Citations

We previously reported initial results of the pivotal phase II trial of atezolizumab for patients with alveolar soft part sarcoma (ASPS; ClinicalTrials.gov identifier: NCT03141684 ). Here, we report on three additional years of observation. Fifty-three patients with ASPS received atezolizumab. Median duration of response increased to 37.0 months. Objective response rate (ORR) and median progression-free survival (mPFS) remained essentially as previously reported (35.8% [95% CI, 23.1 to 50.2] and 20.8 months [IQR, 7.6-not reached], respectively). ASPSCR1::TFE3 fusion type was determined for 47/53 patients; ORR and mPFS were higher among the 41 patients expressing type 1 (43.9% [95% CI, 28.5 to 60.2] and 28.3 months [IQR, 9.2-not reached], respectively) than the six patients expressing type 2 (0% [95% CI, 0 to 45.9] and 7.5 months [IQR, 3.9-not reached], respectively, PFS HR, 3.2 [95% CI, 1.01 to 10.2]). Eleven patients chose a per-protocol drug holiday (range, 3.5-26.4 months) after ≥2 years of treatment; two experienced disease progression during the holiday. Nine eligible patients elected to receive bevacizumab plus atezolizumab after progressing on monotherapy; ORR was 0% and mPFS was 18.5 months (IQR, 7.9-21.1) in this small cohort. Long-term results support using atezolizumab to treat ASPS, even for several years; a drug holiday with careful monitoring may be an option for some patients.

Abstract Background The first international clinical standards of care for the gender-diverse population were formulated in the late 1970s. In the last 15 years, multiple subspecialty societies within the United States have developed clinical care guidelines for those with gender dysphoria, including gender-affirming hormone therapy (GAHT) and surgical treatments. To date, there are no pathology- and laboratory medicine–specific recommendations in the United States for the gender-diverse population. Content This document outlines pathology- and laboratory medicine–specific recommendations for providing optimal care to the gender-diverse population, with a predominant focus on the adult population. The scope of this document focuses on the following 5 topics: (a) reference intervals and interpretation of laboratory tests impacted by use of GAHT (testosterone for transgender men; estradiol with or without antiandrogens for transgender women), focusing on those stably on GAHT for 6 months or longer; (b) transfusion medicine considerations for the gender-diverse patient population, (c) consideration of gender diversity in autopsy and death investigation, (d) interpretation of histology from tissues that are impacted by GAHT and surgical procedures; and (e) pathology and laboratory medicine informatics challenges and opportunities. Summary A relatively small group of laboratory tests is significantly impacted by GAHT. The histology of some tissues shows changes attributable to GAHT or to nonhormonal medical procedures. Autopsy and transfusion medicine practices for the gender-diverse population currently lack standardization, although this is evolving. The landscape of pathology informatics related to gender diversity is complicated by varying electronic health record and laboratory informatics systems functionality.

