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Evaluating evidence for UFMylation client diversity

High‐Efficiency Targeted Mitochondrial Transfer and AUTAC4‐Enhanced Dual Renewal Strategy for Rheumatoid Arthritis (Adv. Mater. 32/2026)

Dual‐Color Tunable Circularly Polarized Luminescence With Anti‐Thermal‐Quenching Enabled by Asymmetric Hydrogen‐Bonding Networks in Hybrid Manganese Halides

ABSTRACT Constructing chiral metal halides without relying on chiral organic cations offers exceptional compositional and structural freedom, yet their rational design remains challenging due to the limited understanding of the origins of structural chirality. Here, by employing the achiral 4‐benzylpiperidine (4‐BPP) cation and controlling the crystallization pathways, we access two distinct manganese bromide polymorphs: centrosymmetric α‐(4‐BPP) 2 MnBr 4 (space group I 2/a) and chiral β‐(4‐BPP) 2 MnBr 4 (space group P 2 1 ). Detailed crystallographic analysis reveals that asymmetric hydrogen‐bonding interactions at the organic‐inorganic interface of β‐(4‐BPP) 2 MnBr 4 amplify the distortion of [MnBr 4 ] 2− tetrahedra, driving symmetry breaking and giving rise to inherent chirality. The resulting chiral phase exhibits anti‐thermal‐quenching green‐red dual emission, in which the red component originates from distortion‐induced self‐trapped excitons and is further modulated via energy transfer from green‐emissive Mn 2+ centers. Consequently, dual‐color tunable circularly polarized luminescence (CPL) is realized in chiral metal halides for the first time, featuring a large dissymmetry factor (g lum ) of 7 × 10 −2 . Moreover, the non‐centrosymmetric crystal structure enables efficient second‐ and third‐harmonic generation. These findings elucidate how hydrogen‐bonding interactions govern structural chirality at the molecular level and establish a general design principle for engineering chiroptical and nonlinear optical properties in metal halides.

Sustained efficacy and long-term outcomes of autologous oral mucosal epithelial cell sheet transplantation for pediatric esophageal anastomotic restenosis

Abstract Refractory anastomotic restenosis following surgery for congenital esophageal atresia (CEA) or congenital esophageal stenosis (CES) remains a serious complication in pediatric surgery. Repeated endoscopic balloon dilatation (EBD) under general anesthesia often impairs growth, feeding function, and overall quality of life (QOL). We have developed a regenerative therapy using autologous oral mucosal epithelial cell sheets. This study aimed to evaluate the long-term safety and efficacy of epithelial cell sheet transplantation for refractory esophageal restenosis in pediatric patients. Between 2018 and 2024, epithelial cell sheet transplantation was performed immediately after EBD in six patients (aged 8–41 years) with refractory anastomotic restenosis following surgery for CEA and/or CES. The cell sheets were fabricated by culturing oral mucosal tissue harvested from each patient in temperature-responsive culture dishes with autologous serum, then non-enzymatically detached and endoscopically transplanted onto the stricture site. Postoperatively, patients were monitored for 48 weeks to assess EBD frequency, endoscopic patency, dietary status, and adverse events. In later cases, evaluation for eosinophilic esophagitis (EoE) was also performed. No serious adverse events were observed in any of the patients, confirming the safety of the procedure. One patient showed only temporary improvement and required surgical reconstruction. In four patients, long-term patency was achieved without the need for additional EBD, with the longest recurrence-free period lasting up to five years. Swallowing function, dietary intake, and overall QOL markedly improved in all of these cases. Notably, two patients had concomitant EoE, suggesting that inflammation control may influence therapeutic outcomes. Transplantation of autologous oral mucosal epithelial cell sheets appeared to promote safe and sustained epithelial regeneration and functional recovery in pediatric patients with refractory esophageal strictures. Combining intervention before irreversible fibrotic remodeling is established with control of inflammation and optimization of the local environment to support engraftment may further enhance therapeutic efficacy. Trial registration: UMIN, UMIN000034566, registered 19 October 2018, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039393 . jRCT, jRCTb030190278, registered 31 March 2020, https://jrct.mhlw.go.jp/en-latest-detail/jRCTb030190278 .

