GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.

AIMS: Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A. METHODS AND RESULTS: Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure. CONCLUSION: Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.

Does the Primary Tumor Site Drive Biology for Patients With Synovial Sarcoma?

OBJECTIVE: We evaluated survival outcomes by primary tumor site in synovial sarcoma (SS) patients with localized and metastatic disease at diagnosis. METHODS: We conducted a retrospective review of 504 SS patients diagnosed from 1974 to 2020. Kaplan-Meier method, log-rank test, and Cox-proportional hazards regression were used. RESULTS: Among 504 patients, 401 (79.6%) presented with localized disease, and 103 (20.4%) with metastases. For patients with localized disease, (1) 5-year OS by tumor site was as follows: 80% (95% CI, 67%-89%) for head/neck, 30% (95% CI, 18%-42%) for intrathoracic, 51% (95% CI, 35%-65%) for abdomen/pelvis, 71% (95% CI, 62%-79%) for proximal-extremity, and 83% (71%, 91%) for distal-extremity. (2) On multivariable analysis, tumor site (compared with proximal-extremity: intrathoracic tumors [HR: 1.95; 95% CI, 1.22-3.16]; hand/foot [HR: 0.52; 95% CI, 0.28-0.97]), tumor size (compared with <5 cm, 5-10 cm [HR: 1.80; 95% CI, 1.14-2.85]; ≥10 cm [HR: 4.37; 95% CI, 2.69-7.11]), and use of neo/adjuvant radiation (HR: 0.54; 95% CI, 0.37-0.79) remained significantly associated with OS. For patients with metastatic disease, (1) 5-year OS was 12% (95% CI, 6%-21%) and (2) the only factor that remained significantly associated with OS on multivariable analysis was surgical resection for the primary tumor (HR: 0.14; 95% CI, 0.08-0.26). CONCLUSIONS: The primary tumor location plays a significant role in predicting outcomes for patients with localized SS. Even though patients present with metastatic disease, surgical resection of the primary tumor improves their survival. These findings are critical for patient counseling and designing a personalized treatment plan that reflects the corresponding outcomes.

Zoom Boom or Bust? Understanding Post-Pandemic Interest in Facial Plastic Surgery via Google Trends.

OBJECTIVE: To understand post-pandemic interest in plastic surgery procedures via Joinpoint analysis of Google Trends search data. METHODS: Google Trends was used to quantify search volumes from January 2019-December 2022 for select cosmetic face and body procedures in the United States. A keyword analytic tool (Keywords Everywhere) extracted absolute search volumes (average monthly searches). Joinpoint analysis assessed search trends over time reported as monthly percentage change (MPC). RESULTS: All procedures queried, including a non-cosmetic control (cataract surgery), demonstrated expected declines at the start of the COVID-19 pandemic. Blepharoplasty, face lift, neck lift, and Botox demonstrated statistically significant increase in search volumes that remained elevated relative to pre-pandemic levels. Rhinoplasty, fillers, and abdominoplasty interest increased initially followed by return to pre-pandemic levels by the end of 2022. The remainder of search terms did not show a clear temporal associated with COVID-19 lockdowns. CONCLUSION: The "Zoom Boom" appears to be a real phenomenon reflected by sustained increase in public interest in relation to facial plastic procedures. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Airway obstruction secondary to vocal cord polyp.

ABSTRACT: Patients with vocal cord polyps commonly present with symptoms of hoarseness. Although rare, large polyps can cause shortness of breath and stridor and should be included in the differential for patients with airway obstruction. Dysphonia or hoarseness can be a symptom of underlying disease, such as head and neck cancer. This case illustrates the importance of prompt and accurate diagnosis in a patient with persistent symptoms and a history of smoking. Obtaining a laryngoscopy is crucial to appropriately evaluate the larynx. Proper visualization of the laryngeal structures will help direct patient care toward further diagnostic imaging and medical or surgical intervention if indicated.

Dynamics of amylopectin granule accumulation during the course of the chronic Toxoplasma infection is linked to intra-cyst bradyzoite replication.

