Citations

Abstract Objective In utero fetal spina bifida repair decreases the risk for cerebrospinal fluid (CSF) diversion including ventriculoperitoneal (VP) shunt placement, reverses hindbrain herniation, and improves motor function with a higher likelihood of independent ambulation. Unfortunately, in utero surgery can be complicated by preterm delivery. The goal of this study was to compare pregnancy and neonatal outcomes between individuals who delivered very preterm, and those who delivered later in gestation following in utero spina bifida repair. Methods Data from the North American Fetal Therapy Network Fetal Myelomeningocele Consortium Registry collected from 2011 to 2024 were analyzed. Three cohorts of patients were categorized by gestational age at delivery and compared: <30 weeks, 30–34 weeks, and >34 weeks. Comparisons between groups for maternal and delivery outcomes were completed for the entire cohort and then analyzed for those with available CSF diversion data up to 1 year of life. Chi‐square or Fisher's exact tests were used to compare categorical variables, and Kruskal–Wallis tests were used to determine if there are significant differences between the distributions of the three groups. A p ‐value <0.05 was considered significant. Results A total of 1213 patients were analyzed (<30 weeks, n = 111 [9.2%]; 30–34 weeks, n = 323 [26.6%]; >34 weeks, n = 779 [64.2%]). Overall fetal and neonatal mortality was 2.2%, 85% of which occurred in the <30‐week cohort, where perinatal mortality was 21%. Latency from fetal surgery to delivery averaged 2.1 weeks for the <30‐week group. Rates of abruption, chorioamnionitis, and spontaneous labor were higher in the <30‐week group compared to later gestational age cohorts. Neonatal morbidity was also significantly higher in the <30‐week cohort for sepsis, apnea, respiratory distress, patent ductus arteriosus, intraventricular hemorrhage, and periventricular leukomalacia in the <30‐week cohort. CSF diversion data were available for 677 neonates (<30 weeks, n = 53; 30–34 weeks, n = 186; >34 weeks, n = 438). There was no significant difference in VP shunt placement between the different gestational age groups. Conclusion Very preterm birth following in utero spina bifida repair results in significant perinatal mortality and neonatal morbidity. Delivery prior to 30 weeks of gestation occurs in 9% of patients after in utero spina bifida repair, resulting in a 21% perinatal mortality rate. However, even among those who delivered very preterm, a reduction in VP shunt rates, a benefit of in utero repair, appears to be preserved. Further data are warranted to assess the impact of prematurity following in utero surgery on ambulation and developmental outcomes.

Background: The relationship between vegetation characteristics in Staphylococcus aureus infective endocarditis (IE) and blood culture time to positivity (TTP) has not been investigated. This study evaluates the correlation between vegetation length and TTP in patients with S. aureus IE. Methods: A retrospective cohort study was conducted that included 164 definite cases S. aureus IE. Vegetation length was determined by transesophageal echocardiography (TEE), and TTP was measured in hours from the initial time of blood culture incubation to positivity. Correlations between vegetation characteristics and TTP were analyzed using Spearman’s rank correlation coefficient. Results: A modest but statistically significant negative correlation was observed between vegetation length and TTP (Spearman ρ = −0.18, p = 0.020), suggesting that larger vegetations were associated with shorter TTP. No significant correlations were found for other vegetation characteristics (e.g., vegetation mobility, location, or number) and TTP. Conclusions: Larger vegetation size in S. aureus IE was associated with shorter TTP. These findings highlight the importance of vegetation size in the pathophysiology of S. aureus IE and its role in bacteremia dynamics.

