Browse Articles
Discover research articles across all indexed journals
Efficacy and safety of neoadjuvant therapy in resectable pancreatic cancer: Updated systematic review and meta-analysis of RCTs.
e16458 Background: The clinical value of neoadjuvant therapy (NAT) for resectable pancreatic ductal adenocarcinoma remains debated. While NAT may improve pathologic endpoints such as margin-negative resection, its impact on perioperative safety and survival outcomes is uncertain, and newer randomized evidence has emerged. We performed an updated systematic review and meta-analysis of randomized controlled trials comparing NAT with upfront surgery to reassess efficacy and safety using contemporary data. Methods: We identified randomized controlled trials enrolling adults with resectable pancreatic cancer treated with NAT versus upfront surgery. Outcomes included major postoperative complications, nodal status at resection (N0), R0 resection margin, overall survival (OS), and progression-free survival (PFS). Risk ratios (RRs) were pooled for binary outcomes and hazard ratios (HRs) for time-to-event outcomes using random-effects models. Heterogeneity used I²; bias assessed via funnel plots. Results: Five trials contributed to major complications; NAT did not significantly increase major postoperative complications versus upfront surgery (RR 0.94, 95% CI 0.61–1.47; I² = 48.7%). Three studies reported nodal status; NAT showed a non-significant increase in N0 resection (RR 1.30, 95% CI 0.85–1.99; I² = 32.7%). Six studies reported margin status; NAT significantly improved R0 resection rates (RR 1.30, 95% CI 1.10–1.55; I² = 55.0%). For survival, NAT did not significantly improve OS (HR 0.87, 95% CI 0.67–1.11; I² = 43.9%) or PFS (HR 0.94, 95% CI 0.52–1.70; I² = 81.9%). Funnel plots did not suggest major publication bias, and leave-one-out analyses supported stability of pooled estimates. Conclusions: NAT improves R0 resection rates without increasing major complications, but survival benefits remain uncertain, particularly given heterogeneity and limited PFS data.
Nivolumab and Ipilimumab (NIVO IPI) as first-line (1L) treatment for patients with metastatic renal-cell carcinoma (mRCC): A real-world benchmarking analysis from the International mRCC Database Consortium (IMDC).
4549 Background: NIVO IPI has demonstrated durable overall survival (OS) benefit with long-term follow-up in patients with mRCC. Real world outcomes and benchmarks for subgroups as well as conditional survival (CS) are required in the real world. Methods: Patients with mRCC treated with 1L NIVO IPI from the IMDC were analyzed, including various subgroups of interest. Outcomes reported will be objective response rates (ORR), median overall survival (mOS) and conditional survival (CS). CS is defined as survival among patients who were alive and on treatment after the requisite 3-month interval landmarks, as estimated using the Kaplan–Meier method. CS was calculated at landmarks while patients were still on treatment, and at landmarks regardless of treatment. Results: 2115 patients received 1L NIVO IPI; 148/1042/549 were categorized by IMDC risk group as favorable/intermediate/poor risk; 90% of patients had clear-cell histology, 32% had bone metastases, and 14% had sarcomatoid features. Median follow-up was 34 months (m); median duration of treatment was 4.8 m, and median time to next treatment was 11.2 m. 66% of patients received second-line treatment. ORR was 39.5% (8.3% CR) with primary progression seen in 28 mOS was longer in clear cell (47.8 m) than in non–clear cell (26.3 m) (p<0.001). mOS was significantly shorter in patients with sarcomatoid features (34.2 vs 47.0 m; p=0.02 mOS was also different by IMDC risk group: 53.3 m for favorable, 45.7 m for intermediate and 18.8 m for poor risk patients (p<0.001); and by response: 4-year was OS of 93.6% for patients with CR, 60.1% for PR, 43.6% for SD and 15.4% for patients with PD (p<0.001). CS during 1L NIVO IPI is detailed in Table 1 with greater survival with each successive landmark. Conclusions: We provide real-world benchmark survival results for patients with mRCC treated with 1L NIVO IPI, including subgroup analysis regarding the presence of sarcomatoid features, IMDC risk group, and ORR. Conditional survival provides a key understanding of a patient’s prognosis after having been on therapy or been alive for at certain time points. This is essential information for patient counselling and clinical trial design. Conditional survival (CS) through time landmarks, either on treatment or regardless of treatment. Landmark(mo) CS on NIVO IPI (N) CS on treatment If patient is still on therapy past landmarkmo (95% CI) CS (N) regardless of treatment continuation CS regardless of treatment continuationIf patient survived past landmarkmo (95% CI) 0 1965 41.4 (37.7–45.3) 2038 40.2 (36.7–44.5) 3 1129 54.5 (49.7–67.3) 1826 44.6 (40.7–49.4) 6 822 93.0 (60.9–NR) 1626 49.2 (44.6–53.5) 9 627 93.0 (84.2–NR) 1436 53.5 (49.2–59.2) 12 483 114 (84.2–NR) 1276 56.9 (51.1–66.8) 24 210 NR (NR–NR) 805 93.0 (72.8–NR) 36 101 NR (NR–NR) 519 NR (93.0–NR)
A phase 1 study of PHST001, an anti-CD24 monoclonal antibody, in adult patients with advanced relapsed and/or refractory solid tumors.