The contribution of amylopectin granules (AG), comprised of a branched chain storage homopolymer of glucose, to the maintenance and progression of the chronic Toxoplasma gondii infection has remained undefined. Here we describe the role of AG in the physiology of encysted bradyzoites by using a custom developed imaging-based application AmyloQuant that permitted quantification of relative levels of AG within in vivo derived tissue cysts during the initiation and maturation of the chronic infection. Our findings establish that AG are dynamic entities, exhibiting considerable heterogeneity among tissue cysts at all post infection time points examined. Quantification of relative AG levels within tissue cysts exposes a previously unrecognized temporal cycle defined by distinct phases of AG accumulation and utilization over the first 6 weeks of the chronic phase. This AG cycle is temporally coordinated with overall bradyzoite mitochondrial activity implicating amylopectin in the maintenance and progression of the chronic infection. In addition, the staging of AG accumulation and it rapid utilization within encysted bradyzoites was associated with a burst of coordinated replication. As such our findings suggest that AG levels within individual bradyzoites, and across bradyzoites within tissue cysts may represent a key component in the licensing of bradyzoite replication, intimately linking stored metabolic potential to the course of the chronic infection. This extends the impact of AG beyond the previously assigned role that focused exclusively on parasite transmission. These findings force a fundamental reassessment of the chronic Toxoplasma infection, highlighting the critical need to address the temporal evolution of this crucial stage in the parasite life cycle.

Polyfracture and Cranial Injuries Drive the Cost and Inpatient Burden of Zygoma Fractures.

IMPORTANCE: Facial trauma makes up a significant number of emergency room visits, with morbidity costs in excess of 1 billion dollars each year. Few studies have evaluated the economic outcomes of management and inpatient burden of facial trauma, most focusing solely on the mandible and isolated midface fractures. OBJECTIVE: The authors aim to evaluate characteristics associated with increased cost and length of hospitalization of zygoma fracture management. DESIGN: Cross-sectional study. SETTING: Level 1-trauma academic medical center. PARTICIPANTS: Patients with zygoma fractures who presented to our institution from 2008 to 2021. MAIN OUTCOMES AND MEASURES: Demographics, injury mechanisms, associated injuries, treatment information, and associated costs were collected. Univariate and multivariate analyses were performed to identify the patient and fracture characteristics associated with increased cost and length of hospitalization. RESULTS: Our 14-year experience identified 689 patients with zygoma fractures who presented from 2008 to 2021. Seventy percent were male, and 40% occurred in Caucasian patients. The mean cost, adjusted for inflation, was $21,799.34, and the mean length of hospitalization was 5.5 days. Four or more fractures, associated cranial or intracranial injuries, and length of stay were associated with significantly higher cost, and 4 or more fractures, associated cranial or intracranial injuries, and female gender were associated with significantly longer length of hospitalization. CONCLUSIONS AND RELEVANCE: This study represents one of the largest comprehensive databases of zygoma fractures and one of the first to provide a descriptive cost and inpatient burden analysis. To improve outcomes and reduce hospital cost and inpatient burden, protocols should be implemented to address the factors that the authors identified as contributing to increased cost and length of hospitalization.

CD9 and Aryl Hydrocarbon Receptor Are Markers of Human CD19+CD14+ Atypical B Cells and Are Dysregulated in Systemic Lupus Erythematous Disease.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose expression regulates immune cell differentiation. Single-cell transcriptomic profiling was used to ascertain the heterogeneity of AHR expression in human B cell subpopulations. We identified a unique population of B cells marked by expression of AHR, CD9, and myeloid genes such as CD14 and CXCL8. Results were confirmed directly in human PBMCs and purified B cells at the protein level. TLR9 signaling induced CD14, CD9, and IL-8 protein expression in CD19+ B cells. CD14-expressing CD9+ B cells also highly expressed AHR and atypical B cell markers such as CD11c and TBET. In patients with active lupus disease, CD14+ and CD9+ B cells are dysregulated, with loss of CD9+ B cells strongly predicting disease severity and demonstrating the relevance of CD9+ B cells in systemic lupus erythematosus and autoimmune disease.