Abstract Real-time, proactive detection has become a necessity as health systems face converging pressures that legacy tools cannot solve: rising acuity, workforce strain, and persistent quality gaps that erode margins, capacity, and reputation. Clinical decision support has historically lagged because rudimentary rules-based systems drown clinicians in false alerts, eroding trust without reliably changing outcomes at the bedside. Bayesian Health’s real-time clinical intelligence platform was built to close this gap by continuously synthesizing multimodal EHR data (vitals, labs, medications, procedures, and longitudinal history) to learn patient-specific baselines and surface only the most actionable, high-precision signals to care teams. Across diverse health systems, this platform has been used to enable earlier recognition and intervention for a range of high-impact conditions, improving both bedside care and system performance. This talk will focus on concrete, real-world applications of the platform for sepsis, clinical deterioration, and palliative care needs, illustrating how earlier detection and workflow-integrated interventions drive measurable gains in clinical outcomes and margins, and why the value of early, precise detection is amplified in high-risk populations such as oncology patients, whose higher baseline acuity and treatment-related toxicities both elevate their risk of harm and make emerging deterioration harder to recognize. Case Study: Detecting Sepsis within a Oncology Patient Subpopulation. Background: Sepsis remains one of the leading causes of in-hospital mortality, and traditional rules-based alerts have struggled to deliver timely, actionable detection without overwhelming clinicians with false alarms. Oncology patients experience an elevated risk for sepsis and septic shock, and those who experience sepsis are more likely to suffer in-hospital mortality than non-cancer patients with sepsis. Early recognition of sepsis onset is challenging due to the overlap between signs of sepsis and inflammation and tumor- and treatment-related toxicities. We investigated the ability of Bayesian Health’s real-time artificial intelligence-based computational algorithm to perform timely detection of sepsis onset in hospitalized patients with cancer. This algorithm ingests data directly from the electronic health record, such as vital signs, laboratory results, medications, procedures, and patient-specific historical results, processing it in a continuous manner to flag presence of sepsis as early as possible. Methods: Analysis included 7480 adult emergency and inpatient encounters from three tertiary and quaternary academic centers (Cleveland Clinic Main Campus, Sinai Hospital of Baltimore, and Strong Memorial Hospital) and one community hospital (Cleveland Clinic Fairview Hospital) with sufficient data for inclusion (age ≥ 18, presence in an emergency or inpatient care unit, and at least one measurement of a panel of vital signs). Patients with cancer (including subgroups of solid tumor and hematologic malignancy) were identified by current or past recorded diagnoses (ICD-10 codes). All included patient records underwent a multi-tiered retrospective adjudication process. An automated screen labeled records with no evidence of infection or organ dysfunction as non-sepsis, removing them from need for manual review. Two independent physicians then adjudicated a sample of the eliminated records in addition to each remaining record for both presence of sepsis and time of onset, with a third physician reconciling disagreements. Evaluation of the algorithm included all discrete flags generated by the system during a period of time it was not in clinical use and not visible to care teams. Results: In the overall population, 3.1% of all patients and 6.0% of cancer patients were adjudicated to have had sepsis, including zero from a sample of 200 of the records marked as non-sepsis in automated screening. The detection algorithm identified sepsis with high and consistent accuracy across all patients and across cancer patients, including those with solid tumors and with hematologic malignancies (Table). A flag for sepsis occurred in 85.8% of all sepsis patients and 86.1% of cancer patients with sepsis within 4 days of sepsis onset. Sepsis was present in 24.2% of all cancer patients flagged (22.9% of solid tumor patients and 27.9% of hematologic malignancy patients). Compared to patients who were never flagged, all patients who were flagged, whether they had sepsis or not, were more likely to experience in-hospital mortality (7.9% vs 0.3%, p < 0.001) or ICU transfer (38.2% vs 7.9%, p < 0.001). This was also true within oncology patients (in-hospital mortality: 8.8% vs 0.4%, p < 0.001; ICU transfer: 34.7% vs 9.7%, p < 0.001). Implementation of an automated sepsis detection system with high accuracy in populations such as cancer patients, who have elevated risk of poor outcomes following sepsis, provides an opportunity to meaningfully improve timely delivery of care and reduce subsequent morbidity and mortality while minimizing alert fatigue for clinicians. Citation Format: Suchi Saria, Varesh Prasad, Nicasia Beebe-Wang, Ellie Zhang, Neri Cohen, David Graham, Conrad Gleber, James Morrison, Jacob Strand, Alexandra Tallman. Real-time multimodal AI enables individualized care in challenging subpopulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr PL03-03.

Abstract Background: Pyrimidine synthesis is a therapeutic vulnerability in cancer but inhibition results in toxicity to normal cells. Differential targeting of CTP synthase 1 (CTPS1), sparing the CTPS2 isoenzyme, is a therapeutic strategy in lymphoid cancers, supported by human genetic studies, that can potentially avoid toxicity; however, CTPS2 activity may compensate in epithelial tumours. Loss of CTPS2 protein expression characterises 25% of solid tumours and is predicted to expose a synthetic lethal vulnerability to CTPS1 inhibition. Dencatistat (STP938) is a first in class oral CTPS1 inhibitor showing >1,300-fold selectivity over CTPS2. In preclinical studies, CTPS2 expression was confirmed as a key modulator of response to CTPS1 inhibition, and dencatistat induced tumour regression in an in vivo model of CTPS2 negative ovarian cancer. Study design: The study comprises a standard 3+3 phase 1a dose escalation design, in which intra-patient dose escalation is encouraged, followed by a phase 1b safety expansion. The dose escalation study is recruiting participants with high grade advanced tumours who have exhausted standard of care therapy (excluding haematological cancers, salivary gland tumours and low grade tumours of any tissue). In addition, participants with high grade serous ovarian cancer whose tumours lack expression of CTPS2 (per central laboratory testing by immunohistochemistry) are eligible for backfill into cleared cohorts during dose escalation. The recommended phase 2 dose (RP2D) will be nominated based on safety, tolerability, target engagement and early signs of clinical efficacy. The phase 1b safety expansion study will recruit participants with CTPS2 negative ovarian, lung or endometrial cancer who will receive treatment at the RP2D. Standard inclusion criteria apply; patients with ECOG performance score >2 (>1 for phase 1a in France) or active/symptomatic CNS metastases are not eligible. The primary objectives of the study are to evaluate the safety and tolerability of single agent dencatistat and to determine the RP2D for further development. Secondary objectives comprise evaluation of pharmacokinetic properties and preliminary clinical activity. Exploratory endpoints include evaluation of target engagement, molecular features associated with response, and determination of drug metabolites. The study opened to enrolment in the UK, France and USA in September 2024 and is currently in dose escalation (NCT06297525). The phase 1b study is expected to commence mid-2026 and will include additional centres in Spain. Citation Format: Donna M. Graham, David Sommerhalder, Douglas Orr, Rowan Miller, Neeharika Makani, David O'Malley, Ira Winer, Philip A. Beer, Karen Smith, Maureen Higgins, John R. Hawse, Xiyin Wang, Saravut J. Weroha, Christophe Massard, Patricia Roxburgh. Lack of CTPS2 expression exposes synthetic lethal vulnerability to selective CTPS1 inhibition: A phase 1 dose escalation study of dencatistat (STP938) with safety expansion in biomarker selected cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT075.