TPS2685 Background: Macrophages are the most abundant immune cells in tumors and can directly phagocytose tumor cells and promote broad anti-tumor immunity. However, phagocytosis can be inhibited by macrophage checkpoints, also known as ‘don’t eat me’ signals. One such checkpoint is the immunomodulatory protein CD24 that is overexpressed in many tumors and associated with poor clinical prognosis. CD24 inhibits macrophage phagocytosis of tumor cells via binding to Siglec-10 on macrophages. PHST001 is a high affinity anti-CD24 IgG4 antibody that blocks multiple glycoforms of CD24 and induces macrophage phagocytosis of tumor cells in a wide range of preclinical models. In addition, PHST001 improves tumor control and survival in murine models when combined with multiple chemotherapies as chemotherapy-induced tumor cell stress may improve macrophage phagocytosis of tumor cells when combined with CD24 blockade. Thus, CD24 blockade has potential as monotherapy and in combination with other cancer therapies to enhance tumor cell phagocytosis and improve patient survival. Methods: PHST001-101 is an open-label, first-in-human, Phase 1 study in patients ≥ 18 years of age with advanced relapsed and/or refractory solid tumors (NCT06840886). In Phase 1a, patients receive escalating doses of PHST001 administered Q3W as an IV infusion at one of nine dose levels. Phase 1b combines PHST001 with chemotherapy in patients with ovarian cancer, endometrial cancer, or cholangiocarcinoma in safety run-in groups and tumor-specific expansion cohorts. Key inclusion criteria include age ≥ 18 years, evidence of measurable disease, an ECOG performance status of 0 or 1, and adequate organ function. Key exclusion criteria include a diagnosis of immunodeficiency, active CNS disease, or active autoimmune disease. The primary objective is to assess the safety and tolerability of PHST001 as monotherapy and in combination with chemotherapy, and to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy. Secondary objectives include assessing antitumor activity of monotherapy and pharmacokinetics (PK) of PHST001. Exploratory objectives include evaluating the relationship between PK and pharmacodynamics (receptor occupancy, cytokine profiling, changes in ctDNA, and immune cell subsets in the tumor), immunogenicity of PHST001, antitumor activity in patients treated beyond progression, and patient-reported outcomes. The study enrolled the first patient treated in April 2025 and is currently enrolling patients in Phase 1a at Dose Level 8 (18 mg/kg) with no DLTs to date. Enrollment in Phase 1b is anticipated to begin in early 2026. Clinical trial information: NCT06840886 .
Treatment patterns, acute-care utilization, and clinical outcomes among patients with lung cancer and sickle cell disease: A multicenter propensity score–matched real-world analysis.
e20706 Background: Sickle cell disease (SCD) is associated with chronic organ dysfunction, heightened thrombo inflammatory risk, and frequent acute-care utilization. Individuals with SCD who develop lung cancer represent a clinically vulnerable and understudied population, with limited real-world evidence on treatment patterns and inpatient outcomes. We evaluated acute-care utilization and short-term clinical outcomes among individuals with lung cancer with and without coexisting SCD using a large multicenter electronic health record database. Methods: We conducted a retrospective cohort study using the TriNetX Analytics Network, a federated, multicenter platform that aggregates de-identified electronic health record data. Adult individuals with lung cancer were stratified by the presence or absence of SCD. To reduce confounding, individuals with lung cancer and SCD were propensity score–matched 1:1 to individuals without SCD using logistic regression incorporating demographics, baseline comorbidities, and socioeconomic risk factors. Nearest-neighbor matching without replacement was performed using a caliper width of 0.1 pooled standard deviations, with balance assessed using standardized mean differences. Primary outcomes included in-hospital mortality and intensive care unit (ICU) admission. Secondary outcomes included respiratory failure requiring intubation and venous thromboembolism. Results: After matching, 291 individuals with lung cancer and SCD were compared with 291 matched individuals without SCD, achieving excellent covariate balance (all standardized mean differences < 0.02). Prior to matching, individuals with SCD had a higher burden of chronic comorbidities, including chronic kidney disease, heart failure, cerebrovascular disease, liver disease, and chronic obstructive pulmonary disease. Following matching, in-hospital mortality was similar between individuals with and without SCD (24.7% vs 23.4%; effect estimate 1.07, 95% CI 0.77–1.49; p = 0.63). ICU admission rates did not differ (17.2% vs 15.5%; 1.14, 95% CI 0.76–1.70; p = 0.83), nor did respiratory failure requiring intubation (4.5% vs 5.2%; 0.89, 95% CI 0.42–1.88). Venous thromboembolism was numerically higher among individuals with SCD (15.5% vs 11.7%; 1.42, 95% CI 0.91–2.22), without statistical significance. Conclusions: Among hospitalized individuals with lung cancer, coexisting sickle cell disease was not associated with increased in-hospital mortality, ICU admission, or respiratory failure after propensity score matching, despite a substantially higher baseline comorbidity burden. A numerically higher rate of thromboembolic events suggests a potential area for targeted risk mitigation in this vulnerable population.
Central nervous system metastases in hereditary breast cancer according to germline pathogenic variants: A real-world cohort study.
2035 Background: Hereditary breast cancer (HBC) accounts for approximately 5–10% of cases and involves pathogenic germline variants (PGVs) beyond BRCA1/2 . While metastatic patterns differ by tumor subtype, data on central nervous system (CNS) metastases according to germline genetics remain scarce. We evaluated the incidence, clinical characteristics and survival outcomes of CNS metastases in metastatic according to PGV subgroup. Methods: A cohort retrospective study included patients aged ≥18 years with invasive or microinvasive breast cancer and confirmed PGVs treated between 2019 and 2025 at A.C. Camargo Cancer Center. Clinical, histopathologic, and molecular data were analyzed in R. Associations were assessed using chi-square or Kruskal–Wallis tests. Survival outcomes were estimated by Kaplan–Meier. CNS-related progression-free survival (CNS-PFS) was defined from treatment initiation after CNS metastasis to intracranial progression or death. Overall survival after CNS metastasis (OS post-CNS) was defined from CNS metastasis to death. Median survival times with 95% confidence intervals (CIs) were reported. Results: Among 1,353 individuals evaluated, 463 patients with pathogenic germline variants (PGVs) were included. Median age at diagnosis was 43.7 years, and 99.6% were women. The most frequent PGVs were BRCA1 (32.0%), BRCA2 (22.2%), and TP53 (12.1%). BRCA1 carriers were diagnosed earlier than other genotypes (p = 0.0005). CNS metastases occurred in 21 patients (4.5%), mainly among BRCA -associated PGVs and TP53 , with additional cases in PALB2 , ATM , and RAD -related variants; none occurred in CHEK2 , FANCA , or Lynch-associated variants. CNS involvement was mainly parenchymal-only (71.4%), with meningeal-only (19.0%) or combined disease (9.5%). Lesions were supratentorial-only in 47.1% and both supra- and infratentorial in 47.1%. Diagnosis was symptom-driven in 70.0%. Single CNS metastasis occurred in 38.9%, and local therapy alone was most commonly used (66.7%). No statistically significant differences in CNS metastatic patterns were observed across PGV subgroups (p > 0.05). Median OS after CNS diagnosis was 14 months (95% CI, 5–NR), and median CNS-PFS was 17 months (95% CI, 7–NR). Conclusions: In metastatic HBC, CNS metastases are uncommon but preferentially occur among patients harboring BRCA -associated and TP53 pathogenic germline variants. Germline genetics may contribute to distinct metastatic phenotypes and support risk-adapted CNS surveillance strategies and therapeutic strategies in metastatic HBC.