Clinical characteristics and outcomes of adult alveolar rhabdomyosarcoma patients on first-line systemic therapies: A single-institution cohort.

Background: Rhabdomyosarcomas are the most common soft tissue sarcoma in children, and pediatric alveolar rhabdomyosarcoma (ARMS) prognosis has improved based on cooperative studies. However, in adults, ARMS is significantly rarer, has poorer outcomes, and currently lacks optimal treatment strategies. Objective: This study aimed to evaluate the clinical outcome of an adult ARMS population with different front-line systemic chemotherapies and determine if any chemotherapy regimen is associated with improved survival. Materials and methods: This is a retrospective study of histologically confirmed fusion-positive ARMS patients over 18 years of age, who were treated at MD Anderson Cancer Center (MDACC) from 2004 to 2021 and received systemic chemotherapy. Descriptive clinical statistics were performed, including staging, front-line chemotherapy, multimodal therapy usage, response rates, and survival analyses. Results: 49 ARMS patients who received upfront chemotherapy were identified. Locoregional treatments included radiotherapy (RT) alone (29%, n = 14), surgery alone (10%, n = 5), or both (45%, n = 22). Median overall survival (OS) for the entire cohort was 3.6 years, and the overall response rate to systemic therapy was 89%. No chemotherapy regimen showed OS benefit, specifically analyzing the pediatric-based vincristine, actinomycin-D, cyclophosphamide (VAC) or adult-based vincristine, doxorubicin, ifosfamide (VDI) regimens, even when controlled for other clinical risk factors. Conclusion: In this single-center contemporary series, adult ARMS patient outcomes remain poor. There was no statistically significant OS difference in patients who did or did not receive adult or pediatric based ARMS regimens, although a high overall response rate to chemotherapy was seen across the entire cohort. Based on these observations, further randomized prospective studies are necessary to delineate which frontline chemotherapy regimen is most beneficial in this rare adult cancer.

Probing Ferryl Reactivity in a Nonheme Iron Oxygenase Using an Expanded Genetic Code.

The ability to introduce noncanonical amino acids as axial ligands in heme enzymes has provided a powerful experimental tool for studying the structure and reactivity of their FeIV=O ("ferryl") intermediates. Here, we show that a similar approach can be used to perturb the conserved Fe coordination environment of 2-oxoglutarate (2OG) dependent oxygenases, a versatile class of enzymes that employ highly-reactive ferryl intermediates to mediate challenging C-H functionalizations. Replacement of one of the cis-disposed histidine ligands in the oxygenase VioC with a less electron donating N δ-methyl-histidine (MeHis) preserves both catalytic function and reaction selectivity. Significantly, the key ferryl intermediate responsible for C-H activation can be accumulated in both the wildtype and the modified protein. In contrast to heme enzymes, where metal-oxo reactivity is extremely sensitive to the nature of the proximal ligand, the rates of C-H activation and the observed large kinetic isotope effects are only minimally affected by axial ligand replacement in VioC. This study showcases a powerful tool for modulating the coordination sphere of nonheme iron enzymes that will enhance our understanding of the factors governing their divergent activities.

Screening Strategies and Methodologies.

PRCIS: While glaucoma is a leading cause of irreversible vision loss, it presents technical challenges in the design and implementation of screening. New technologies such as PRS and AI offer potential improvements in our ability to identify people at high risk of sight loss from glaucoma and may improve the viability of screening for this important disease. PURPOSE: To review the current evidence and concepts around screening for glaucoma. METHODS/RESULTS: A group of glaucoma-focused clinician scientists drew on knowledge and experience around glaucoma, its etiology, and the options for screening. Glaucoma is a chronic progressive optic neuropathy affecting around 76 million individuals worldwide and is the leading cause of irreversible blindness globally. Early stages of the disease are asymptomatic meaning a substantial proportion of cases remain undiagnosed. Early detection and timely intervention reduce the risk of glaucoma-related visual morbidity. However, imperfect tests and a relatively low prevalence currently limit the viability of population-based screening approaches. The diagnostic yield of opportunistic screening strategies, relying on the identification of disease during unrelated health care encounters, such as cataract clinics and diabetic retinopathy screening programs, focusing on older people and/or those with a family history, are hindered by a large number of false-positive and false-negative results. Polygenic risk scores (PRS) offer personalized risk assessment for adult-onset glaucoma. In addition, artificial intelligence (AI) algorithms have shown impressive performance, comparable to expert humans, in discriminating between potentially glaucomatous and non-glaucomatous eyes. These emerging technologies may offer a meaningful improvement in diagnostic yield in glaucoma screening. CONCLUSIONS: While glaucoma is a leading cause of irreversible vision loss, it presents technical challenges in the design and implementation of screening. New technologies such as PRS and AI offer potential improvements in our ability to identify people at high risk of sight loss from glaucoma and may improve the viability of screening for this important disease.

