Citations

Abstract Despite therapeutic advances, ovarian cancer (OC) recurrence remains common and outcomes for advanced disease are poor, highlighting the need for novel therapeutic targets. To this end, we identified CTPS1 as a highly expressed and essential gene for the survival of many OC cell lines, including models resistant to chemotherapy and PARP inhibitors. CTPS1 is one of two enzymes, alongside CTPS2, responsible for the de novo synthesis of cytidine triphosphate (CTP), a critical nucleotide required for DNA and phospholipid biosynthesis. We discovered that CTPS1 is the predominant isoform expressed in OC cells, with significantly higher levels of expression in advanced and resistant disease compared to normal tissue, benign lesions and treatment naïve cancers. Intriguingly, 25% of all OC samples were found to completely lack CTPS2 protein expression suggesting their near complete reliance on CTPS1 for survival. Using CTPS1 siRNAs and genetically engineered OC cells with a degradation tag (dTAG) fused to the C-terminus of endogenous CTPS1 alleles, we showed that CTPS1 knockdown or proteasomal degradation induces an S-phase cell cycle arrest followed by apoptosis. Leveraging a first-in-class, highly selective, and orally bioavailable CTPS1 inhibitor (STP938) developed by Step Pharma, we identified nanomolar-range IC50 values across a panel of over 20 OC cell lines and validated its anti-neoplastic activity in ex vivo patient-derived xenograft (PDX) models. STP938 synergized with standard-of-care chemotherapy and PARP inhibitors, even in resistant models, further supporting its clinical potential. To elucidate STP938’s mechanism of action, we performed multi-omic profiling (bulk RNAseq, phospho- and total proteomics) on sensitive and isogenic resistant OC lines, as well as single-cell RNAseq of an OC PDX tumor following in vivo treatment with vehicle or STP938, revealed dysregulation of DNA replication, cell cycle, and metabolic pathways. As expected, STP938 rapidly depleted CTP levels, which remain suppressed for 72 hours, suggesting insufficient salvage pathway compensation which ultimately compromised cancer cell viability. As CTP is also a direct precursor for activated intermediates in phospholipid biosynthesis. Mass-spectrometry based lipidomics and metabolomics were employed to interrogate the impact of STP938 in these processes where numerous changes were found. To uncover mechanisms of resistance to STP938 and reveal therapeutic vulnerabilities, we conducted genome-wide CRISPR knockout screens in multiple treatment naïve and STP938 resistant models and analysis of results are ongoing. In collaboration with Step Pharma, a Phase 1a/b clinical trial of STP938 is currently enrolling patients with advanced solid tumors, including an expansion cohort for CTPS2 null OC patients (NCT06297525). These laboratory discoveries and ongoing clinical efforts aim to enable broader uptake of this novel therapeutic approach to improve long-term outcomes in patients with CTPS1-dependent disease. Citation Format: Xiyin Wang, Michael J. Emch, Lauren A. Voll, Rebecca Epp, Esther P. Rodman, Noa Odell, Nicole A. Pearson, Xiaonan Hou, Matthew P. Goetz, Scott H. Kaufmann, S. John Weroha, Philip Beer, John R. Hawse. Exploiting CTPS1 dependency for the treatment of ovarian cancerPR005: Exploiting CTPS1 dependency for the treatment of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR005.