Context: There is need for an up-to-date comprehensive review of baseball interval throwing programs in the literature. Objective: To (1) understand the origin and basis of interval throwing programs; (2) evaluate the content of programs in the peer-reviewed literature including target audience, initiation criteria, throwing specifics, arm care, and performance evaluation metrics; (3) classify these variables as well defined, ambiguous, or missing; and (4) analyze variability in key aspects including starting criteria, length, progression, and completion criteria. Data Sources: Medline, Embase, Cochrane Reviews, Web of Science, and Scopus Study Selection: The full text of studies, in English, had to be available. Included studies had to contain a complete interval throwing program designed for baseball players. Study Design: Systematic review. Level of Evidence: Level 4. Data Extraction: Initial screening was conducted based on article title and abstract. Full text of the remaining articles was evaluated for fulfillment of inclusion criteria. Results: Nine studies initially met inclusion criteria. The programs’ comprehensiveness was poor, with a mean Interval Throwing Program Checklist score of 20 (range 14-23) on a scale of 0 to 30. There were a variety of components, including progressive long toss, weighted ball, and throwing mechanics exercises. The programs identified had significant heterogeneity in duration, intensity, progression, and focus. Overall, there was a significant lack of attempts at validation or formal study of efficacy for published throwing programs. Conclusion: Current published interval throwing programs are mostly variations of an original program published many years ago and were based on principles of progressive loading with pain as sign of injury that should be monitored carefully. However, these programs have minimal clinical validation and objective measures to quantify their effectiveness. This work identifies several limitations in the current literature and can serve as a foundation for future development of evidence-based interval throwing programs.

Background: Traditional Medicare (TM) claims data are widely used by researchers and registries to report survivorship following total knee arthroplasty (TKA). The purpose of the present study was to investigate whether the mass exodus of patients from TM to Medicare Advantage (MA) has compromised the fidelity of TM data. Methods: We identified 11,717 Medicare-eligible patients (15,282 knees) who had undergone primary TKA from 2000 to 2020 at a single institution. Insurance type was analyzed, and 84% of TKAs were covered by TM. The rates of survivorship free from revision or reoperation were calculated for patients with TM coverage. The same survivorship end points were recalculated after censoring of patients who transitioned to MA after primary TKA, thereby modeling the impact of losing patients from the TM dataset. Differences in survivorship were compared. The mean duration of follow-up was 10 years. Results: From 2000 to 2020, there was a decrease in TM insurance (from 94% to 68%) and a corresponding increase in MA insurance (from 0% to 19%) among patients undergoing TKA. Following TKA, 25% of patients with TM coverage switched to MA. For patients with TM at the time of surgery, the 15-year rates of survivorship free from any reoperation or revision were 90% and 96%, respectively. When patients were censored upon transition from TM to MA, the 15-year rates of survivorship free from any reoperation (92% versus 90%; hazard ratio [HR] = 1.2; p = 0.001) or any revision (97% versus 96%; HR = 1.3; p = 0.002) were significantly higher. Conclusions: One in 4 patients left TM for MA after primary TKA, effectively making them lost to follow-up within TM datasets. The mass exodus of patients out of TM resulted in falsely elevated estimates of survivorship free from reoperation and from revision, with increasing divergence in survivorship over time, when MA data were excluded. As MA continues to grow, efforts to incorporate these data will become increasingly important. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background: Given the dramatic rise in incidence of colorectal cancer in young adults, there remain limited treatment options effective in metastatic disease. Although T cell-based therapies have been successful in treating highly antigenic cancers, like melanoma and lung, they have not yet been shown to induce consistent and durable tumor regression in common epithelial malignancies, including metastatic colorectal cancer (mCRC). CISH (Cytokine inducible SH2 containing protein) is a novel intracellular checkpoint target demonstrating PD-L1 ligand independent mechanisms of enhanced anti-cancer activity. Given that CISH is not currently tractable via antibody or small molecule drug modalities, we employed CRISPR for precise inhibition of CISH in tumor