Case report: Treatment response of NF-1-associated bladder ganglioneuroma to trametinib.

We present the clinical course of a 4-year-old girl with neurofibromatosis type 1-associated, unresectable, symptomatic urinary bladder ganglioneuroma. She was initially trialed on sirolimus without response and subsequently responded to MEK inhibitor trametinib, with improvement clinically and radiographically over 10 months. This report broadens the repertoire of therapeutic strategies for MEK inhibition in diseases related to the MAPK pathway.

SNO-EANO-EURACAN consensus on management of pineal parenchymal tumors.

Pineal parenchymal tumors are rare neoplasms for which evidence-based treatment recommendations are lacking. These tumors vary in biology, clinical characteristics, and prognosis, requiring treatment that ranges from surgical resection alone to intensive multimodal antineoplastic therapy. Recently, international collaborative studies have shed light on the genomic landscape of these tumors, leading to refinement in molecular-based disease classification in the 5th edition of the World Health Organization (WHO) classification of tumors of the central nervous system. In this review, we summarize the literature on diagnostic and therapeutic approaches, and suggest pragmatic recommendations for the clinical management of patients presenting with intrinsic pineal region masses including parenchymal tumors (pineocytoma, pineal parenchymal tumor of intermediate differentiation, and pineoblastoma), pineal cyst, and papillary tumors of the pineal region.

Partial Nicotine Reduction and E-Cigarette Users' Puffing Behaviors Among Adults Aged 21 to 35 Years: A Randomized Crossover Clinical Trial.

Importance: The advent of salt-based, high-nicotine electronic nicotine delivery systems [e-cigarettes] has contributed to their epidemic use among young people in the US, necessitating the need for policies to address the addictiveness of these products. Objective: To evaluate the effect of partial nicotine reduction on new-generation e-cigarette users' puffing behaviors. Design, Setting, and Participants: This randomized crossover clinical trial was conducted at the Clinical Research Lab for Tobacco Smoking at Florida International University in Miami between April 15, 2022, and October 17, 2023. Using a volunteering sampling method by distributing flyers and advertisements, current e-cigarette users (who preferred 5% nicotine concentration), aged 21 to 35 years, were included. Intervention: In a crossover design, participants completed 2 sessions of the same product (JUUL or NJOY) that differed by nicotine concentration (3% [JUUL] or 2.4% [NJOY] and 5% [JUUL or NJOY]) in random order. In each session, participants vaped up to 60 minutes ad libitum, preceded by 12 hours of nicotine abstinence. Main Outcomes and Measures: The primary outcomes were puffing topography parameters (eg, total session time, puffing time, total puffing number, interpuff interval, total inhaled volume, average puff volume, duration, and flow rate) measured during each session and plasma nicotine measured before and after each session. Results: Among 735 participants who were approached for eligibility, 675 were excluded, and 10 did not complete session 2. Of the 50 remaining current e-cigarette users (mean [SD] age, 23 [3] years; 56% men), 23 (46%) were low nicotine dependent. The median topography parameters were significantly higher during the e-cigarette use sessions with 3% or 2.4% nicotine concentration compared with 5% nicotine concentration for 3 outcomes: puffing time (1.3 minutes [IQR, 0.3-9.4 minutes] vs 1.2 minutes [IQR, 0.2-5.6 minutes]; P = .02), puff duration (2.6 seconds [IQR, 0.8-6.9 seconds] vs 2.4 seconds [IQR, 0.4-6.6 seconds]; P = .02), and total inhaled volume (1990.0 mL [IQR, 279.0-24 400.0 mL] vs 1490.0 mL [IQR, 148.0-14 300.0 mL]; P = .05). The median plasma nicotine boost observed in the 5% nicotine concentration condition (0.0060 mg/L [IQR, 0.0001-0.0249 mg/L]) was significantly higher than that in the 3% or 2.4% session (0.0043 mg/L [IQR, 0.0008-0.0225 mg/L]) (P = .001). Additionally, deeper puffing (increased average puff duration and average puff volume) was observed in participants with higher nicotine dependence (1.42 seconds [95% CI, 1.12-1.80 seconds]; P = .03) and male users (1.38 mL [95% CI, 1.09-1.75 mL]; P = .04) in response to nicotine reduction. Conclusions and Relevance: This randomized crossover clinical trial provides direct evidence that partial nicotine reduction in salt-based e-cigarettes was associated with acute compensatory puffing and the potential for increased exposure to toxicants. However, given the reduced nicotine delivery associated with nicotine reduction, the acute compensatory response observed in this study may not preclude a population benefit due to the marketing of less addictive products. These results suggest that at least for current e-cigarette users, partial nicotine reduction can lead to enhanced exposure to some toxicants in the short term. Trial Registration: ClinicalTrials.gov Identifier: NCT05205382.