Impact of concomitant <i>NPM1</i> mutations on genomic and transcriptomic patterns of <i>PTPN11</i> -mutant myeloid leukemias.
6532 Background: PTPN11 mutations are associated with worse treatment outcomes in acute myeloid leukemia (AML) and frequently co-occur with NPM1 mutations. However, the impact of concurrent NPM1 mutations in PTPN11 mut myeloid leukemia is not well understood. This work aims to 1) characterize genomic features of a single-center cohort of patients with PTPN11 mut /NPM1 wt and PTPN11 mut / NPM1 mut -myeloid leukemia and 2) assess associated transcriptomic patterns. Methods: Patients with myeloid leukemia with PTPN11 and/or NPM1 mutations observed in blood (PB) or bone marrow (BM) were identified from the UMass Leukemia Registry. Next-generation sequencing (NGS) data were annotated for co-occurring variants and cytogenetic abnormalities. RNA-seq data from PB and BM samples from the Beat AML 1.0 trial were accessed via The Cancer Genome Atlas. Sample IDs with PTPN11 mut , NPM1 mut and PTPN11 mut /NPM1 mut were identified using the Vizome platform. High-throughput analysis of these samples and NPM1/PTPN11 wt was then performed using DESeq2. Results: 107 patients with myeloid leukemias at UMass Cancer Center harboring PTPN11 mutations (n = 34) or NPM1 mutations (n=74) were identified, 14 of whom had both. Subgroup analysis of chromosomal maps of PTPN11 mut /NPM1 mut cohort and PTPN11 mut / NPM1 wt cohort showed that the PTPN11 mut / NPM1 wt group had a higher cytogenetic abnormality burden compared to the PTPN11 mut /NPM1 mut group, demonstrating 18 observations of 12 distinct abnormalities compared to 5 observations of 3 distinct abnormalities, respectively. Analysis of RNA-seq from BM tissue of PTPN11 mut /NPM1 wt AML (n = 6) from the Beat AML 1.0 dataset revealed only 22 differentially expressed genes compared to PTPN11 wt /NPM1 wt samples. Of these, 12 were mitigated in the PTPN11 mut /NPM1 mut (n = 9) group. This trend was less pronounced in analysis of PB tissue. However, review of 20 most differentially expressed genes of both BM and PB in the PTPN11 mut /NPM1 wt group revealed many changes in long intergenic non-coding RNAs (lincRNAs). Conclusions: Genomic analysis of PTPN11 mut /NPM1 wt BM and PB highlighted widespread cytogenetic heterogeneity compared to the PTPN11 mut NPM1 mut subgroup. RNAseq analysis of PTPN11 mut BM and PB revealed significant differential expression in multiple lincRNAs, particularly in BM. These changes were mitigated in the double mutant group. Larger studies are needed to validate these findings and investigate whether presence of subtle regulatory shifts serve as a driving factor in the poor outcomes underlying PTPN11 mut AML. Further chromatin accessibility profiling studies may help elucidate the regulatory mechanisms driving these transcriptomic changes.
Activating MPN patients through empowering, patient-centered education.
6577 Background: Patients living with myeloproliferative neoplasms (MPNs) face complex disease management, evolving treatment options, and barriers to accessing reliable, culturally relevant information. These challenges disproportionately affect underrepresented populations, including Black, Latinx, Indigenous, rural, LGBTQIA+, and veteran communities. The [ACT]IVATED MPN program was developed to improve health literacy, patient activation, and self-advocacy among individuals newly diagnosed with MPNs, while remaining relevant across all stages of disease. Methods: The [ACT]IVATED MPN program delivers expert-verified, multimedia educational content designed to support patient and care partner engagement in care. Program components include multilingual expert interview videos, real-world patient vignettes, downloadable health literacy tools, and a comprehensive resource guide available in English and Spanish. Content is distributed digitally and through culturally trusted community organizations to increase reach among underserved populations. Program reach and impact are assessed through digital engagement analytics and post-program participant feedback. Results: To date, the [ACT]IVATED MPN program has reached over 5,000 patients and care partners. Preliminary program evaluation data indicate that 100% rated their overall experience as positive or somewhat positive, with 83.3% reporting a positive experience. Following participation, 90.9% of respondents agreed or strongly agreed that the program increased their understanding of MPNs. Indicators of patient activation were high, with 100% of participants reporting increased confidence to speak up with questions about their care and 95.7% reporting greater knowledge and confidence to take an active role in treatment decisions. Conclusions: The [ACT]IVATED MPN program demonstrates the feasibility and value of a patient-centered, equity-focused education model in supporting health literacy, self-advocacy, and engagement in care among individuals living with MPNs. Scalable, multilingual educational interventions may complement clinical care by promoting shared decision-making and reducing disparities in access to MPN-related information and resources. Hibbard, J. H., & Greene, J. (2013). What the evidence shows about patient activation: Better health outcomes and care experiences; fewer data on costs. Health Affairs, 32 (2), 207–214. https://doi.org/10.1377/hlthaff.2012.1061.