infiltrating lymphocytes (TILs). Here, we provide the first clinical report of safety and anti-tumor activity of CISH edited TILs in 12 patients with metastatic gastrointestinal cancers (NCT04426669), including a clinical complete response (CR) in a young-adult patient with immunotherapy-refractory mCRC. Methods: Tumors were surgically resected for TIL harvest, followed by a rapid expansion protocol and CRISPR/Cas9 knockout (KO) CISH. CISH KO, neoantigen-reactive TILs were expanded, then infused following non-myeloablative lymphocyte depleting (LD) chemotherapy (cyclophosphamide & fludarabine) followed by high-dose IL-2. To establish mechanistic attribution of the CR, we used iR-RepSeq+ for serial analysis of the TCR immune repertoire. Results: Our CRISPR engineering led to KO of CISH in T cells with high-efficiency (&gt;90%) without detectable off-target editing. We safely dosed patients at all five dose levels (range: 1.91e8 to 9.93e10 cells). No dose-limiting toxicities attributable to the CISH-KO TIL product were observed. Adverse events were consistent with established risks of LD chemotherapy, IL-2, or disease progression. A durable ongoing complete response (&gt;21 months) was achieved in a patient with microsatellite instability-high (MSI-H) mCRC refractory to anti-PD1/CTLA-4 combination therapy. Conclusions: We provide the first clinical report of CISH checkpoint targeting via genetically modified T cell therapy, with complete response in a patient with mCRC. Persistence and expansion of unique TCR clonotypes detected in neoantigen responsive TIL was temporally consistent with spikes in CISH edited alleles detected by NGS assay; in the patient with CR, four of the clonotypes exhibiting prolonged persistence greater than one-year post-infusion exhibited significantly reduced or undetectable expression of CISH compared to the total infused TIL population. Given these findings, further investigation of CISH checkpoint inhibition, via gene and cell therapy, and next-generation small molecule drugging modalities, is underway. Citation Format: Emil Lou, Modassir S. Choudhry, Timothy K. Starr, Timothy Folsom, Jason Bell, Blaine Rathmann, Anthony P. DeFeo, Ji Hyun Kim, Nicholas Slipek, Zhaohui Jin, Darin Sumstad, Christopher A. Klebanoff, Katherine Ladner, Akshat Sarkari, R Scott McIvor, Thomas A. Murray, Jeffrey Miller, Madhuri Rao, Eric Jensen, Jacob Ankeny, Mahmoud A. Khalifa, Anil Chauhan, Benjamin Spilseth, Ajay Dixit, Paolo P. Provenzano, Wenjing Pan, Daniel Weber, Miranda Byrne-Steele, Tom Henley, David H. McKenna, Matthew J. Johnson, Beau R. Webber, Branden S. Moriarity. First-in-human trial in patients with metastatic colorectal cancer using CRISPR-engineered tumor infiltrating lymphocytes in which the intracellular immune checkpoint CISH is inhibited [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT269.

Abstract Background: Endocrine therapy (ET) with aromatase inhibitors (AI) plus ovarian function suppression (OFS) is standard for premenopausal women with ER+/HER2- breast cancer. However, many premenopausal women are intolerant of AI + OFS, leaving tamoxifen (with or without OFS) as their only option. Extensive studies have demonstrated that premenopausal women treated with neoadjuvant ET whose tumors exhibit Ki-67 ≤ 10% following 4 weeks of therapy (defined as endocrine sensitive disease (ESD)) achieve 5-year distant disease-free survival &gt; 96%. Problematically, only 41% of patients reach this ESD threshold with tamoxifen compared to 78% with AI+OFS (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent selective estrogen receptor modulator (SERM) that inhibits ERα at plasma concentrations of 3-5 ng/ml and dually targets PKCβ1, a suspected oncogene in breast tumors, at concentrations ≥ 500 ng/ml. We therefore developed the EVANGELINE study (NCT05607004) is an open label, randomized neoadjuvant phase II study that includes a pharmacokinetic (PK) Run-in, aiming to evaluate whether ENDX +/- goserelin is non-inferior to exemestane plus goserelin with respect to ESD rate. Following the completed PK run-in portion of the study, where 40mg/day or 80mg/day ENDX were assessed, the 40 mg/day dose was selected for further evaluation in the second part of the trial. The second part is comprised of a randomized treatment cohort, for patients with a Ki-67% &gt;10% at preregistration randomized to either 40mg (Z)-endoxifen + goserelin or exemestane + goserelin neoadjuvant treatment and a Single Arm Treatment Cohort for patients who have a Ki-67 ≤ 10% at pre-registration assigned to 40mg/day (Z)-endoxifen monotherapy neoadjuvant treatment. Methods: To investigate ENDX further in premenopausal women, a multicenter study in the United States, was designed(EVANGELINE; NCT05607004). This phase 2, open-label, randomized, neoadjuvant trial includes a PK run-in phase designed to assess whether the 4-week ESD rate with (Z)-endoxifen + goserelin