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Mortality trends from sepsis and gastrointestinal cancer among United States adults: A CDC WONDER–based analysis.
e15673 Background: Sepsis is a major contributor to mortality among patients with gastrointestinal (GI) cancers. Population-level related mortality trends and disparities among the United States population remain underexplored. This study evaluates national trends and demographic differences in GI cancer-related sepsis mortality in the United States. Methods: We analyzed mortality data from the CDC WONDER Multiple Cause-of-Death dataset from 1999 to 2023. We calculated age-adjusted mortality rates (AAMRs) per 100,000, stratified by age, sex, race/ethnicity, states, and urban-rural classification. Joinpoint regression was used to estimate average annual percent change (AAPC) and annual percent change (APC) with 95% confidence intervals (CIs). Statistical significance was defined as p<0.05. Results: Between 1999 and 2023, 171,744 deaths occurred from GI cancer-related sepsis. The AAMR per 100,000 raised from 2.98 in 1999 to 3.81 in 2023 (AAPC: 1.26%; 95% CI: 0.97-1.55; p<0.001). Males showed a higher mean AAMR of 3.91 versus 2.28 in females. Age analysis showed the highest mortality rate in the age group of more than 65 years (10.55). By race, non-Hispanic (NH) Black or African American individuals had the highest AAMR (4.90), followed by NH Asian or Pacific Islander (3.48), Hispanic or Latino (3.46), NH American Indian or Alaska Native (3.04), and NH White (2.75). Urbanization disparities revealed higher AAMRs in Metropolitan (2.95) than Non-Metropolitan areas (2.70). The Northeast region had the highest AAMR (3.18), followed by the West (3.17), the South (3.01), and the Midwest (2.62). In state-wise analysis, the District of Columbia had the highest AAMR (6.12), while the state of Maine had the lowest (0.94). Conclusions: GI cancer-related sepsis mortality in the United States has increased significantly over the past two decades, with significant disparities by sex, race/ethnicity, geography, and urbanization. These findings underscore the need for equity-focused interventions and enhanced clinical recognition of demographic-based risk factors, which could lead to a quicker estimation of the prognosis and improved sepsis management in cancer care. Deaths and age-adjusted mortality rates (AAMRs) per 100,000 for trends related to sepsis and gastrointestinal cancer mortality among United States adults between 1999 and 2023. Variable Deaths (n) AAMR (95% CI) Overall 171,744 3.00(2.93-3.07) SEX Male 99,411 3.91(3.78-4.03) Female 72,333 2.28(2.19-2.36) RACE/ETHNICITY NH American Indians 1313 3.04(2.20-4.10) NH Asians 8200 3.48(3.07-3.89) NH Blacks 27747 4.90(4.60-5.20) NH White 130374 2.75(2.67-2.82) Hispanics 17114 3.46(3.17-3.74)
Deciphering the genomic landscape of renal cell carcinoma brain metastases.
4524 Background: Brain metastases from renal cell carcinoma (RCC) remain a major cause of morbidity and mortality, yet the drivers of metastatic dissemination remain poorly understood. Methods: Whole-exome sequencing was performed on 72 RCC brain metastasis samples with matched normal. To identify candidate metastatic drivers, the genetic alterations detected in the brain metastases were compared against alterations in extracranial metastases from the MSK-ECM cohort (n=137) and primary RCC tumors from TCGA (n=432) by case-control analyses. Candidate drivers were also identified by matched-pair analyses on the brain metastases vs. matched primary tumors or extracranial metastases from the same patient (n=25). A random survival forest model incorporating the candidate CNA events was developed to predict overall survival. The candidate metastatic drivers were further evaluated using functional experimental data from MetMap and DepMap. Survival analyses were conducted to assess the prognostic significance of the candidate drivers. Results: We identified metastatic drivers that were significantly enriched in RCC brain metastases, including 4q loss, 7p gain, 7q gain, 8p loss, 8q gain, 9p21.3 deletion, 12q15 amplification, and 14q loss. These driver events were associated with significantly poorer patient survival among RCC patients. A random survival forest model based on these CNA events stratified TCGA-KIRC patients into prognostically distinct risk groups (C-index = 0.64). Among the drivers, 8p loss, 8q gain, 9p21.3 deletion were associated with increased incidence of brain metastases across multiple primary cancer types in xenograft mouse models. These drivers were also strongly associated with metastatic progression and poor prognosis across RCC, lung adenocarcinoma, breast cancer, and melanoma. Conclusions: Somatic copy-number alterations represent key drivers of brain metastasis in RCC and other tumors that frequently metastasize to the brain. These findings indicate a shared genomic basis for brain tropism across cancers and highlight the potential utility of copy-number biomarkers for risk stratification and clinical decision-making.
Adjuvant platinum-based chemotherapy vs observation after resection of stage I–IIa (N0) NSCLC: A real-world propensity-matched analysis from TriNetX.
e20059 Background: Lung cancer remains the leading cause of cancer-related mortality worldwide, accounting for approximately 1.8 million deaths annually, with non–small cell lung cancer (NSCLC) comprising nearly 85% of cases (Siegel et al., 2024; Sung et al., 2021). Approximately 25–30% of patients present with early-stage disease, for which surgical resection is potentially curative (Goldstraw et al., 2016). While randomized trials and meta-analyses have demonstrated a survival benefit for adjuvant platinum-based chemotherapy in resected stage II–III NSCLC (Pignon et al., 2008), its role in stage I–IIA disease without nodal involvement remains uncertain and variably applied in clinical practice (NCCN Guidelines, 2024). We compared real-world outcomes of adjuvant platinum-based chemotherapy versus observation following complete resection in patients with stage I–IIA (N0) NSCLC. Methods: We performed a retrospective cohort study using the TriNetX U.S. Collaborative Network. Adult patients with pathologic stage I or IIA NSCLC and N0 disease who underwent lung resection were included. Adjuvant chemotherapy was defined as receipt of a platinum-based doublet within 6 months after surgery, while observation was defined as no systemic therapy. Propensity score matching (1:1) balanced demographics and baseline comorbidities. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan–Meier methods and Cox proportional hazards models. Results: After propensity score matching, 1,107 patients remained in each cohort. Adjuvant chemotherapy was associated with significantly inferior overall survival compared with observation (hazard ratio [HR] 1.586, 95% CI 1.378–1.826; p < 0.001). Progression-free survival was also significantly worse among patients receiving adjuvant chemotherapy (HR 1.612, 95% CI 1.387–1.873; p < 0.001). Conclusions: In this large real-world propensity-matched cohort of patients with completely resected stage I–IIA (N0) NSCLC, adjuvant platinum-based chemotherapy was associated with inferior overall and progression-free survival compared with observation. These findings highlight the need for careful patient selection and underscore the importance of prospective studies to better define the role of adjuvant chemotherapy in early-stage, node-negative NSCLC. Summary of key outcomes after propensity score matching. Outcome Adjuvant Chemotherapy vs Observation (HR, 95% CI) p-value Overall Survival 1.59 (1.38–1.83) <0.001 Progression-Free Survival 1.61 (1.39–1.87) <0.001
Efficacy of chemotherapy with salvage surgery for locoregionally recurrent nasopharyngeal carcinoma: A multicenter cohort study.