Uncertainty-aware AI triage for LUAD histologic subtyping: Flagging cases for expert review.
e20018 Background: AI-assisted histological subtyping of lung adenocarcinoma (LUAD) shows promise but imperfect accuracy in the setting of histologic heterogeneity raises concerns about clinical deployment. Current AI systems provide predictions without indicating confidence, leaving clinicians unable to identify cases requiring expert review. Misclassification of high-risk patterns (e.g., solid and micropapillary) can affect risk stratification. We developed an uncertainty-aware triage framework that identifies difficult cases for pathologist review while allowing confident AI predictions to proceed, optimizing workflow efficiency. Methods: We analyzed 143 resected LUAD whole slide images with five predominant subtypes: acinar (n = 60, 42%), solid (n = 55, 38%), lepidic (n = 16, 11%), micropapillary (n = 10, 7%), papillary (n = 5, 4%). Two Attention-Based Multiple Instance Learning (ABMIL) classifiers were trained on identical 5-fold cross-validation splits using Virchow2 and concatenated (Virchow2/UNI2/CONCH/GigaPath) embeddings. Prediction uncertainty was quantified via Monte Carlo dropout (T = 30 stochastic forward passes) with entropy of mean probabilities as the uncertainty measure. Multi-model disagreement was computed as a binary indicator when classifier predictions differed. A fixed-weight triage score (0.5× entropy + 0.5×disagreement) ranked cases for referral to pathologist review. Performance was evaluated at 10%, 20%, and 30% referral thresholds on non-referred cases. Results: For five-class LUAD predominant-pattern subtyping, baseline balanced accuracy was 65.2% with macro-F1 of 0.65. Model disagreement strongly predicted classification errors: accuracy was 81.7% when models agreed versus only 44.1% when models disagreed. Uncertainty also tracked errors: entropy was higher in incorrect than correct predictions (0.60 (95% CI 0.51–0.68) vs 0.83 (95% CI 0.71–0.94)). Using the combined uncertainty–disagreement triage score, performance improved on non-referred cases (Table 1). At 30% referral, balanced accuracy increased by 15.6 percentage points. Conclusions: This framework enables risk-stratified AI deployment where the system self-identifies cases requiring expert review. In clinical workflow, the system would prioritize 20–30% of uncertain cases for focused review, while remaining cases would still undergo pathologist sign-out with AI decision support. This addresses a critical barrier to clinical AI adoption: the inability to distinguish reliable from unreliable predictions. The approach transforms AI from an autonomous classifier into an intelligent triage system that appropriately allocates expert pathologist attention to diagnostically challenging cases. Triage performance by referral rat. Referral % Balanced Acc Macro-F1 Cases Retained 0% 65.2% 0.65 143 10% 68.6% 0.66 129 20% 74.4% 0.76 114 30% 80.8% ± 10.1% 0.80 ± 0.09 100
Improving internal medicine residents’ confidence in oncology goals-of-care conversations.
TPS9047 Background: Internal medicine (IM) residents frequently participate in goals-of-care (GOC) discussions for patients with cancer, yet formal training in oncology-specific serious illness communication remains limited across residency programs. As a result, residents often rely on oncology or palliative care teams to lead these conversations, which may delay timely GOC discussions and subsequent care decisions. Prior educational interventions in serious illness communication have demonstrated improvements in resident confidence; however, oncology-specific GOC training tailored to IM residents is underrepresented. We aim to address this educational gap through the development of a brief, case-based curriculum focused on oncology-related GOC conversations. The objective is to evaluate whether a brief, case-based educational intervention improves IM residents’ confidence and knowledge in conducting oncology-related goals-of-care discussions. Methods: This is a pilot educational intervention involving IM residents (postgraduate years 1–3) at a large academic residency program. The intervention consists of a 60-minute, case-based session delivered during a scheduled conference. Content focuses on key oncology GOC topics, including prognostic uncertainty, transitions to comfort-focused care, transitions to palliative-intent treatment, and use of structured communication frameworks. Participants will complete pre- and post-intervention surveys assessing self-reported confidence in conducting GOC discussions, comfort discussing prognosis and treatment transitions, and knowledge using two brief case-based vignettes. Pre- and post-intervention survey responses will be compared using paired t-tests. Qualitative feedback will be collected and analyzed thematically.
Treatment-emergent thyroid disorders and outcomes of first-line pembrolizumab plus chemotherapy in metastatic triple-negative breast cancer: A real-world study.
e13125 Background: Pembrolizumab+chemotherapy (P+C) is a standard first-line treatment for PD-L1 positive metastatic triple-negative breast cancer (mTNBC). Thyroid dysfunction is a common immune-related adverse event (irAE) of PD-1 blockade and has been associated with improved outcomes in other malignancies, particularly non–small cell lung cancer and melanoma. We evaluated the association between treatment-emergent thyroid dysfunction and real-world effectiveness of first-line P+C in mTNBC. Methods: CEBCC-101 was a retrospective, multicenter real-world study including 178 patients treated with first-line P+C for mTNBC across 20 centers in Poland, the Czech Republic and Slovakia. Treatment-emergent thyroid dysfunction was the primary exposure of interest. Endpoints included progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Survival was estimated using Kaplan–Meier methods and compared with the log-rank test; categorical outcomes were compared using chi-squared or Fisher’s exact tests. A p value < 0.05 was considered statistically significant. Results: Treatment-related thyroid dysfunction occurred in 34 patients (19.1%), including hypothyroidism in 28 (15.7%) and hyperthyroidism in 6 (3.4%). The median onset was cycle 4 (range 1-10). All events were grade 1 (n = 7, 21%) or grade 2 (n = 27, 79%). Median OS was 20.4 months in patients without thyroid dysfunction versus 19.5 months in those with any thyroid dysfunction (log rank p = 0.863), and median PFS was 8.4 versus 9.0 months, respectively (p = 0.567). ORR did not differ between groups (53.47% vs 58.82%, p = 0.61). Exploratory analyses by thyroid dysfunction type, grade and time of onset showed no statistically significant differences in survival or response outcomes. Conclusions: The real-world frequency of thyroid dysfunction in this study closely aligned with data from KEYNOTE-355 trial. Although thyroid irAEs have been linked to improved outcomes in several malignancies, evidence in advanced breast cancer is limited. Prior data suggest a positive association between pembrolizumab-related thyrotoxicosis and pathologic complete response in early-stage TNBC treated with neoadjuvant P+C. In contrast, in this real-world cohort of mTNBC, treatment-emergent thyroid dysfunction was not associated with better outcomes. These findings indicate that, in first-line P+C for mTNBC, thyroid dysfunction should be interpreted with caution and should not serve as a robust on-treatment surrogate of benefit. Since irAEs are time-dependent exposures, future confirmatory analyses should address the potential impact of event timing on outcome estimates.