YhbO is a DJ-1 family glyoxalase and α-oxoaldehyde hydratase that confers resistance to reactive carbonyl stress (112)

A phase II study of perioperative cadonilimab (AK104) in patients with recurrent resectable head and neck squamous cell carcinoma.

2529 Background: Salvage surgery is standard of care for patients with recurrent, resectable head and neck squamous cell carcinoma (HNSCC); However, the efficacy of salvage surgery remains limited. Therefore, there is an urgent need to explore new therapeutic strategies to further improve the survival of this patient subset. Cadonilimab, a PD-1/CTLA-4 bispecific antibody, uses an IgG-ScFv structure with Fc domain point mutations, allowing for high retention in tumor tissue, and providing enhanced stability and improved safety. In this study, we aim to explore the efficacy and safety of neoadjuvant and adjuvant Cadonilimab combined with salvage surgery in patients with recurrent, resectable HNSCC. Methods: This was an open-label, single-institutional phase II clinical trial (ChiCTR2400079741). Patients aged 18-75 years, pathologically confirmed recurrent HNSCC (oral, laryngeal, hypopharyngeal, and oropharyngeal carcinoma), and with resectable diseases assessed by surgeons were included. Eligible patients received two cycles of Cadonilimab (6mg/kg, ivgtt, q2w) 2-4 weeks before surgery, then treated by salvage surgery, followed by 12 cycles of adjuvant Cadonilimab. Primary endpoint was 1-year disease free survival (DFS), and secondary endpoints were objective response rate (ORR), major pathological response (MPR), OS and safety. Results: From November 2023 to December 2024, a total of 32 patients were enrolled. One patient refused surgery, and 31 patients were included in the final analysis. According to radiological assessment, the ORR was 28.1% (9/32), with 2 cases of complete response (CR) and 7 cases of partial response (PR). Among the patients receiving surgical resection, the MPR rate was 32.3% (10/31), with 9.7% (3/31) of patients achieving pathological CR. With a median follow-up of 18.8 months (range, 13.0-25.7 months), the 1-year DFS rate was 77.4%, and the 1-year OS rate was 87.1%. Treatment-related adverse events (TRAEs) occurred in 74.2% (23/31) of patients. The majority of TRAEs were grade 1 or 2. Grade ≥3 TRAEs occurred in 6.5% (2/31) of patients, including one case of grade 3 neutropenia and one case of grade 4 immune-related hepatitis. The most common TRAEs were hypothyroidism (25.8%, n=8), anemia (25.8%, n=8), lymphocytopenia (19.4%, n=6), fatigue (16.1%, n=5), myocarditis (12.9%, n=4), constipation (12.9%, n=4), rash (12.9%, n=4), elevated ALT/AST levels (12.9%, n=4), and neutropenia (6.5%, n=2). Conclusions: Cadonilimab demonstrated encouraging anti-tumor activity and acceptable safety profile in patients with recurrent, resectable HNSCC. Cadonilimab may change the therapeutic approach for recurrent, resectable HNSCC. Clinical trial information: ChiCTR2400079741.

Beyond survival: Understanding unmet needs among a diverse cohort of ovarian cancer survivors.