e18073 Background: The role of chemotherapy combined with salvage surgery for locoregionally recurrent nasopharyngeal carcinoma (lrNPC) remains uncertain. This multicenter cohort study evaluated whether adding chemotherapy to salvage surgery improves survival outcomes and assessed associated toxicity. Methods: Ninety-one patients with resectable lrNPC treated between August 2013 and August 2023 at five institutions in Guangxi, China, were analyzed. Patients received either salvage surgery with chemotherapy (n = 48) or surgery alone (n = 43). Survival outcomes, including overall survival (OS), progression-free survival (PFS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS), were estimated using the Kaplan–Meier method and compared by the log-rank test. Prognostic factors were identified with multivariate Cox models, and adverse events (AEs) were graded per CTCAE v5.0. Results: After a median follow-up of 55.0 months, no significant differences were observed between the chemotherapy plus surgery and surgery-alone groups in 5-year OS (64.1% vs 61.0%; P = .894), PFS (45.3% vs 49.9%; P = .740), LRFS (47.6% vs 54.9%; P = .421), or DMFS (52.9% vs 56.4%; P = .836). Multivariate analysis revealed that chemotherapy was not an independent prognostic factor; however, it was significantly associated with higher incidences of anemia, leukopenia, and gastrointestinal toxicity (all P < .05). Conclusions: The addition of platinum-based chemotherapy to salvage surgery does not improve long-term survival in patients with resectable lrNPC and increases treatment-related toxicity. Salvage surgery alone may represent a more appropriate therapeutic approach pending confirmation in larger-scale prospective trials.
Cancer disparities in Latinx communities of Western North Carolina and Appalachia: A scoping review of barriers and pathways to equity.
e13754 Background: Appalachia experiences some of the highest cancer incidence and mortality rates in the United States. In Western North Carolina (WNC), rapid growth of Latinx communities—many employed in seasonal agricultural work—intersects with rural health inequities. However, cancer-related data specific to Latinx populations in Appalachia are often limited or obscured within broader geographic categories. We conducted a scoping review to characterize existing evidence on cancer prevention, screening, diagnosis, treatment, and survivorship among Latinx populations in WNC/Appalachia and comparable rural Appalachian regions, and to identify strategies to advance equity. Methods: Using PRISMA-ScR and Joanna Briggs Institute scoping review methodology, we will search MEDLINE/PubMed, Embase, CINAHL, Scopus, and gray literature for studies evaluating cancer-related outcomes or care processes among Latinx/Hispanic individuals residing in Appalachia, including WNC. Eligible studies will include quantitative, qualitative, and mixed-methods designs addressing any cancer type across the cancer continuum. Two reviewers will independently screen studies and extract data on population characteristics, rurality, cancer site, outcomes, barriers, facilitators, and interventions. Findings will be categorized using multilevel frameworks and summarized descriptively. Results: Preliminary mapping demonstrates a limited evidence base focused on rural Appalachian Latinx communities. Recurrent multilevel barriers include: (1) structural factors such as unstable insurance coverage, concerns related to documentation status, limited access to oncology services, and transportation challenges; (2) work-related constraints among farmworkers, including seasonal migration and inflexible schedules; (3) language and cultural barriers, including limited English proficiency, low health literacy, stigma, and lack of Spanish-language services; and (4) inequities in care processes, such as delays in diagnosis and treatment, incomplete follow-up after abnormal screening results, and underrepresentation in research. Interventions reported in similar rural Latinx settings include community health worker navigation, culturally tailored education in trusted community venues, mobile health services, and telehealth-based specialist collaboration models. Conclusions: Improving cancer equity for Latinx communities in WNC and Appalachia will require more granular surveillance that disaggregates ethnicity within rural cancer data and the implementation of evidence-informed, community-engaged care models. This scoping review will identify gaps in the literature and inform region-specific interventions and policy efforts aimed at reducing late-stage diagnoses and disparities in access to timely cancer care.
Chemoimmunotherapy for large cell neuroendocrine carcinoma (LCNEC) of the lung: A multi-institutional prospective study (NEJ044).