Inequality of access to breast reconstruction in Brazil: An ecological study.
e13742 Background: Breast reconstruction (BR) is an important step in breast cancer treatment, and several authors have reported disparities in its access across different populations. Brazil has a universal public healthcare system, and 25% of the population has access to a private system through healthcare insurance. In this study, we conducted an ecological analysis to identify national and regional discrepancies in access to breast reconstruction in Brazil, from both private and public perspectives. Methods: The number of mastectomies, breast conserving surgeries (BCS), and BR performed between 2015 and 2022 in the private and public health care systems was obtained from publicly available registries and was used to determine each procedure's incidence, according to the covered population of each system. A regression analysis was applied to estimate the differences in relative risks of having access to the surgery in the public and private. Results: In 8-year, 400,566 mastectomies or BCS and 267,781 BRs were performed on a population of over 100 million women. 58.8% of all BRs performed were under the private perspective. The risk of undergoing a BR procedure relative to the risk of undergoing a BCS or a mastectomy varied from 1.05 to 1.35 in the private perspective, whereas from the public perspective, it varied between 0.24 and 0.4 (Table 1). Overall, a woman who underwent a breast oncological procedure was 3 to 5 times more likely to undergo a BR if she was covered by private health care insurance. Conclusions: Our data suggests that in low resources constrained healthcare systems, women that survive breast cancer have limited access to BR, and there is an important disparity in access to BR between people who has access to private insurance and who don’t in Brazil. Risk of receiving a BR procedure relative to the risk of receiving a breast oncological procedure, according to year and system of coverage. Year Private Public 2015 1,12 0,24 2016 1,05 0,25 2017 1,11 0,33 2018 1,12 0,37 2019 1,21 0,37 2020 1,20 0,36 2021 1,30 0,41 2022 1,35 0,40
Cardiovascular disease incidence in women with early-onset breast cancer.
12018 Background: Early-onset breast cancer (BC) before age 40 is generally associated with advanced stage at diagnosis and worse outcomes. Improvements in detection and treatment have led to reduction in BC mortality. Cardiovascular disease (CVD) is the leading cause of non-BC death in women with BC, but younger women are traditionally considered to be at lower risk for CVD. Given the limited data on CVD in early-onset BC, this study evaluates incident CVD in women younger than age 40 in the Pathways Heart Study. Methods: The Pathways Heart Study (R01/U01CA214057) is an ongoing, prospective cohort study including 14,402 women diagnosed with BC at KPNC from 2005-2013 and followed through 2021. In this study, eligible BC cases were women age 18-39 years at time of stage I-III BC diagnosis without pre-existing CVD. Cases were matched 1:5 to controls without BC on age at diagnosis and race/ethnicity. Cancer treatment, CVD (ischemic heart disease, heart failure, cardiomyopathy, stroke) and cardiometabolic risk factors (hypertension, diabetes, hyperlipidemia) were extracted from electronic health records. Cumulative incidence rates (CIR) were calculated as number of incident CVD events divided by total person-time at risk and expressed per 1,000 person-years. Results: A total of 535 women with early-onset BC were matched to 2,651 controls. Mean age was 35.1 years with mean follow up of 7.8 years. Overall, cases had a higher CIR of CVD (3.40 per 1,000 person-years (PY)) than controls (1.37/1000 PY). CIRs of hypertension, dyslipidemia, and diabetes were higher in cases compared to controls (14.89, 12.14, and 9.74/1000 PY, respectively). Among BC types and stage, women with hormone receptor-positive HER2-positive and stage III BC had the highest CVD CIRs (7.14 and 5.65/1000 PY, respectively). Women who received chemotherapy with anthracyclines and those who received endocrine therapy had higher CVD CIRs compared with those who did not, while there were no differences by receipt of radiation therapy (Table 1). Conclusions: Although the absolute incidence of CVD was low in BC patients younger than 40 years, these patients experienced a >2 fold higher CVD rate compared with matched controls. Patients treated with anthracyclines and endocrine therapy had higher CIR of CVD compared with those not treated. Future analyses will include formal comparison through survival and regression models of incident CVD and cardiometabolic disease in women with early-onset BC, accounting for confounders, including treatments received, education, income, and comorbidities. Cumulative incidence rates (CIR) of cardiovascular disease (CVD) in women age <40 years in the Pathways Heart Study. CIR of CVD per 1,000 person-years (95% CI) Chemotherapy With Anthracycline 4.15 (2.07, 7.43) Without Anthracycline 3.39 (0.70, 9.89) None 0.00 (0.00, 6.31) Endocrine Therapy Yes 3.77 (1.88, 6.74) No 2.50 (0.51, 7.29) Radiation Therapy Yes 3.40 (1.55, 6.45) No 3.40 (1.10, 7.93)
Mapping the exhausted and tolerized myeloid populations in the glioblastoma tumor microenvironment.