is non-inferior to that of exemestane + goserelin in premenopausal women with Stage IIA or IIB ER+/HER2- breast cancer with diagnostic Ki67 &gt; 10%. Additionally, a single arm Phase 2, open-label neoadjuvant Cohort was designed to assess the 4-week ESD rate with ENDX monotherapy in premenopausal women with Stage IIA or IIB ER+/HER2- BC with diagnostic Ki67 ≤10%. Subjects will undergo neoadjuvant treatment for six months before receiving surgical treatment in the involved breast. This study will additionally assess safety, tolerability, response rates, surgical outcomes, and monitor disease progression. Comprehensive biomarker evaluations will be conducted using paired tumor biopsies and blood samples collected at baseline and week four, as well as 6 month surgical specimens. Enrollment in the PK run-in phase (n-22) was completed in Fall 2024 with the second portion of the trial slated to begin early in 2025. Citation Format: Matthew P. Goetz, Vera J. Suman, Claudia Lopez, Hayley Erickson, Lonnissa Nguyen, Sandra S. Hammer, Lida Mina, Pooja Advani, Roberto Leon-Ferre, Karthik Giridhar, Felipe Batalini, Daniel Flora, Jason M. Jones, Nusayba A. Bagegni, Katie N. Hunt, Mara Piltin, Amy Degnim, James N. Ingle, Judy C. Boughey, Sarah A. Buhrow, Joel M. Reid, Matthew Schellenberg, John R. Hawse, Steven C. Quay. A randomized phase 2 non-inferiority trial of (Z)-endoxifen + goserelin and exemestane + goserelin as neoadjuvant treatment for premenopausal women with ER+/HER2- breast cancer (EVANGELINE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT237.

Abstract Background: Pancreatic ductal adenocarcinoma (PDA) is a disease with guarded prognosis with a 5-year overall survival (OS) of 3.1% in patients with metastatic disease. The need for innovative treatments for this lethal disease is paramount. TTFields is a novel treatment modality that employs low intensity, alternating, and intermediate frequency electrical fields that abrogates cancer cell proliferation through different mechanisms. These include inhibition of mitosis, disruption of cancer cell membranes, metabolomic dysregulation of cancer cells, and immunogenic activation of the tumor microenvironment (TME). TTFields are approved in glioblastoma multiforme, non-small cell lung cancer and malignant mesothelioma. The PANOVA trial demonstrated promising efficacy for TTFields plus chemotherapy in patients with PDA. A trial of GCN in patients with PDA demonstrated exceptional efficacy in patients with metastatic disease. Here in, we present our ongoing clinical trial investigating the safety and efficacy of TTFields plus GCN in patients with PDA (NCT04605913). Methods: This a phase I/II trial with an initial safety run-in phase followed by the phase II portion. The primary objective of the trial is to determine the safety (CTCAE v 5.0) of GCN plus TTFields. Secondary objectives include determining the 6-month progression free survival (PFS) rate, overall response rate (ORR, RECIST v1.1), 12-month survival rate, OS, and QOL (EORTC QLQ-C30, version 3.0.2.3). Inclusion criteria include PDA with liver metastasis (patients can have additional sites of metastasis), ECOG 0-1, measurable disease, and ability to operate the Novo TTF-100L (P)/Novo TTF-200T system. Treatment consisted of TTFields (150 kHz 18 hours/day) and GCN (G: 1000 mg/m2, C 30 mg/m2, and N: 150 mg/m2 every 2 weeks, 28 days cycle), followed by a maintenance phase after 6 months (G: 1000 mg/m2 every 2 weeks) plus TTFields until progression. Six patients were to be enrolled in the phase I portion and if ≤1/6 patients experienced a dose limiting toxicity (DLT, treatment emergent adverse event, or skin toxicity of Gr4), the plan would be to move to a phase II trial enrolling 34 more patients. If 2/6 patients experienced a DLT, 6 patients would be enrolled in dose level -1 (GCN plus TTFields for 9 hours/day followed by the maintenance treatment) and if tolerated the phase II portion would start with dose level -1 regimen. The phase I portion was completed without any DLTs and the trial is currently enrolling to the phase II portion. The total number of patients (40) was powered to the 6-months PFS rate and ORR (estimated using the lower bound of exact one-sided 90% confidence intervals). The goal is to "reject" a 6-month PFS rate of 66% and an ORR of 71% (based on previous GCN trial). Time-to-event endpoints will be assessed using the Kaplan-Meier method. Citation Format: Hani M. Babiker, Jason Starr, Jeremy Jones, Conor O’Donnell, Robert Jones, Jacqueline Boni, Lashundra Stewart, Josh Cameron, Oudom Kour, Kabir Mody, Robert R. McWilliams, Daniel H. Ahn, Tanios Bekaii-Saab, Mitesh J. Borad, Umair Majeed. A phase I/II pilot trial, single arm, open label, of gemcitabine, cisplatin, protein-bound paclitaxel (GCN) combined with Tumor Treatment Fields (TTFields) in patient with metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT190.