8078 Background: Large cell neuroendocrine carcinoma (LCNEC) is a rare pulmonary malignancy, comprising 1-3% of all lung cancers. It is a high-grade tumor exhibiting heterogeneous characteristics that overlap with both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). While chemoimmunotherapy (chemo-IO) has become the standard of care for SCLC and NSCLC, prospective data regarding its efficacy and safety in LCNEC are limited, and the optimal chemotherapy backbone remains unclear. We conducted the NEJ044 study to prospectively evaluate chemo-IO in patients (pts) with advanced LCNEC. Methods: This multi-institutional, prospective, observational study enrolled pts with advanced or recurrent LCNEC. Treatment consisted of atezolizumab and carboplatin combined with either etoposide (IMpower133), paclitaxel and bevacizumab (IMpower150), or nab-paclitaxel (IMpower130). The primary endpoint was the 1-year overall survival (OS) rate. Secondary endpoints included OS, progression-free survival (PFS), objective response rate, disease control rate, and safety. Results: Between July 2020 and June 2024, 77 pts were enrolled across 31 institutions within the North East Japan Study Group, of whom 76 received treatment. The median follow-up was 29.0 months (mos) (95% CI: 15.2–35.7). Baseline characteristics included: median age 71 years (range 51–83); male, 68 (89%); ECOG PS 0-1, 69 (91%); and postoperative recurrence, 29 (38%). Histology was confirmed as LCNEC in 61 pts (80%) and combined LCNEC in 15 pts (20%). Treatment distribution included the IMpower133 regimen in 56 pts (74%) and IMpower150/130 regimens in 20 pts (26%). The study met its primary endpoint with a 1-year OS rate of 70.1% (95% CI: 58.2–79.2). In the overall population, median OS (mOS) and PFS (mPFS) were 18.5 mos (95% CI: 14.3–22.6), and 6.2 mos (95% CI: 4.8–7.6). Exploratory analysis showed no significant differences in survival by chemotherapy backbone. The IMpower133 cohort demonstrated a 1-year OS of 70.3% (95% CI: 56.1–80.6), mOS of 18.4 mos (95% CI: 13.2-22.3), and mPFS of 5.2 mos (95% CI: 3.9-7.6), compared to a 1-year OS of 69.6% (95% CI: 44.5–85.1), mOS of 19.9 mos (95% CI: 7.3-not evaluable), and mPFS of 7.2 mos (95% CI: 4.3-19.9) in the IMpower150/130 cohort. Grade ≥3 non-hematological adverse events occurred in 23 pts (30%), and febrile neutropenia was observed in 9 pts (11%). Biomarker analysis identified oncogenic drivers in 5 pts (including 3 KRAS mutations). PD-L1 expression was ≥50% in 12%, 1–49% in 34%, and < 1% in 51%; PD-L1 TPS ≥1% was marginally associated with improved OS. Conclusions: The NEJ044 study met its primary endpoint, demonstrating that chemoimmunotherapy provides a favorable 1-year OS of approx. 70% with a manageable safety profile in LCNEC. These prospective results support chemoimmunotherapy as a viable standard treatment strategy for this population. Clinical trial information: UMIN000040876.
Pregnancy outcomes in women with myeloproliferative neoplasms: A multicenter real-world analysis.
6574 Background: Pregnancy in women with myeloproliferative neoplasms (MPNs) is associated with increased thrombotic and obstetric risk, yet contemporary real-world data describing maternal and fetal outcomes remain limited. We evaluated pregnancy-related outcomes in women with MPNs and examined potential risk predictors. Methods: We conducted a retrospective cohort study using the TriNetX network, a federated multicenter network of de-identified electronic health records from participating healthcare organizations. Pregnant women with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF) were identified. The primary outcome was all-cause mortality. Secondary outcomes included deep vein thrombosis (DVT), miscarriage, pre-eclampsia, eclampsia, preterm labor, and intrauterine growth restriction (IUGR). Subgroup analyses were performed using propensity score matching for age, race, ethnicity, and comorbidities to compare outcomes by Low Molecular Weight Heparin (LMWH) exposure, race, maternal age, and MPN subtype. Risk ratios (RR) with 95% confidence intervals (CI) were calculated. Results: A total of 1,904 pregnancies were identified (mean age 31.1±7.0 years).The cohort was predominantly non-Hispanic (66.2%) and White (59.1%). ET accounted for 90.3% of cases, followed by PV (8.0%) and MF (1.7%). Overall rates of maternal mortality and DVT were 2.8% and 2.6%, respectively. Adverse obstetric outcomes included miscarriage (9.6%), pre-eclampsia (12.4%), eclampsia (1.3%), preterm labor (9.1%), and IUGR (8.5%). In matched analyses, LMWH use was associated with a numerically lower risk of miscarriage compared with no LMWH (6.8% vs 10.4%; RR 0.66, 95% CI 0.42–1.04), without significant differences in pre-eclampsia, preterm labor, or IUGR. Outcomes were similar between White and African American patients. Advanced maternal age (>35 years) was associated with a lower risk of preterm labor (3.7% vs 9.2%; RR 0.40, 95% CI 0.21–0.75). Obstetric outcomes were comparable between ET and PV. Conclusions: In this real-world cohort, pregnancies in women with MPNs were associated with measurable rates of thrombotic and obstetric outcomes. LMWH use was associated with a numerically lower risk of miscarriage without statistically significant differences in other outcomes. These findings provide contemporary outcome estimates and may inform risk stratification and future prospective studies. Limitations include the retrospective design, potential misclassification due to inherent limitation of the database, limited MF representation, and inability to assess disease activity, aspirin use, or pregnancy-specific dosing strategies.
A randomized phase II/III trial of intraperitoneal paclitaxel plus systemic treatment vs systemic treatment alone in gastric carcinomatosis: STOPGAP II—ECOG-ACRIN EA2234.
TPS4241 Background: Thirty to forty percent of patients with gastric cancer will develop peritoneal carcinomatosis (PC), the survival of which remains poor despite systemic therapy (ST). Limited drug delivery into PC due to blood-peritoneal barrier is considered to decrease the effectiveness of ST. Hence, there is a critical need to develop novel treatment strategies to improve patient outcomes. Intraperitoneal (IP) paclitaxel (PTX) combined with ST had been studied extensively in Asia. In the US, STOPGAP I, a single institution phase II trial has established the safety and feasibility of IP PTX plus ST in Western patients with gastric PC. Based on these results, we developed STOPGAP II trial, which is designed to evaluate the survival benefits of IP PTX plus ST compared to ST alone in patients with gastric PC. Methods: ECOG-ACRIN EA 2234 STOPGAP II is a multi-center randomized phase II/III trial (NCT07001748) evaluating IP PTX plus ST compared to ST alone in patients with gastric PC. Eligible patients must have microsatellite stable gastric/gastroesophageal cancer (Siewert 3) with cytology positive disease or carcinomatosis detected by diagnostic laparoscopy (DL), laparotomy, or radiology and have undergone 3-6 months of first line ST. Patients must not have visceral metastases except ovarian metastases or clinically significant progression of PC. All enrolled patients will undergo DL with peritoneal cancer index (PCI) assessment within four weeks of registration. Patients will be randomized intraoperatively in 1:1 fashion to Arm A- ST or Arm B- IP PTX with ST. In patients randomized to Arm B, an IP port will be placed at the initial DL . Patients in Arm A will continue first line ST and patients in Arm B will receive 40 mg/m2 of IP PTX on days 1 and 8 combined with 50mg/m2 of IV PTX, 5 fluorouracil 400 mg/m2, leucovorin 20mg/m2. Immune checkpoint inhibitors and targeted agents will be continued as per standard of care. Patients will be stratified by PCI (0, 1-6, 7-14, versus >15) and first line ST type (chemo + targeted agent or immunotherapy versus chemotherapy alone). In both treatment arms, patients will undergo reevaluation with repeat imaging and if indicated, DL after three months. Patients with stable disease or response will continue the assigned treatment or could be considered for cytoreduction if PCI <7. The primary endpoints are progression free survival (phase II) and overall survival (OS) (phase III). Assuming the median OS of IP PTX and that of ST to be 22.5 and 12.5 months respectively, and accounting for attrition, 148 patients will be enrolled to achieve 90% power with a hazard ratio of 0.56 (one-sided type I error of 5%). The study is actively enrolling patients with results expected in 2031. Clinical trial information: NCT07001748 .