Abstract Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. Here, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation. SCCOHT primary tumors harbored tumor-associated outlier splicing events compared to normal tissues. Many of the tumor events were retained introns encoding novel peptides predicted to bind to MHC-I complexes. Immune cells were observed in primary SCCOHT tumors, suggesting a potentially immune reactive tumor microenvironment. Mutations in several SWI/SNF subunits were associated with higher rates of outlier retained introns across tumor types in TCGA data. Interestingly, RNA sequencing of isogenic SCCOHT cell lines demonstrated a role for SMARCA4 in intron retention. Distinct protein-protein interactions between splicing factors identified in SCCOHT cell lines supported a role for SMARCA4 in splicing regulation. Further, SWI/SNF localized to genes which were differentially spliced. Mass spectrometry analyses confirmed expression of some of these novel peptides and a subset of these are predicted to bind to MHC-I complexes. A pool of these novel peptides derived from retained introns in SCCOHT triggered proliferation and expression of TNFa and INFb in primary human T cells. Together, these data suggest that SMARCA4 loss in SCCOHT leads to intron retention. Furthermore, T cell activation by novel peptides encoded by these tumor-specific splicing events suggests intron retention could be a source of tumor-associated antigens in SCCOHT. Citation Format: Elizabeth Raupach, Apurva Hegde, Krystine Garcia-Masnfield, Marice Alcantara, David Rose, Rebecca Halperin, Krystal Orlando, Jessica Lang, Ritin Sharma, Victoria David-Dirgo, Salvatore Facista, Rayvon Moore, Rochelle Kofman, Zoe Jensen, Victoria Zismann, Anthony Karnezis, Yemin Wang, Lynda Bennett, Timothy Whitsett, Marcin Kortylewski, William Hendricks, David Huntsman, Lorna Rodriguez-Rodriguez, Bernard Weissman, Jeffrey Trent, Patrick Pirrotte. Loss of SMARCA4 leads to intron retention and generation of tumor-associated antigens in small cell carcinoma of the ovary, hypercalcemic type [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B065.

Abstract Introduction: The purpose of this study is to evaluate the effectiveness of opportunistic salpingectomy (OS), a procedure that aims to remove only the fallopian tubes of general population risk women, for the prevention of epithelial ovarian cancer. Currently, the method of prevention for individuals at high risk of ovarian cancer involves a bilateral salpingo-oophorectomy (BSO), a procedure that removes both the fallopian tubes and ovaries. However, this procedure is not recommended for individuals of the general population, who make up about 80% of ovarian cancers, due to negative health implications to the cardiovascular and skeletal systems because of surgically induced menopause. The effectiveness of the OS in preventing ovarian cancers and how the procedure impacts the histotype distribution of ovarian cancers remains unknown. Study Methods: This study uses a population-based approach and a case-based approach to determine the effectiveness of OS and its impact on histotype distribution, respectively. For the population-based analysis, we will search through clinical databases to acquire cases of individuals who have had an OS and a tumor. A control population who have their fallopian tubes in-tact will also be acquired. A cox-proportional hazard analysis will be performed to determine the effectiveness of the procedure. Using pathological records, the case-based ascertainment of tumors from individuals who have had an OS will be selected and reviewed for histotype confirmation. Fallopian tubes of these patients will also be reviewed for precursor lesions. This cohort will be compared to a historical histotype distribution of ovarian cancers. Results: For the population-based approach, we have to date, identified less than five serous ovarian cancers in individuals who have had an OS (n=40, 477). A comparator surgery was used as a control and showed 21 cancers. For the case-based approach, we have partnered with 23 collaborating institutions from around the world to identify tumors in individuals who have had an OS. We have identified 26 epithelial ovarian cancers, with the most lethal gynecological histotype, high grade serous carcinoma (HGSC), accounting for 23.1% of the total proportion of epithelial ovarian cancer cases (n=6/26). This is significantly less than the historical histotype distribution of HGSC, which is 69.3% (Fisher’s exact test, p<0.0001). One HGSC case had a precursor lesion called a serous tubal intraepithelial carcinoma (STIC) while reviewing fallopian tubes of this individual. TP53 mutation analysis on one HGSC tumor sample showed a frameshift mutation in TP53 (c229fs) with the tumor and the corresponding STIC staining negative for p53 protein expression by immunohistochemistry. Conclusion: This evidence demonstrates the effectiveness of opportunistic salpingectomy for the prevention of ovarian cancer and shows a histotype distribution shift, with the most lethal gynecological malignancy having a significant reduction in cases following the procedure. Citation Format: Ramlogan Sowamber, Alice J. Mei, Paramdeep Kaur, Julianne McLeod, Emily McKay, Alex Lukey, Jamie Bakkum-Gamez, Natalia Buza, Paul Cohen, Kyle Devins, Rhonda Farrell, Christine Garcia, Blake Gilks, Ellen Goode, Anjelica Hodgson, Brooke Howitt, Pei Hui, Jutta Huvila, Anthony Karnezis, Kianoosh Keyhanian, Mary Kinloch, Martin Köbel, Felix KF. Kommoss, Lawrence Kushi, Janice S. Kwon, Kara Long-Roche, Anais Malpica, Jessica N. McAlpine, Dianne Miller, Esther Oliva, Andrea Palicelli, Aleksandra Paliga, Carlos Parra-Herran, Celeste Leigh Pearce, Sharnel Perera, Jurgen M. Piek, Haiyan Qiu, Joseph Rabban, Robert Rome, Miranda Steenbeek, Rebecca Stone, Aline Talhouk, Kristin M. Tischer, Britton Trabert, Penelope M. Webb, John R. Zalcberg, Gillian E. Hanley, David G. Huntsman. Evaluating the effectiveness of opportunistic salpingectomy (OS) for the prevention of epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B045.

Despite European colorectal liver metastases (CRLM) transplant trials having been performed entirely using deceased donor liver transplant (DDLT), there has been speculation about whether similar results can be achieved in the United States, given the lack of MELD score prioritization. A formal transplant protocol for unresectable CRLM was implemented in our center at the start of 2022 with the plan to utilize DDLT. Between 2022 and 2025, 86 patients with CRLM were referred to our program, and 19 patients underwent a formal transplant evaluation. Median time from listing until transplant was 31 days (range 3–115 d). Median allocation MELD was 8 (range 6–15). The donor livers were from DCDs, older donors, or National Share livers, which had been declined by all other centers. All but 2 of the cases underwent advanced perfusion. There were no cases of primary nonfunction, postreperfusion syndrome, acute kidney injury, hepatic artery thrombosis, or ischemic cholangiopathy. The length of stay for the median posttransplant was 5 days. Graft and patient survival were 100% at the time of maximal follow-up. Recurrence developed in 3 recipients (25.0%), 1 of whom was treated and has no evidence of disease. These findings support the viability of DDLT for CRLM using advanced perfusion, contingent on strict protocol adherence. Center-specific waitlist dynamics must inform the choice between DDLT and living donor liver transplant (LDLT).

ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

Abstract Objectives Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays. Methods To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS. Results Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL. Conclusions Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, usability, footprint, and intended use, should be considered.

A 33-year-old female presented with finger pain, swelling, and erythema was diagnosed with cellulitis and treated with antibiotics. Persistent symptoms led to further evaluation including a point-of-care ultrasound revealing a cystic structure, concerning for abscess. Incision and drainage yielded a solid mass rather than fluid. Pathological examination revealed a schwannoma, a benign peripheral nerve sheath tumor. This case highlights the rare presentation of a schwannoma mimicking an infectious process and emphasizes the importance of considering peripheral nerve tumors in the differential diagnosis of soft tissue masses, especially when the clinical course is atypical. It also underscores the value of pathological examination in establishing a definitive diagnosis and preventing misdiagnosis, which can have implications for patient management.

Objective: The purpose of this study was to evaluate the potential clinical value of spectral CT for image guidance during percutaneous thermal ablation, particularly investigating high monoenergetic (MonoE) for metal artifact reduction. Materials and Methods: A phantom experiment was performed in which an ablation probe was scanned in “continuous CT” (CCT) mode on a spectral CT scanner. ROI measurements quantified metal artifacts for conventional and MonoE CCT images. Subsequently, a retrospective reader study was conducted with 10 patient cases. Three radiologists reviewed cases to select the optimal MonoE setting and perform a Likert score rating (+2: MonoE preferred, −2: conventional preferred). Results: Phantom measurements indicated a reduction in metal artifact for high MonoE (150 keV: −46 HU) relative to conventional CCT (−122 HU). The MonoE setting preference was 151±21 keV. The mean Likert score was 1.2±0.7. Radiologists indicated a perceived benefit of high MonoE CCT when probe placement was near a critical structure. Conclusions: This study indicates a clinical preference for high MonoE CCT compared with conventional CCT. Insofar as spectral CCT can be offered at a clinically feasible time frame, our results support the assessment of 150 keV image to reduce metal artifact while maintaining satisfactory soft tissue contrast.