2066 Background: Glioblastoma (GBM) is a highly malignant brain tumor characterized by an immunosuppressive microenvironment and rapid development of therapeutic resistance. In GBM, myeloid cells can comprise 30–50% of the tumor and critically regulate its immune microenvironment. Evidence from aging and CNS diseases suggests that microglia can adopt dysfunctional states of exhaustion and tolerance that extend beyond the M1/M2 paradigm, thus prompting us to investigate whether these phenotypes contribute to immune escape and progression of GBM. Methods: Paired RNA-seq of tumor specimens from newly diagnosed and recurrent GBM patients (n=14) was used to examine aging-related gene expression during treatment and progression. Open-access human glioma single-cell RNA-seq data (GSE182109) were analyzed to characterize exhaustion and tolerance across macrophage subpopulations based on molecular/metabolic signatures. Results: Patient tumor RNA-Seq revealed that the aging-related TREM2-APOE axis is present in recurrent GBM, suggesting accelerated brain aging. Single-cell RNA-seq identified nine myeloid clusters, including four microglial states (homeostatic-, activated-, AP-, and a-microglia) and two macrophage populations (anti-inflammatory and immunosuppressive). We found that AP-microglia showed disease-associated activation, with high CD45/CD11C/TREM2 expression and concurrent upregulation of the exhaustion markers PD-L1 and CD38. Moreover, microglial activation-related signaling in AP-microglia includes increased STAT1/2-IRF9 signaling, which can promote immunosuppression by inducing PD-L1. On the other hand, a-microglia is unique in its high expression of activation-restraining and tolerance markers, such as SPRY/P2RY13, rather than the classic microglial marker TMEM119/P2RY12. Both AP-microglia and a-microglia are shown to lose expression of the inflammatory cytokines TNF-α and IL-1β, consistent with the characteristics of exhausted and tolerized microglia. Unlike resident microglia, the immunosuppressive macrophage cluster exhibits a monocyte-tolerized phenotype, with downregulated FABP4 and increased SOD2, CLEC4E, and SLC2A6. It also shows a similar panel of LPS-induced monocyte exhaustion with TLR4/MyD88/SRC and STAT3/IL-10 upregulation. Conclusions: Our analysis indicates that AP-microglia are exhausted and a-microglia are tolerized in GBM, with shared markers of dysfunction across macrophages linking myeloid impairment to immune suppression and treatment-associated brain aging. These findings implicate myeloid exhaustion in GBM immune escape and identify potential therapeutic targets.
Manipulating Heavy Halogenated Asymmetric Terminals Affords Regio‐Regular Hetero‐Fluorinated/Brominated Dual Asymmetric Acceptor With a Binary Photovoltaic Efficiency of 20.3%
ABSTRACT Asymmetric terminal engineering of small molecular acceptors (SMAs) is one promising approach to efficient organic solar cells (OSCs), while synthesizing regio‐regular dual asymmetric terminal‐based SMAs for boosting binary OSCs remains a critical challenge, and heavier halogenated effects are still underexplored. Herein, three global asymmetric SMAs ( AY2F‐ClF , AY2F‐BrF , and AY2F‐IF ) and symmetric SY‐2(FBr) , featuring one or two regio‐regular, locally asymmetric hetero‐dihalogenated terminals with successively heavier halogens, were successfully synthesized by applying the dual asymmetric terminal strategy. Asymmetric AY2F‐BrF presents a compact 3D molecular packing with the strongest and most multidimensional electronic coupling, which promotes exciton delocalization, and enhanced crystallinity and electron mobility in pure film. Remarkably, D18:AY2F‐BrF OSCs deliver a champion binary PCE of 20.26% with energy loss ( E loss ) of 0.512 eV, surpassing the PCEs of AY2F‐ClF (19.74%), AY2F‐IF (19.15%), and SY‐2(FBr) (19.40%)‐based OSCs, setting a new record for asymmetric terminal SMAs‐based binary BHJ‐OSCs, which is attributed to the optimized phase separation morphology and enhanced and compact crystallinity and faster charge transfer and transport. Our innovative work demonstrates that integrating global asymmetric terminal molecular engineering with a regioisomer‐free hetero‐fluorinated/brominated terminal strategy provides an ingenious dual asymmetric terminal strategy for achieving champion PCE and suppressed E loss of binary OSCs incorporating asymmetric terminal‐based SMAs.
Spin‐Orbit Torque Induced by Switchable Crystal Inversion Symmetry Breaking
ABSTRACT Effective utilization and manipulation of spin‐orbit torque (SOT) is crucial for developing low‐power spintronic devices. Inducing additional inversion symmetry breaking (ISB) can manipulate the Rashba spin splitting and thus control the SOT generation efficiency. However, previous works mainly focus on spatial ISB at the interface introduced by the heterostructure. Effective method to introduce crystal ISB and how it impacts the SOT efficiency remains elusive. Here, we report an exotic crystal ISB in SrRuO 3 (SRO) that can be reversibly manipulated by the ferroelectric (FE) polarization of the adjacent FE material. Scanning transmission electron microscopy reveals that this crystal ISB is a novel crystal distortion, i.e., c / a crystal ratio change, induced by the Ru cation's off‐center displacement within the electrostatic screening depth due to the FE field. By electrical harmonic measurement, we reveal that the existence of this crystal ISB can dramatically enhance the SOT efficiency in the SRO layer by more than 60%. Our work provides an alternative to design highly efficient SOT source layer, paving the way toward low‐power spintronics.
Early risk stratification for sarcopenia in a pan-cancer cohort using quantile regression forests on handgrip strength.
e13585 Background: Sarcopenia, characterized by loss of muscle mass, strength, and physical function, is associated with poorer oncologic outcomes, treatment intolerance, and reduced quality of life. Handgrip strength (HGS) is a low-cost, scalable screening tool, yet oncology-specific reference standards are lacking. We evaluated a quantile regression forest (QRF) model to enable individualized, percentile-based risk stratification for low HGS in patients with solid tumors, aiming at early identification of patients at risk of sarcopenia rather than diagnosis of established disease. Methods: Eligible participants were cancer patients referring to Radio-Chemotherapy service at Fondazione Policlinico Gemelli in Rome. Data collection included demographic characteristics, anthropometric measures, cancer type, and handgrip strength. All variables are collected at baseline and at predefined follow-up visits. Median and interquartile range (IQR) were reported as summary statistics. Quantile regression forest (QRF) algorithm was applied on this sample and descriptive analysis was performed based on QRF findings. Results: Data from 174 patients were included in this analysis. Median age was 61 (IQR 51-68), a total of 127 patients were females (73%) and 47 (27%) males. 70 patients (40%) were aged 65 years or older. The three most frequent malignancies were breast (63, 36%), gynecological (35, 20%) and colorectal cancers (30, 17%). Median handgrip strength in females was 20 kg (16.0-25.0) and 31 kg for males (24.0-40.0). Applying QRF, data showed that a total of 94 subjects (54%) performing handgrip strength fell below their 25 th quantile prediction, and a total of 62 subjects fell below their 10 th predicted quantile. As for the tumor type, 51% of breast patients were under their 25 th quantile and 39% below their 10 th quantile, while gynecologic cancers showed 60% of patients below their 25 th quantile and 23% under their 10 th quantile. In colorectal cancer, 53.3% of patients fell below their 25 th predicted quantile and 30% showed handgrip strength below their 10 th quantile. Notably the median difference between the 50 th predicted percentile and the actual value was -3.8 Kg (-8.47 to -0.40 kg). A total of 134 subjects were identified with a negative difference between the actual handgrip and their predicted 50 th percentile. Conclusions: QRF-based, percentile-referenced modeling of HGS provides individualized, scalable risk stratification to flag cancer patients at risk of functional decline and sarcopenia, potentially enabling earlier supportive interventions (targeted exercise, nutritional optimization, and geriatric assessment in older adults) before overt sarcopenia develops. Ongoing cohort expansion and longitudinal follow-up will assess associations with toxicity, treatment modification, and clinical outcomes.