Decoding the pre-malignant niche in cholangiocarcinoma: A single-cell multi-omic atlas from inflammation to invasion.
e22555 Background: The dismal prognosis of extrahepatic cholangiocarcinoma (eCCA) is primarily attributable to late-stage diagnosis. Although chronic biliary inflammation is a well-established predisposing condition, the specific cellular and epigenetic mechanisms that orchestrate the progression from benign inflammation to invasive malignancy remain elusive, hindering the development of early interception strategies. Methods: We performed integrated single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) on freshly procured human tissue samples representing the full pathological spectrum: normal bile duct, primary sclerosing cholangitis, pre-neoplastic lesions with dysplasia, and eCCA (perihilar and distal). Bioinformatic analyses included cross-sample integration, cell-type annotation, trajectory inference, and regulatory network construction. Results: Our analysis uncovered a co-evolutionary trajectory marked by escalating genomic instability and transcriptional reprogramming. Notably, somatic copy number alterations (SCNAs) were detectable within the epithelial compartment as early as the stage of chronic cholangitis, with their prevalence and genomic complexity increasing substantially towards carcinoma. Pre-neoplastic lesions displayed extreme multi-layered heterogeneity, indicative of a branching evolutionary model with divergent clinical fates. Through integrative analysis of monotonic expression patterns and stage-specific chromatin dynamics, we delineated a core transcriptional circuitry driving this transformation and derived a focused gene signature exhibiting strong discriminatory potential for early detection. Conclusions: This study provides the first high-resolution, single-cell multi-omic map of eCCA pathogenesis, defining the cellular and epigenetic continuum from inflammation to carcinoma. Our work elucidates fundamental mechanisms of inflammatory-driven oncogenesis and delivers a translatable framework for risk stratification and early interception.
Multichannel deep learning network for predicting survival in stage I NSCLC patients treated with SBRT.
e20108 Background: This study aims to develop a deep learning network (DLN)-based model to predict overall survival (OS) by integrating radiomic, dosiomic, and clinical features. The objective is to identify the most influential predictors of OS in patients with non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT) within a DLN-based analytical framework. Methods: Radiomic features, dosimetric parameters, and clinical data were collected from 171 NSCLC patients treated with SBRT. Twenty-two dosiomic and clinical features were obtained for this cohort. In addition, 47 radiomic features were extracted from radiation planning CT images within the planning target volume (PTV), encompassing histogram-based, geometric, and texture features derived from gray-level co-occurrence matrix (GLCM), gray-level run-length matrix (GLRLM), and gray-level size-zone matrix (GLSZM). Univariate analysis identified 19 significant features for model development: 3 clinical (age, age-adjusted Charlson Comorbidity Index, T-stage), 4 dosiomic (gross tumor volume (GTV) size, PTV size, conformity index, mean lung dose), and 12 radiomic features. Radiomic predictors included GLSZM (gray-level non-uniformity, zone entropy, zone percentage, size-zone non-uniformity), GLRLM (run percentage, run-length non-uniformity, run entropy, low gray-level run emphasis), and GLCM (entropy, homogeneity, energy, angular second moment). OS prediction was performed using a DLN with three fully connected hidden layers (256, 128, and 64 neurons) and a dropout rate of 0.5 to reduce overfitting. Results: Across ten randomized training (70%) and testing (30%) splits, the DLN model using 12 radiomic features achieved an ROC-AUC of 0.66 ± 0.05, with a sensitivity of 0.70 ± 0.18 and a specificity of 0.62 ± 0.16 (see Table 1). Expanding the model to include dosiomic and clinical features (19 features total) substantially enhanced predictive performance, increasing sensitivity to 0.73 ± 0.13, specificity to 0.72 ± 0.16, and ROC-AUC to 0.72 ± 0.03. Conclusions: Integrating dosiomic and clinical information with radiomic features significantly strengthens deep learning–based prediction of overall survival in patients with NSCLC treated with SBRT, yielding an approximately 9% improvement in ROC-AUC over radiomics-only models. These findings underscore the clinical potential of multimodal feature integration, with ongoing multi-institutional studies underway to confirm robustness and generalizability. Performance of the DLN-based OS prediction model. Methods ROC-AUC Sensitivity Specificity F1-score Precision 12 significant radiomic features only 0.66 (±0.05) 0.70 (±0.18) 0.62 (±0.16) 0.74 (±0.12) 0.81 (±0.07) Combing radiomic (12), dosiomic (4) & clinical (3) features 0.72 ( ± 0.03) 0.73 ( ± 0.13) 0.72 ( ± 0.16) 0.78 ( ± 0.07) 0.85 ( ± 0.08)
Cadonilimab combined with anlotinib in patients with advanced NSCLC refractory to prior systemic therapy and anti–PD-(L)1 antibodies: A phase II study.