ABSTRACTWe describe a case of a 56‐year‐old male who developed severe, refractory hypotension after an intentional ingestion of clozapine and who became hemodynamically stable after one session of therapeutic plasma exchange (TPE). The patient, who presented after an ingestion of clozapine, was found to have altered mental status and hypotension in the emergency department. Escalating catecholamine vasoactive agents were necessary to maintain adequate hemodynamics. Angiotensin II was added and rapidly up titrated in efforts to maintain adequate blood pressure. Due to persistent hemodynamic instability despite four vasoactive agents, TPE was attempted to enhance the elimination of the highly protein bound medication. Within 2 h of completing TPE, the catecholamines and vasopressin were stopped, and angiotensin II dosing was significantly decreased. This is the first report of utilizing TPE as a method of enhanced elimination of a toxic clozapine ingestion resulting in severe hemodynamic compromise. Further study is necessary to determine if TPE should be incorporated into the care of patients experiencing clozapine toxicity.

Introduction: Takotsubo cardiomyopathy (TCM), also known as stress cardiomyopathy or Broken Heart Syndrome, is a reversible, transient state of myocardial dyskinesis and apical ballooning. Infrequently, TCM may progress to severe life-threatening complications such as cardiogenic shock. Early mechanical circulatory support (MCS) is crucial to myocardial recovery in these cases. We present one of the first cases of TCM successfully treated with the advanced micro-axial minimally invasive Impella 5.5 with SmartAssist MCS device. Case Presentation: A female in her late 70s with a history of hypothyroidism, atrial fibrillation post-ablation, and cholelithiasis was referred to our facility for an elective cholecystectomy. Post-anesthesia induction with propofol 2.1 mg/kg (140 mg bolus), she became bradycardic and hypotensive, eventually leading to asystole, requiring CPR and termination of the procedure. Echocardiography revealed a left ventricular ejection fraction (LVEF) of 24% with mid-ventricular akinesis and apical ballooning with mild mitral regurgitation, suggesting the diagnosis of TCM. Cardiac catheterization showed RA 20 and mean PA 42 mmHg. Lactate was 18.7 mmol/L and LDH 1776 U/L, suggesting progressive shock. Continuous epinephrine 0.1 mcg/kg/min and norepinephrine 0.06 mcg/kg/min were titrated for BP 97/58, and she was initially supported with the Impella CP device. Despite aggressive efforts, rising LDH levels and increased vasopressor needs indicated inadequate organ perfusion, requiring an upgrade to Impella 5.5. Impella 5.5 support for 11 days led to impressive myocardial recovery, leading to reductions, and eventual discontinuation, of inotropes and vasopressors. Post-Impella 5.5 explantation, her LVEF was 59–65% and she was discharged with Mobile Cardiac Outpatient Telemetry (MCOT) monitoring for her arrhythmias and reinitiation of guideline-directed medical therapies (GDMTs) for her comorbidities. Her 2-month follow-up shows sustained LVEF greater than 45% with functional improvements. Conclusions: Early escalation within 24 h of Impella CP to Impella 5.5 provided stabilization of cardiometabolic shock, preventing end-organ damage, allowing recovery of native heart function while maintaining ambulatory status, and allowing for optimizing medical therapy. It presents a safe, minimally invasive, and cost-effective intervention in TCM cases refractory to GDMT or when additional time is needed for decision-making in cases presenting with CS.