5578 Background: Improvements in therapy have resulted in a growing population of ovarian cancer survivors, with both incidence and survivorship increasing among non-White racial and ethnic groups. Despite increasing survivors, supportive care for ovarian cancer survivors has been reported as insufficient. Existing instruments to address survivorship needs were developed in homogenous populations, predominantly consisting of White patients. The purpose of this study was to gain a deeper understanding of the needs and experiences in a diverse cohort of ovarian cancer survivors. Methods: Structured focus groups of ovarian cancer survivors were conducted at a single academic NCI-designated cancer center. During focus groups, participants were guided in discussion about their experience, perspective, and unmet needs as an ovarian cancer survivor. The topics were developed in consultation by providers involved in direct ovarian cancer research and patient care. Thematic analysis was used to systematically code and analyze focus group transcripts, allowing for identification of recurrent patterns and themes within the data. Results: Three focus groups of 20 patients were conducted. 12 (60%) patients identified as White, 4 (20%) as Asian, 3 (15%) as Black, and 1(5%) as Hispanic; additional patient characteristics are in Table 1. Participants generally reported their care during treatment was efficient and streamlined; however, gaps in survivorship care emerged. Key themes included poor care coordination with non-oncologic providers, feelings of abandonment after active treatment, limited communication about long-term expectations after surgery and/or chemotherapy, lack of individualized care plans, and uncertainty about where to find reliable resources. Suggested improvements included centralized access to survivorship resources, expanded peer support opportunities, and more tailored, patient-specific communication. Conclusions: The study highlights specific gaps in ovarian cancer survivorship among a diverse patient population. Deficits in care coordination, individualized communication, and access to tailored resources may contribute to feelings of abandonment and uncertainty following treatment. Targeted survivorship interventions addressing these areas may help to improve quality of life among an increasingly diverse population of ovarian cancer survivors. Focus group characteristics (N=20). Patient Characteristics # of Participants Age Range (Years) <50 4 50-59 7 60+ 9 Time Since Diagnosis (years) >10 2 5-10 4 3-5 2 <3 12

A phase Ib/IIa study of BAT8010+BAT1006, an anti-HER2 monoclonal antibody-exatecan conjugate combined with an ADCC-enhanced HER2 mAb in patients with advanced solid tumors: Results from the HER2-positive GC/GEJC cohort.

e16034 Background: BAT8010 is an ADC argeting HER2, while BAT1006 is a humanized monoclonal antibody targeting another epitope of HER2, with ADCC enhancement activity via completely devoid of fucose. Expansion cohort of ≥1st-line HER2-positive gastric/gastroesophageal junction cancer patients enrolled, treated with BAT8010 + BAT1006. Methods: Patients in this open-label, multicenter clinical trial received BAT8010 +BAT1006 on day 1 of a 21-day cycle until intolerable or disease progression occurred. The study objectives included assessing tolerability, safety, pharmacokinetic characteristics, immunogenicity, and preliminary efficacy. Results: As of January 5, 2026, 34 HER2-positive GC/GEJC patients were enrolled, with a median of 2 prior lines of therapy, and received BAT8010 2.4 mg/kg in combination with BAT1006 15 mg/kg.Favorable efficacy was observed with a manageable and predictable safety profile; dose optimization is ongoing in the BAT8010 2.1 mg/kg in combination with BAT1006 15 mg/kg dose cohort. Safety: Among the 34 patients who received at least one dose of BAT8010 in combination with BAT1006, at least one treatment-emergent adverse event (TEAE) was reported in 32/34 (94.1%) patients. The most common TEAEs (≥25%) were neutropenia, leukopenia, anemia, thrombocytopenia, elevated alanine aminotransferase, hypoalbuminemia, diarrhea, and infusion-related reaction (IRR). Most TEAEs were Grade 1/2; however, Grade 3 or higher AEs were reported in 68.8% of patients, including neutropenia (22/34, 64.7%), leukopenia (10/34, 29.4%), thrombocytopenia and anemia (each 5/34, 14.7%). No cases of interstitial lung disease (ILD)/pneumonitis were reported. Efficacy: Among 34 patients with at least one tumor assessment, 15 achieved PR and 18 SD, yielding an ORR of 44.1% (15/34) and a DCR of 97.1% (33/34); the mPFS was 7.52 months (95% CI: 4.53–NR).The overall survival (OS) data remain immature due to insufficient follow-up duration. Conclusions: BAT8010 in combination with BAT1006 is well-tolerated with manageable toxicity, and demonstrates promising preliminary antitumor activity in HER2-positive GC/GEJC. Dose expansion studies in this patient population are ongoing, and further confirmatory clinical trials are planned to initiate for the additional validation of its safety and efficacy. Clinical trial information: NCT06376136 .

Comparison of the toxicity profile of different ADT + ARPI combinations in prostate cancer (PC) patients (pts): A systematic review and meta-analysis.

e17020 Background: ARPI selection in PC pts is primarily guided by comorbidities and drug interactions. To date, there are few direct comparisons between ARPIs with regard to toxicity profiles. Methods: we conducted a systematic review of all trials assessing treatment with ADT+ARPI vs ADT alone for PC pts, using the PubMed/Medline and Cochrane library databases. We then performed a meta-analysis including all adverse events (AEs) of interest: asthenia, cardiac arrhythmia, cardiac disorders (CD), coronary artery disease (CAD), falls, fractures, fatigue, hot flushes (HF), hypertension (HTN), mental impairment (MI), psychiatric disorders, seizure, skin toxicity (ST), weight loss (WL), weight gain. The comparison between ADT+ARPI vs ADT in terms of AEs was assessed using odds ratio (OR) as meta-analytic outcome. Results: We identified 21 trials including 18,453 pts (10,422 ADT+ARPI; 8,031 ADT): 7 studies evaluated abiraterone (abi), 4 apalutamide (apa), 4 darolutamide (daro) and 6 enzalutamide (enza). All ARPIs increased fracture risk (abi: OR 2.07 95%CI 1.17-3.68; apa: OR 2.38 95%CI 1.82-3.11; daro: OR 1.52, 95%CI 1.12-2.07; enza: OR 1.88, 95%CI 1.28-2.75) and HTN (abi: OR 1.87, 95%CI 1.43-2.45; apa: OR 1.27, 95%CI 1.09-1.47; daro: OR 1.27, 95%CI 1.02-1.58; enza: OR 2.43, 95%CI 1.5-3.95), vs ADT. The addition of abi increased the risk of CD (OR 1.43, 95%CI 1.18-1.73) and HF (OR 1.09, 95%CI 1.03-1.15), while no significant difference was found in other AEs. The addition of apa increased the risk of falls (OR 1.35, 95%CI 1.06-1.72), ST (OR 4.15, 95%CI 3.18-5.4) and WL (OR 3.08, 95%CI 2.08-4.57) no significant difference was found in other AEs. The addition of daro increased the risk of CAD (OR 1.57, 95%CI 1.03-2.4), while no significant difference was found in other AEs. The addition of enza increased the risk of asthenia (OR 1.64, 95%CI 1.35-1.99), falls (OR 2.39, 95%CI 1.77-3.24), fatigue (OR 1.53, 95%CI 1.25-1.86), HF (OR 1.64, 95%CI 1.26-2.14), MI (OR 2.77, 95%CI 2.02-3.79) and WL (OR 1.38, 95%CI 1.07-1.78) while no significant difference was found in other AEs. Analyzing the confidence intervals, enza caused more asthenia and HF than abi, more falls than daro and apa, and more HTN than apa while apa caused more ST and WL than daro and enza. Conclusions: Our results identified differences in toxicity profile of different ARPIs, which could help clinicians identify the most appropriate ARPI for each individual patient.

Alirocumab plus cemiplimab in immuno-refractory metastatic NSCLC: A single-arm, multi-center, phase 2 study.