e20507 Background: The combination of immunotherapy and antiangiogenic therapy represents a promising first-line strategy for NSCLC, supported by early clinical data showing favorable efficacy and safety. However, immunotherapy resistance remains a critical challenge. This study aimed to evaluate the efficacy and safety of cadonilimab, the first-in-class bispecific anti–PD-1/CTLA-4 antibody, combined with anlotinib, in patients with advanced NSCLC refractory to prior systemic therapy including anti–PD-(L)1 antibodies. Methods: Patients and Treatment: Eligible patients had unresectable locally advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC and had progressed on prior systemic therapy, including anti–PD-(L)1 agents. Patients received cadonilimab (10 mg/kg intravenously every 3 weeks) plus oral anlotinib (10 mg once daily in a 2-weeks-on/1-week-off schedule) per 21-day cycle for 4 to 6 cycles, followed by maintenance therapy until disease progression, unacceptable toxicity, completion of 24 months of treatment, or meeting other protocol-defined discontinuation criteria. Assessments: Tumor response was assessed regularly according to RECIST v1.1. Radiographic evaluations were performed every 6 weeks (±7 days) for the first 48 weeks, then every 12 weeks (±7 days) thereafter. For subjects who discontinued treatment for reasons other than progression or death, tumor assessments continued per schedule until subsequent progression, initiation of new antitumor therapy, or study withdrawal. Objective responses required confirmation ≥4 weeks after the initial documentation. Results: At the January 2026 data cutoff, 33 evaluable patients had a median follow-up of 11.0 months (95% CI: 7.2–13.2). The confirmed ORR was 24.2%, and the disease control rate (DCR) was 75.8%. The 1-year overall survival (OS) and PFS rates were 77.6% and 55.5%, respectively. Notably, the PFS curve plateaued at 55.5% and remained stable through the maximum follow-up of 24.0 months. Treatment-related adverse events (TRAEs) occurred in 30.3% (10/33) of patients, with Grade ≥3 TRAEs observed in 9.1% (3/33). No Grade 4 or 5 TRAEs were reported. Mucocutaneous reactions were the most frequently reported TRAEs. Conclusions: This preliminary analysis suggests that cadonilimab combined with anlotinib shows promising antitumor activity and manageable safety in advanced NSCLC patients after systemic therapy failure and resistance to anti–PD-(L)1 antibody treatment.Enrollment is ongoing.
Phase IIa study of tosposertib, a dual TGFβRI and VEGFR2 inhibitor, in combination with pembrolizumab in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
2635 Background: Tosposertib (TU2218) is a highly potent dual inhibitor of the transforming growth factor-β type I receptor (TGFβRI/ALK5) and vascular endothelial growth factor receptor 2 (VEGFR2), designed to simultaneously target immunosuppressive tumor microenvironment signaling and angiogenesis. This open-label, multicenter, non-randomized phase IIa trial evaluated the efficacy and safety of tosposertib in combination with pembrolizumab in patients with R/M HNSCC (NCT05784688). Methods: Eligible patients included anti–PD-(L)1–naïve patients with PD-L1 combined positive score (CPS) ≥1. Tosposertib (97.5 mg twice daily; 2 weeks on/1 week off) was administered orally in combination with pembrolizumab (200 mg intravenously every 3 weeks). Results: As of December 31, 2025, 29 patients (median age, 61 years; 76% male) had been enrolled, with a median follow-up duration of 6.0 months (range, 8–401 days). Primary tumor sites included the oral cavity (n=11, 37.9%), oropharynx (n=6, 20.7%), larynx (n=3, 10.3%), and nasal/paranasal regions (n=3, 10.3%). HPV positivity was observed in 13.8% (4/29) of patients. Among 26 efficacy-evaluable patients, responses were assessed by treatment line. In the first-line setting, 9 of 12 patients achieved an objective response (ORR, 75.0%), including 1 confirmed complete response (CR) and 8 partial responses (PRs; 6 confirmed, 2 unconfirmed). Among the 14 patients who had received at least one prior systemic therapy, the ORR was 42.9%, with 1 confirmed CR and 5 confirmed PRs. A numerically higher ORR was observed in patients with PD-L1 CPS ≥20 compared with those with CPS 1–10 (66.7% vs 52.9%). The most frequent any-grade treatment-emergent adverse events (TEAEs), (≥20%) [and ≥ Gr3 TEAEs], were rash (48.3% [20.7%]), mucosal inflammation (34.5% [13.8%]), pruritus (27.6% [3.4%]), weight loss (27.6% [0%]), and elevations in aspartate aminotransferase (AST; 20.7% [3.4%]) or alanine aminotransferase (ALT; 20.7% [3.4%]). Discontinuations due to TEAEs occurred in three patients. No treatment-related deaths were reported. Conclusions: Tosposertib in combination with pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity in patients with R/M HNSCC, with particularly robust efficacy observed in the first-line setting and a favorable trend in PD-L1–high tumors. Clinical trial information: NCT05784688 . Best overall response by subgroups. Best Overall ALL(n=26) Prior lines of therapy Prior lines of therapy PD-L1status, n (%) PD-L1status, n (%) Response, n (%) None(n=12) ≥1(n=14) CPS 1-19(n=17) CPS ≥20(n=9) Complete Response 2 (7.7) 1 (8.3) 1 (7.1) 1 (5.9) 1 (11.1) Partial Response 13 (50.0) 8 (66.7) 5 (35.7) 8 (47.1) 5 (55.6) Stable Disease 5 (19.2) 2 (16.7) 3 (21.4) 3 (17.6) 2 (22.2) Progressive Disease 6 (23.1) 1 (8.3) 5 (35.7) 5 (29.4) 1 (11.1) Response Rate (%) 57.7 75.0 42.9 52.9 66.7
A prospective randomized controlled trial of FAPI PET/CT-guided radiotherapy combined with second-line standard systemic treatment and cadonilimab versus second-line standard systemic treatment alone in patients with peritoneal metastasis from colorectal cancer (TORCH-PM01).