IvoLoC: A phase II trial of ivonescimab (IVO) in endocrine-refractory hormone receptor (HR)–positive or triple-negative (TN) metastatic invasive lobular carcinoma (mILC).
TPS1166 Background: ILC accounts for approximately 10–15% of breast cancers and is predominantly hormone receptor–positive (HR+)/HER2–. Patients with endocrine-refractory mILC have poor outcomes, with median progression-free survival (PFS) of less than three months following standard therapies. ILC is biologically distinct from invasive ductal carcinoma, with unique tumor microenvironmental features. Molecular profiling of primary untreated ILC has demonstrated marked heterogeneity, including immune-enriched (IE) and highly vascularized (HV) molecular functional portraits associated with PD-1/PD-L1 signaling and VEGF pathway activation. IVO is a novel bispecific antibody targeting PD-1 and VEGF, designed to enhance antitumor immunity while inhibiting angiogenesis. We hypothesize that dual immune and vascular targeting will improve clinical outcomes in patients with endocrine-refractory HR+/HER2– or TN mILC. Methods: Trial Design: IvoLoC (NCT07229417) is a single-center, open-label, phase II study conducted at The University of Texas MD Anderson Cancer Center. Eligible patients include those with HR+/HER2– mILC with progression on prior endocrine therapy, including combinations with CDK4/6, PI3K, AKT, and/or mTOR inhibitors, as well as patients with TN mILC. Patients may have received any number of prior endocrine-based regimens but no more than two prior cytotoxic therapies, including antibody–drug conjugates, in the metastatic setting. IVO is administered intravenously at 20 mg/kg every three weeks until disease progression or unacceptable toxicity. Radiographic assessments are performed every 9 weeks and evaluated per RECIST v1.1. Endpoints: The primary endpoint is 6-month PFS. Secondary endpoints include 12-month PFS, median PFS, objective response rate, disease control rate, duration of response, overall survival, and safety. Exploratory objectives include correlation of outcomes with molecular functional portraits, longitudinal circulating tumor DNA analyses, and integrated genomic and transcriptomic biomarker discovery. Enrollment: The study plans to enroll 29 patients. Accrual is ongoing in the United States. Clinical trial information: NCT07229417 .
First-in-human dose escalation trial of an engineered salmonella delivering L-methioninase in advanced bone and soft tissue sarcomas.
11530 Background: Advanced bone and soft-tissue sarcomas have limited treatment options. Tumor-selective methionine dependency is a known metabolic vulnerability. SGN1 is designed to deplete methionine locally within tumors via intratumoral colonization of an attenuated Salmonella vector expressing L-methioninase. Preclinical studies have demonstrated safety and targeted antitumor activity. Here, we report the results from the escalation and expansion phases of the Phase I study in patients (pts) with advanced bone and soft-tissue sarcomas. Methods: The Phase I study includes a dose-escalation phase where pts received intravenous (IV) (2.0×10⁸ to 4.0×10⁸ CFU) or intra-arterial (IA) infusion (2.0×10⁸ to 6.0×10⁸ CFU) once a week (QW) in 28-day cycles, followed by an expansion phase with the putative recommended Phase 2 dose (RP2D) (2.0×10⁸ CFU for IV or 6.0×10⁸ CFU for IA QW) in 6 cohorts, including pts with recurrent either bone or soft tissue sarcoma after at least 2 lines of chemo therapies. SGN1 was administered in combination with physician's choice systemic therapy. Administration of SGN1 was via one of three routes: IV, IA, or a combined IV/IA regimen. Efficacy was assessed by RECIST version 1.1. Results: At the cut-off of Aug 19, 2024, 25 pts with advanced bone and soft-tissue sarcomas were enrolled in the escalation and expansion phases (median follow-up of 5.6 months; range, 0.5-18.2), including pts with bone sarcoma (n=10) and soft tissue sarcoma (n=15). Treatment was administered via IV (n=13), IA (n=8), or a combined IV/IA (n=4) route. The disease control rate (DCR) was 76.0% (95% CI: 56.5, 93.0) in all, 70.0% (95% CI: 34.8, 93.3) in bone sarcoma, 80.0% (95% CI: 52.0, 95.6) in soft tissue sarcoma pts, and 69.2% (95% CI: 38.5, 90.9) in IV, 75.0% (95% CI: 34.8, 93.3) in IA, 100% in combined IV/IA route. Quantitative PCR analysis confirmed significant intra-tumoral colonization by SGN1 post-treatment. The median progression-free survival (mPFS) was 11.5 months (95% CI: 11.1, NE) in all, 11.1 months (95% CI: 1.1, NE) in bone sarcoma, not reached (NR) (95% CI: 3.2, NE) in soft tissue sarcoma pts, and NR (95% CI: 2.7, NE) in IV, 11.5 months (95% CI: 1.3, NE) in IA, NR (95% CI: 11.1, NE) in combined IV/IA route. Complete tumor necrosis was observed in at least two soft tissue sarcoma patients. In all pts, the most frequent treatment-related adverse events (TRAEs) were pyrexia (32.0%) and elevation of blood LDH increased (20.0%). No TRAEs leading to temporary drug discontinuation, no serious TRAEs resulting in withdrawal from the study, and no treatment-related deaths occurred. Conclusions: SGN1 exhibits a manageable safety profile, and showed encouraging clinical benefit in advanced bone and soft-tissue sarcoma, as evidenced by mPFS and DCR. The promising data from this phase I study supports further testing of SGN1 in Phase II studies. Clinical trial information: ChiCTR2400085361.