INTRODUCTION: Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC) are cholestatic disorders, which may be difficult to differentiate. Importantly, PSC is an untreatable progressive fibroinflammatory disease, whereas IgG4-SC responds to immunosuppression if recognized in a timely manner. This systematic review and meta-analysis aimed to identify and define the performance of clinical, biochemical, radiographic, and histologic features to differentiate between these 2 diseases. METHODS: A systematic search for comparative studies of IgG4-SC and PSC through November 2023 (with repeat evaluation for interval literature in December 2024) was performed and data extraction performed in duplicate. Pooled proportions, odds ratios, means, and standardized mean differences of pertinent diagnostic features were calculated using random-effects inverse-variance models. RESULTS: We identified 38 studies comparing patients with IgG4-SC and PSC. IgG4-SC patients were more likely to have pancreatic disease ( P < 0.001) but less likely to have inflammatory bowel disease ( P < 0.001) than those with PSC. Serum IgG4 was significantly higher in IgG4-SC ( P < 0.001), as anticipated. Radiographically, IgG4-SC demonstrated long distal strictures ( P = 0.02) and symmetric ductal thickening ( P < 0.001), whereas PSC showed a beaded appearance ( P = 0.038). With the exception of IgG4 staining, histologic features including periductal fibrosis were similar between these entities, although sample size was limited for these features. DISCUSSION: Our meta-analysis shows that IgG4-SC and PSC present with similar clinical and radiographic features and possibly comparable histology. A history of unusual pancreatitis and elevated IgG4 (serum or tissue) prompts assessment for more specific radiographic features which if present warrant a therapeutic treatment trial.

Background/Objectives: While doxorubicin (DOX) and trastuzumab (TRZ) improve overall survival in women with breast cancer, these two anti-cancer drugs increase the risk of developing heart failure. As a novel and largely unexplored approach, our aim was to evaluate whether the prophylactic use of the sodium-glucose co-transporter 2 inhibitor empagliflozin (EMPA), with and without the angiotensin converting enzyme inhibitor perindopril (PER), is cardioprotective in preventing DOX + TRZ-mediated cardiotoxicity. Methods: In a chronic in vivo murine model, female mice received prophylactic treatment with PER (3 mg/kg), EMPA (10 mg/kg), or EMPA + PER via oral gavage for a total of 3 weeks as a run-in period prior to weekly administration of DOX + TRZ (8 mg/kg and 3 mg/kg, respectively) intraperitoneally for an additional 3 weeks (total of 6 weeks). Results: In mice treated with DOX + TRZ, the left ventricular ejection fraction (LVEF) decreased from 75 ± 2% at baseline to 40 ± 4% at week 6. Prophylactic treatment with either PER, EMPA, or EMPA+PER improved LVEF to 58 ± 3%, 66 ± 3%, and 67 ± 4% at week 6, respectively (p < 0.05). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX + TRZ-treated mice. Prophylactic administration with PER, EMPA, or EMPA + PER, however, improved myofibril integrity at week 6 in mice receiving DOX + TRZ. Finally, although the Bax/Bcl-xL ratio was significantly elevated by 1.5-fold in mice treated with DOX + TRZ, this marker of apoptosis was attenuated by prophylactic treatment with either PER, EMPA, or EMPA + PER. Conclusions: Prophylactic administration of EMPA mitigated adverse cardiovascular remodeling in a chronic in vivo model of DOX + TRZ-mediated cardiotoxicity.