3545 Background: This study evaluates the efficacy and safety of FAPI PET/CT-guided radiotherapy combined with second-line systemic treatment and cadonilimab compared to second-line systemic treatment alone in patients with peritoneal metastasis from colorectal cancer. Methods: In this prospective randomized controlled trial, we enrolled patients with peritoneal metastasis from colorectal cancer who progressed after first-line systemic therapy. Patients were randomly assigned to the control group, receiving second-line standard systemic treatment (n = 20), or the study group, which received hyopfractionated radiotherapy (20-25 Gy in 5 fractions) combined with second-line systemic treatment and cadonilimab (n = 20). The primary endpoint was overall response rate (ORR). A total of 40 patients were enrolled, with 19 evaluable patients in each group following loss to follow-up. Results: The ORR was significantly higher in the study group at 63.2% (12/19) compared to 15.8% (3/19) in the control group (p = 0.003). Adverse events (AEs) of grade 3-4 in the study group included neutropenia (26.3%, 5/19), nausea (15.8%, 3/19), vomiting (15.8%, 3/19), and diarrhea (15.8%, 3/19). In the control group, the most common grade 3-4 AE was neutropenia (21.1%, 4/19) and vomiting (10.5%, 2/19). Immune-related AEs of grades 1-2 in the study group included skin reactions (15.8%, 3/19), hypothyroidism (5.3%, 1/19), hepatitis (5.3%, 1/19), and myocarditis (15.8%, 3/19). One case of grade 3-4 skin reaction (5.3%) was observed in the study group. Conclusions: FAPI PET/CT-guided radiotherapy combined with second-line systemic treatment and cadonilimab significantly improves ORR in patients with peritoneal metastasis from colorectal cancer compared to standard second-line treatment alone, with manageable toxicity profiles. These findings support a promising therapeutic strategy for this challenging patient population. Clinical trial information: NCT07079462 .
Delays in receipt of neoadjuvant chemotherapy in patients with localized muscle-invasive bladder cancer.
e13538 Background: Delay in time from muscle invasive bladder cancer (MIBC) diagnosis to neoadjuvant chemotherapy (NACT) > 60 days, can negatively impact cancer related outcomes. Identifying patients at highest risk for treatment delays may inform targeted interventions. We evaluated clinical and system-level factors associated with delays in NACT initiation. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of MIBC stages II-IIIB between 1/1/2010 – 12/31/2022 who were treated with NACT followed by surgery. Time to NACT was recorded for each patient in days and > 60 days was categorized as delay. Multivariate logistic regression was used to identify demographic, socioeconomic, and tumor characteristics associated with delay. Linear regression was used in a restricted cohort of patients over 70 years of age to investigate the relationship of age on time to chemotherapy initiation. Results: We identified 5260 eligible patients. The median age of the cohort was 67 years of age (IQR: 60-74). Across the cohort, 83.7% of patients had cT2-T4aN0 disease while 16.3% had cT2-T4aN1-3 disease. Urothelial carcinoma histology accounted for 92% of the cohort. Patients who were White made up 88% of the cohort and 3792 (72%) were male. Median time from diagnosis to initiation of NACT was 50 days (IQR: 11-121) and 48.4% had a delay to initiation of NACT. In an adjusted logistic regression, patients who were Black (OR 1.43 95% CI 1.15-1.79), Hispanic (OR 1.64 95% CI 1.21-2.23), insured with Medicaid (OR 1.62 95% CI 1.30-2.02), resided in the lowest income bracket by zip code (OR 1.61 95% CI 1.32-1.96), male (OR 1.13 95% CI 1.00-1.28), Northeast region (OR 1.73 95% CI 1.44-2.08), treated at an academic facility (OR 1.50 95% CI 1.16-1.93) were more likely to be delayed. Tumor T and N stage and Charlson comorbidity score were not significantly associated with treatment delay. In an adjusted linear regression for a restricted cohort of patients older than 70 years of age, each additional year of age was associated with a 0.82-day decrease in time to treatment (p = 0.005). Conclusions: Among patients with MIBC, patients who were Black, Hispanic, and non-commercially insured had nearly a 50% increase in odds of a delay in NACT initiation. These findings will inform future studies and system-level interventions to reduce treatment delays and promote equitable cancer care.
A population tumor kinetics analysis for early-cycle ctDNA-guided therapy decisions in DLBCL.
3054 Background: Early circulating tumor DNA (ctDNA) kinetics may be instrumental in identifying patients with DLBCL who can safely discontinue therapy after three cycles, as well as those who are less likely to benefit from completing the full six cycles. However, the optimal timing for ctDNA measurement, added value of early cycle data, and influence of assay sensitivity remain uncertain. Through population tumor kinetics (pop-TK) modeling of Pola-R-CHP (Pomeroy et al., Blood Cancer Discovery, 2025), we evaluated how adding data from cycles 1 and 2 enhances risk stratification beyond the assessment conducted after cycle 3. Methods: A 5-drug pop-TK model calibrated to Pola-R-CHP single-agent sensitivity distributions and clinical outcomes simulated tumor cell populations and patient-level parameters. Predicted residual disease after each cycle was mapped to ctDNA titers under assays of varying detection thresholds, representing conventional ctDNA, high-sensitivity ctDNA, and PET. We evaluated (1) ctDNA negativity at cycle three only, (2) adding cycles 1 and 2 for prediction, and (3) using cycles 1 and 2 to identify non-responders. For detection thresholds, representative values were selected to reflect overall trends. Results: Among ctDNA-negative patients at cycle 3 (n=557), stopping therapy at cycle 3 led to a recurrence rate of 0.172, while completing six cycles eliminated all recurrences. Adding ctDNA from cycles 1 and 2 separated cycle 3-negative patients into a high-risk group with much higher recurrence (90/121; 0.744) and a low-risk group with very low relapse risk (6/436; 0.014). Across assay sensitivities, high-sensitivity ctDNA reduced recurrence after cycle 3 cessation to 0.093 (43/464), whereas PET-level sensitivity showed a higher recurrence rate (0.288; 171/593), and adding data from cycles 1 and 2 consistently improved sensitivity. Early-cycle ctDNA (C1, C2) stratified patients into a high-risk non-responder group (5-year PFS 0.009), who can benefit from transferring treatment plans, and a low-risk group with favorable outcomes (5-year PFS 0.961). Conclusions: Pop-TK modeling suggests that although most patients with cycle 3 ctDNA negativity do not relapse when treatment is continued through cycle 6, some patients may still experience relapse that might not have occurred if treatment had been completed through cycle 6. Adding early cycles produces a large low-risk subgroup, supporting safer de-escalation, while still identifying patients who will consistently relapse if therapy is stopped early. Higher assay sensitivity reduces false negatives, but early-cycle ctDNA remains very informative. Furthermore, early cycle ctDNA enables identification of non-responding patients before completion of therapy. These findings support the addition of early cycle ctDNA into response-adapted de-escalation and early treatment switching in trials for DLBCL treated with Pola-R-CHP.