[18F]F-AraG imaging reveals association between neuroinflammation and brown- and bone marrow adipose tissue.

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.

Venetoclax-Obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the phase 3 CLL14 study.

Venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, patients with previously untreated CLL and coexisting conditions were randomized to 12 cycles of Ven-Obi (n=216) or chlorambucil-obinutuzumab (Clb-Obi, n=216). Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS) and rates of adverse events. Patient reported outcomes (PROs) of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs 36.4 months; HR 0.40[95%CI 0.31-0.52], p<0.0001). Likewise, TTNT was longer after Ven-Obi (6-year-TTNT 65.2% vs 37.1%; HR 0.44, 95%CI 0.33-0.58, p<0.0001). In the Ven-Obi arm, presence of del(17p), unmutated-IGHV and lymph node size ≥5 cm were independent prognostic factors for shorter PFS. Five years after treatment, 17 patients (7.9% of intention-to-treat-population) in the Ven-Obi arm had uMRD (<10-4 in peripheral blood) compared to 4 (1.9%) in the Clb-Obi arm. 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69[95%CI 0.48-1.01], p=0.052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi compared to the Clb-Obi arm (median 82.1 vs 65.1 months; HR 0.70[95%CI 0.51-0.97]). Follow-up adjusted SPM incidence rates were 2.3 and 1.4/1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival, uMRD and QoL benefits support the use of one-year fixed-duration Ven-Obi in CLL. NCT02242942, EudraCT 2014-001810-24.

A phase 2 study of a brachyury-targeting vaccine in combination with radiation therapy for the treatment of advanced chordoma.

BACKGROUND: This was a single-arm, phase 2 clinical trial of Bavarian Nordic (BN)-Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression-free survival (PFS), and safety of the combination in chordoma. METHODS: A total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury and one vaccine dose of fowlpox virus (FPV)-Brachyury before RT. After RT, booster vaccinations were given with FPV-Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients. RESULTS: Two of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6-20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4-90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7-25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study. CONCLUSIONS: This trial confirms the safety of BN-Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine-based study in chordoma, an ultra-rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.

Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5-191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

High-Grade Pleomorphic Sarcomas Treated with Immune Checkpoint Blockade: The MD Anderson Cancer Center Experience.

BACKGROUND: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available. PURPOSE: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution. METHODS: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded. RESULTS: Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS (p = 0.0012, p = 0.0019 and p = 0.036, respectively). No new safety signal was identified, and the toxicity was overall manageable with no toxic deaths and only four patients (11%) stopping treatment due to toxicity. CONCLUSIONS: Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors.