher likelihood of clinical improvement at 1 year. In the multivariable model for clinical improvement with MCID, symptom duration (<3 months: OR, 3.00 [95% CI, 1.45-6.19]; 3-6 months: OR, 2.03 [95% CI, 1.10-3.72], compared with >6 months), KL grade (grade 0: OR, 3.54 [95% CI, 1.66-7.54]; grade 1: OR, 3.04 [95% CI, 1.48-6.26]; grade 2: OR, 2.31 [95% CI, 1.02-5.27], compared with grade 3), and preoperative KOOS Pain value (score <45: OR, 3.00 [95% CI, 1.57-5.76]; score of 45-60: OR, 2.80 [95% CI, 1.47-5.35], compared with score >60) were independent significant predictors for clinical improvement. The scoring algorithm demonstrated that a higher total score predicted a higher likelihood of achieving the MCID: 0 = 40%, 1 = 68%, 2 = 80%, 3 = 89%, and 4 = 96%., Conclusion: Using this model, the authors developed an index score that, using preoperative factors, can help identify which patients will achieve clinical improvement after APM. Longer symptom duration and higher KL grade were associated with a decreased likelihood of clinical improvement as measured by KOOS Pain at 1 year postoperatively., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: J.N.K. has received honoraria from Pfizer. E.G.M. has received support for education from Peerless Surgical and Kairos Surgical. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.