Ciltacabtagene autoleucel in lenalidomide-refractory multiple myeloma responding to bridging therapy: CARTITUDE-4 cytogenetic subgroup analysis.
7536 Background: CARTITUDE-4 (NCT04181827) showed significant overall (OS) and progression-free survival (PFS) benefits of ciltacabtagene autoleucel (cilta-cel) in patients with lenalidomide-refractory multiple myeloma (MM) after 1–3 lines of therapy. Emerging data underscore the importance of successful bridging therapy (BT); deeper responses (partial response or better, ≥PR) during BT were associated with better survival and safety outcomes in patients treated with cilta-cel. Here, we present efficacy and safety in patients who received cilta-cel as study treatment with high- and standard-risk cytogenetics who responded to BT. Methods: CARTITUDE-4 as-treated set comprised patients who received a single cilta-cel infusion as study treatment after apheresis, ≥1 BT cycle, and lymphodepletion. High-risk cytogenetics were defined as positivity for del(17)p, t(14;16), t(4;14) or gain/amp(1q); standard-risk patients were negative for these mutations. Responses to BT were assessed based on International Myeloma Working Group criteria. Efficacy and safety from as-treated patients with ≥PR to BT were analyzed in high- and standard-risk cytogenetics subgroups. Results: Of 176 patients who received cilta-cel as study treatment (median follow-up, 33.6 months), 64 patients had high-risk cytogenetics and achieved ≥PR to BT. In these patients, median PFS and OS were not reached; 30-month PFS and OS rates were 65.1% (95% CI, 51.4–75.8) and 87.2% (95% CI, 76.1–93.4), respectively. In 40 patients with standard-risk cytogenetics and ≥PR to BT, median PFS and OS were not reached; 30-month PFS and OS rates were 85.0% (95% CI, 69.6–93.0) and 92.5% (95% CI, 78.5–97.5), respectively. Safety analysis included 64 patients with high-risk and 40 with standard-risk cytogenetics. In the high-risk subgroup, cytokine release syndrome was reported in 73.4% of patients, serious nonhematological adverse events in 64.1%, grade 3/4 infections in 43.8%, and immune effector cell-associated neurotoxicity syndrome in 7.8%. Corresponding rates in the standard-risk subgroup were 70.0%, 57.5%, 30.0%, and 0. Nonrelapse mortality (NRM) occurred in 9 patients (high-risk, 7; standard-risk, 2); there were 4 infection-related deaths in the high-risk population. No cases of immune effector cell (IEC)-parkinsonism were reported in high- and standard-risk subgroups. Conclusions: This analysis showed survival and response benefits of cilta-cel in patients with high- and standard-risk cytogenetics who had achieved ≥PR to BT, with >85% of patients alive at 30 months. No patients had IEC-parkinsonism, and infections were a key cause of NRM. These data highlight the profound benefit that cilta-cel can provide to patients with high- and standard-risk cytogenetics when MM is well controlled at time of infusion. Clinical trial information: NCT04181827 .
Effect of eligibility burden on survival time in pancreatic cancer clinical trials.
e23023 Background: Pancreatic ductal adenocarcinoma (PDAC) has median survival measured in months, yet the survival time cost of trial eligibility remains unquantified. We examined whether cumulative eligibility burden consumes a clinically meaningful share of expected remaining survival in PDAC and may thereby bias enrollment away from patients reflective of the real-world population. Methods: We identified 298 U.S. interventional PDAC trials that were recruiting or active but not recruiting. Eligibility criteria were extracted from ClinicalTrials.gov using a predefined rule-based search and manually validated on a random subset. Criteria were scored using a predefined Eligibility Time-Burden Score (ETBS, 0–4), a pragmatic, non-causal summary measure designed to capture time-critical eligibility barriers, with one point assigned for each of the following: ECOG ≤1 restriction, washout ≥21 days, mandatory tissue or biopsy, and major comorbidity exclusions. ETBS distributions were examined by trial phase, start year, and sponsor type. Population-level survival benchmarks were derived from SEER year-of-diagnosis 2018–2021 1-year relative survival to contextualize eligibility delays relative to expected remaining survival in newly diagnosed PDAC. Results: For many patients, a ≥28-day washout alone represents approximately 10% of expected remaining survival based on SEER benchmarks. Overall eligibility burden was substantial (mean ETBS 2.31). ECOG criteria were specified in 86.6% of trials, with 59.4% restricting enrollment to ECOG ≤1. Washout ≥21 days occurred in 69.1%, including ≥28 days in 63.4%. Mandatory tissue or biopsy was required in 28.9%, and 73.8% of trials excluded patients with major comorbidities. ETBS ≥2 occurred in 75.5% of trials, ETBS ≥3 in 48.7%, and the maximum ETBS (4) in 16.1%. Eligibility burden persisted beyond early-phase development, including Phase II trials (mean ETBS 2.27; ETBS ≥3 51.5%), with similar patterns across sponsor types. Conclusions: Protocol-defined eligibility criteria in contemporary pancreatic cancer trials represent a substantial time burden relative to patients’ expected remaining survival, with implications for trial feasibility and generalizability. These burdens persist beyond early-phase trials. Strict performance status thresholds, prolonged washouts, mandatory tissue collection, and broad comorbidity exclusions preferentially limit eligibility for patients who are older, have multimorbidity, or experience early functional decline. Eligibility burden reflects modifiable trial design choices and represents an actionable opportunity to align trial eligibility with the survival urgency of the PDAC population.