Evaluation of serum folate receptor alpha levels in colon cancer: Association with diagnosis, clinical stage, and metastasis.
e15052 Background: Folate and folate receptor alpha (FRα) are critical for cell proliferation and DNA synthesis. FRα is overexpressed in various malignancies, including ovarian and lung cancer. This study aimed to analyze serum folate and FRα levels in colon cancer patients and evaluate their association with diagnosis, staging, and metastasis. Methods: This prospective case-control study included 77 patients with colon cancer and 81 healthy controls. Serum folate and Folate Receptor Alpha (FRα) levels were measured by ELISA method, and statistical comparisons were made between cancer and control groups. The associations between these biomarkers and tumor stage, metastasis status, Neutrophil-to-Lymphocyte Ratio (NLR) levels were evaluated in the colon cancer cohort. Results: Demographic and clinical characteristics of the groups are presented in Table 1. Serum FRα levels were elevated in colon cancer versus controls (p < 0.001), while serum folate levels were reduced (p < 0.001). Multivariate logistic regression identified serum FRα as an independent predictor of colon cancer (p = 0.019), after adjusting for sex, age, and folate status. After Propensity Score Matching based on age, median serum FRα in the colon cancer group was 3244.01 pg/mL (IQR: 2603.45 – 4301.04 pg/mL), higher than matched controls (median: 2340.20 pg/mL, IQR: 2028.70 – 3520.41 pg/mL). This confirmed FRα levels remained significant after age adjustment (Wilcoxon Signed-Rank Test, p = 0.016), indicating elevated serum FRα is associated with colon cancer. Post-hoc analyses showed FRα expression was higher in Stage 4 patients versus Stage 2 and 3 disease (p = 0.005), with increased levels in metastatic cases (p = 0.001). FRα levels were elevated in liver metastasis compared to extrahepatic metastases (p < 0.001). ROC analysis indicated moderate diagnostic potential (AUC: 0.665) but high sensitivity (83.1%). The predictive value for metastasis was stronger (AUC: 0.727), with serum levels elevated in liver versus extrahepatic spread (p < 0.001). Elevated FRα levels were associated with high NLR≥3 (p = 0.014). Conclusions: This study is the first prospective investigation showing elevated serum FRα levels in colon cancer, particularly in patients with liver metastases and stage 4 disease. While serum FRα showed high sensitivity for colon cancer detection, its limited specificity suggests it cannot serve as a standalone diagnostic marker. However, its predictive value for metastatic disease was stronger, with significantly higher levels in liver metastasis compared to extrahepatic spread. The demonstration of elevated serum FRα in hepatic metastasis highlights its prognostic value and potential as a non-invasive tool for identifying aggressive phenotypes and guiding FRα-targeted therapies in advanced colon cancer.
Healthcare provider perceptions and barriers to palliative care in Pakistan: A narrative synthesis.
e13640 Background: Palliative care integration in Pakistan remains limited despite a high cancer burden in this low-resource setting. Knowledge gaps, cultural/religious ethical concerns, socioeconomic barriers, and opioid restrictions lead to delayed engagement, late diagnoses, and poor symptom control. This review synthesizes provider, caregiver, and trainee perceptions and systemic obstacles to delivery. Methods: Targeted PubMed/MEDLINE search using MeSH terms (“Palliative Care,” “Terminal Care,” “Health Personnel,” “Pakistan,” etc.). Narrative synthesis of observational, survey, qualitative, and guideline studies from Pakistan or relevant South Asian contexts. Results: Non-oncologists show major gaps in hospice awareness, referrals, and pain management despite cancer involvement (Shaikh et al.). Caregivers often misunderstand palliative principles (~45% adequately informed), but support disclosure and holistic care when educated (Shah et al.). Oncologists increasingly recognize time toxicity, with 85% modifying regimens to reduce patient burden (Hameed et al.). Ethical hesitancy limits end-of-life decisions due to legal, religious, and cultural factors (Zaheer et al.). Recent evidence highlights depression in up to 52% of palliative patients (moderate-severe common), with adaptive coping but need for psychological integration (Ali et al., 2025); undertreated cancer pain reliant on weak opioids (tramadol 69%), minimal strong opioids/alternatives (3%) due to regulations/costs (Sami, 2025); persistent student misconceptions and stagnant knowledge across training (Bilal et al., 2024); South Asian emphasis on family care, religious rites, poverty-moderated choices, and pain-free death (Wijeyaratne et al., 2025); high neonatal treatment withdrawal rates (47%) but parental overrides leading to poor survival (Iqbal et al., 2025); localized NCCN guideline adaptations addressing primary care gaps (Hashmi et al., 2024); and emerging non-opioid analgesics offering potential to overcome opioid access limitations in restricted environments. Conclusions: Palliative care in Pakistan faces persistent knowledge gaps, limited training, socioeconomic/religious barriers, and symptom undertreatment (especially opioids). Growing oncologist awareness of holistic needs offers promise, but progress requires standardized education, policy reforms, guideline localization, and innovative alternatives to enable equitable, timely access in resource-limited settings.
Multi-omic characterization of high tumor mutational burden in colorectal cancer.
e15724 Background: High Tumor Mutational Burden (TMB-H) is a primary biomarker for immune checkpoint inhibitor response in colorectal cancer (CRC). While the correlation between TMB and microsatellite instability (MSI) is established, the specific co-occurring driver mutations and the downstream transcriptomic programs that define TMB-H tumors in clinical cohorts remain to be fully elucidated. This study integrates TMB, DNA mutations, and RNA expression to define the molecular architecture of TMB-H tumors in 192 CRC patients. Methods: We performed integrated genomic and transcriptomic profiling of 192 CRC samples. Patients were stratified by TMB values into TMB-H (n = 54) and Low-TMB (n = 138). Mutation enrichment analysis was performed using Fisher’s exact test, and differential expression analysis (DEA) was conducted to identify mRNA signatures associated with mutational load. Results: TMB-H tumors demonstrated a significantly higher prevalence of key oncogenic drivers compared to Low-TMB tumors: KRAS (66.7% vs 47.8%, p < 0.05), PIK3CA (24.1% vs 10.9%, p < 0.05), and FBXW7 (16.7% vs 2.2%, p < 0.01). This suggests that high mutational load is strongly linked to heightened activation of the MAPK and PI3K/AKT signaling axes. Integrated differential expression analysis identified a robust mRNA profile for TMB-H tumors, most notably characterized by the significant upregulation of RBP4 (retinol binding protein 4; p = 0.0003). Furthermore, the oncogenic growth factor MDK (midkine) was markedly elevated in the TMB-H subset (p = 0.02), suggesting that these tumors are associated with a distinct molecular program. TMB-H tumors exhibited a profound downregulation of stromal and myogenic markers, including CNN1 (calponin-1, p = 0.0006) and DES (desmin, p = 0.0014). This depletion of structural extracellular matrix components in TMB-H tumors suggests a more proliferative epithelial state with reduced stromal interference, potentially facilitating better immune cell infiltration. Conclusions: High-TMB CRC is characterized by a distinct molecular phenotype defined by KRAS/PIK3CA driver enrichment and a qualitative transcriptomic shift ( RBP4 / MDK high, CNN1 / DES low). The specific upregulation of RBP4 suggests an altered metabolic or retinoid signaling state, highlighting a potential novel therapeutic vulnerability and co-target for TMB-H patients.