Abstract Background: Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein, highly expressed on the cell surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers and showing limited expression in normal tissues. Given this expression profile, FAP appears to be a promising target for radioligand therapy that has pan-cancer potential. [177Lu]Lu-NNS309 is a FAP-targeted radiopharmaceutical that shows improved tumor retention and demonstrates promising anti-tumor activity in translationally relevant preclinical models (e.g., PDAC, NSCLC) where FAP is expressed on CAFs. Methods: CFXX489A12101 (NCT06562192) is a first-in-human phase I, open-label, multi-center study of [177Lu]Lu-NNS309 in patients with pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), breast cancer (BC), and colorectal cancer (CRC). The study includes a dose escalation part followed by a dose expansion part. Key eligibility criteria include prior treatment for locally advanced unresectable or metastatic disease and having all measurable lesions (per RECIST 1.1) showing [68Ga]Ga-NNS309 uptake on positron emission tomography/computed tomography (PET/CT). Patients who are eligible for treatment receive one dose of [177Lu]Lu-NNS309 on day 1 of each cycle. A 6-week and a 4-week dosing schedule will be explored. Dosimetry data will be obtained from patients in the dose escalation part after the first dose and will be used to calculate the cumulative radiation exposure. Dose escalation will be guided by a Bayesian hierarchical logistic regression model with overdose control (EWOC) principle, and assessment of all relevant data available from all dose levels including safety, tolerability, clinical dosimetry, pharmacodynamics, and preliminary efficacy. Once the recommended dose(s) (RD) and schedule(s) of [177Lu]Lu-NNS309 are determined, the expansion part may open and will include patients with locally advanced or metastatic PDAC (n∼20), locally advanced or metastatic NSCLC (n∼20), HR+/HER2- ductal BC (n∼15), HR+/HER2- lobular BC (n∼15), and triple negative BC (; n∼24).The primary objectives of the study are to evaluate the safety and tolerability of [177Lu]Lu-NNS309 and to identify the RD(s) and regimen(s) of [177Lu]Lu-NNS309 for further clinical evaluation. Secondary objectives of the study are to evaluate the preliminary anti-tumor activity of [177Lu]Lu-NNS309, characterize the pharmacokinetics of [177Lu]Lu-NNS309 in blood and urine, the radiation dosimetry for organs and tumor lesions, and to evaluate the safety and imaging properties of [68Ga]Ga-NNS309. Conclusion: The study is currently enrolling in the dose escalation part. Citation Format: Ravit Geva, Daniel Juneau, Shadi Abdar Esfahani, Cristiano Ferrario, Farshad Moradi, Amir Iravani, Jordi Ahnert, Ivan Manuel Victoria Ruiz, Thibaud Koessler, Aitana Calvo Ferrandiz, Bernard Doger de Speville, Patrick Flamen, Albiruni Razak, Desiree Deandreis, Laure Al-Mansour, Niklaus Schaefer, James Nagarajah, Hilde Nienhuis, Marco Maccauro, Angelina Filice, Jonathan Goldman, Ken Herrmann, Matthias Eiber, Alexander Drzezga, Martin Heuschkel, Jonathan McConathy, Johnson Geoffrey, Ephraim Parent, Yasutoshi Kuboki, Shizuka Origuchi, Xuan Mai Couillebault, Elisa Garcia Garayoa, Jayarama Naidu Roopa, Christopher Straub, Dominik Hainzl, Xinyu Chen, Fang Yang, Eirini Pectasides, Brandon Mancini. Phase I open-label, multi-center study to evaluate the safety, tolerability, dosimetry, and preliminary activity of FXX489 ([177Lu]Lu-NNS309) in patients with pancreatic, lung, breast and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT112.