BI-1808 + pembrolizumab: Responses to a chemotherapy-free regimen in advanced ovarian cancer.
2605 Background: Up to 80% of individuals with advanced ovarian cancer experience disease progression after standard platinum-based chemotherapy, leaving few approved therapeutic options and poor prognosis. Anti-PD-1 therapies such as pembrolizumab have shown modest efficacy in recurrent ovarian cancer as single agent therapy with an ORR of 8% (KEYNOTE-100), while adding pembrolizumab to weekly paclitaxel±bevacizumab regimen (KEYNOTE-B96) demonstrates statistically meaningful improvement in OS and PFS in all comers and the PD-L1 CPS ≥1 population. BI-1808 is an IgG1 mAb targeting TNFR2. It blocks TNF-α binding and, via FcγR engagement, depletes Tregs and reprograms myeloid cells, expanding antitumor CD8+ T cells. These mechanisms of action differentiate BI-1808 from the relief of T cell suppression mediated by anti-PD1. Accordingly, in preclinical models BI-1808 synergizes with anti-PD-1 leading to an additive tumor inhibition. During BI-1808 monotherapy exploration, one case of complete response in a platinum-resistant patient was observed. The combination of BI-1808 and pembrolizumab could offer a chemotherapy-free treatment alternative in ovarian cancer. Methods: Safety and efficacy of BI-1808 plus pembrolizumab are being evaluated in patients with advanced pretreated ovarian cancer in a sub-cohort of the ongoing Phase 2a trial (19-BI-1808-01). The signal-seeking cohort aimed to enroll 20 patients at BI-1808 1000 mg Q3W plus pembrolizumab 200 mg Q3W, followed by dose optimization. Results: As of Dec 18, 2025, 24 subjects received BI-1808 plus pembrolizumab. Among 17 response-evaluable patients, 4 achieved confirmed partial response (ORR 24%). Disease control rate was 65%, with 7 patients showing prolonged stable disease, several ongoing beyond 10 months. Strong activity was observed in both high-grade serous and clear cell subtypes. The combination was generally safe and well tolerated; immune related events were manageable and did not lead to treatment discontinuation. Analysis of circulating immune cells shows significant T reg depletion and strong signs of CD8 + T cell activation. Conclusions: Early data from this cohort are highly encouraging, with ORR 24% and DCR 65%. BI-1808 plus pembrolizumab demonstrated a manageable safety profile and promising activity in advanced heavily pretreated ovarian cancer. Based on these findings, the cohort will expand by 20 additional patients focusing on clear cell and high-grade serous subtypes. Further data, including biomarker analyses, will be presented on poster. Clinical trial information: NCT04752826 .
Forecasting global disparities in cervix and corpus uteri cancers: GLOBOCAN 2022–2040 projections.
5614 Background: Uterine cancers, including cervix uteri (C53) and corpus uteri (C54), are a major burden on global healthcare with marked geographic and socioeconomic disparities. Key risk factors including persistent high-risk HPV infection for cervical cancers), limited screening access, and modifiable factors like obesity and exogenous hormone exposure (e.g., oral contraceptive use), which vary across settings and could influence future burden. Predicting epidemiological trends is essential to guide prevention, screening, and treatment modalities. This study compares predicted changes in incidence and mortality for C53 and C54 across countries, WHO regions, income groups, and HDI categories from 2022 to 2040. Methods: Incidence and mortality data for 2022 and predictions for 2040 were extracted from GLOBOCAN database for 185 countries. Countries were classified by WHO region, World Bank income level, and HDI categories. Percentage changes in incidence and mortality were calculated for both cancer types across all categories. Results: Globally, C53 incidence is forecasted to rise from 1.32 million to 5.94 million cases (+348.4%), with mortality increasing from 697,418 to 3.41 million deaths (+389.5%). C54 shows a modest increase in incidence (840,256 to 899,224; +7.0%) but substantial increase in mortality (195,310 to 899,224; +360.5%). Across WHO regions, the largest increases in C53 incidence and mortality occur in AFRO and EMRO (+1043%, +1066% and +918%, +1029%, respectively). C54 incidence advances most in AFRO (+279%) and EMRO (+254%) and least in EURO (+97.8%). Mortality growth is highest in EMRO (+1205%) and AFRO (+1106%). Income-level patterns show increasing disparities: low-income countries have the highest increases for C53 incidence (+1062%) and mortality (+1073%), with high-income regions showing the lowest (+693%, +781%). Similar trends are observed for C54, with incidence rising most in low-income settings (+302%) and least in high-income regions (+139%), while mortality increases range from +1096% (low-income) to +872% (high-income). HDI patterns are similar to income trends: Low-HDI countries reveal the highest increases for C53 (+1062% incidence, +1073% mortality) and C54 (+302%, +1096%), while Very-High-HDI regions show the lowest rises for both cancers. Conclusions: Burden of uterine cancer is predicted to rise steeply by 2040, with greatest increases in low-income, low-HDI, AFRO, and EMRO regions. The disproportionate escalation in mortality (especially for corpus uteri cancers) highlight the importance of prevention, screening, early detection, and equal access to treatment to prevent expanding global disparities, including improved availability of HPV vaccination, targeted public education efforts, and engagement of primary care physicians and OB/GYNs to ensure that patients are vaccinated and screened appropriately.