2619 Background: Immunotherapy resistance remains a significant unmet clinical need for most non-small cell lung cancer (NSCLC) patients. PCSK9 was shown in preclinical models to mediate cancer immunotherapy resistance and may serve as a novel immuno-inhibitory target. Methods: This is a first-in-class, multi-center, single arm, phase II study evaluating the clinical activity and safety of the PCSK9 inhibitor, alirocumab, in combination with the anti-PD1 antibody cemiplimab, in non-small cell lung cancer (NSCLC) patients whose tumors were previously resistant to immune checkpoint blockade. The primary endpoint was objective response rate (ORR). Secondary endpoints were safety, progression free survival (PFS), overall survival (OS), duration of response (DOR) and disease control rate (DCR). The correlative objective was to analyze the biomarkers of response. Results: A total of 60 patients were enrolled between May 2023 and August 2025. In the 58 evaluable patients, the estimated ORR for the two-stage design was 14.98% (90% CI, 5.45, 25.52). The median duration of response was not estimable. The median OS was 7.2 months (95% CI, 5.3 – 13.6). No new safety signals were seen. Non-hematologic adverse events (AEs) were more prevalent than hematologic AEs and were predominantly grade 2 or less. Two grade 3 events were seen. Biomarker analysis identified superior outcomes in NSCLC harboring PIK3CA, AKT1 , or PTEN alterations, with ORR of 31.5% (95% CI,13.9%, 68.4%,), significantly associating with response, p 0.0008 (two-sided, Fisher’s exact). No objective responses were observed in the absence of PIK3CA, PTEN or AKT1 alterations. Median OS was numerically longer in the altered group was 13.64 months (95% CI, 3.1 – NR) compared to 7.2 months (95% CI, 5.2-12.8) in the unaltered group. Analysis of the cancer genome atlas (TCGA) in NSCLC cohorts demonstrated a correlation between PIK3CA, PTEN and AKT1 expression and PCSK9 expression. Preclinical translational studies further elucidated the impact of PIK3CA, PTEN or AKT1 in intratumoral PCSK9 secretion, a novel immune-oncological finding for this pathway, and provided a biological rationale for the observed pattern of response. Conclusions: These findings provide clinical proof-of-principle that PCSK9 inhibition can overcome immunotherapy resistance in a subset of patients and suggest that PIK3CA/PTEN/AKT1 pathway may play a significant role in PCSK9 mediated immune evasion and could be a biomarker of response. These findings warrant further investigation in a larger confirmatory study. Clinical trial information: NCT05553834 .

Leronlimab in combination with trifluridine/tipiracil (TAS-102) plus bevacizumab for patients with refractory metastatic colorectal cancer (mCRC): The phase 2 CLOVER study.

e15525 Background: C-C chemokine receptor 5 (CCR5) is implicated in tumor progression, immune modulation, and metastatic behavior in colorectal cancer. Leronlimab (LRM) is a humanized monoclonal antibody targeting CCR5 already showing promising activity in patients with metastatic triple-negative breast cancer. The open-label phase-2 CLOVER (CCR5-targeting leronlimab with Oral chemotherapy and VEGF-inhibitor Enriched Regimen) trial evaluates the efficacy and safety of LRM in combination with TAS-102 plus bevacizumab (BEV). Methods: CLOVER (NCT06699836) plans to enroll up to 60 patients with refractory mCRC eligible for TAS-102 plus BEV and with CCR5-positive tumors by IHC. LRM will be administered weekly at 350 mg (cohort 1) or 700 mg (cohort 2) subcutaneously, with TAS-102 plus BEV at standard doses. Cohort 2 will be initiated if no LRM dose-limiting toxicities (DLTs) are seen in cohort 1. Primary objectives include safety and objective response rate per RECIST v1.1 criteria. Other evaluations include ctDNA kinetics, and PD-L1 expression on circulating tumor cells (CTCs) and cancer associated macrophage-like cells (CAMLs). Results: All pre-screened patients with evaluable archival samples met prespecified criteria for CCR5 expression (Table). As of abstract drafting 23/37 (62.2%) screened patients have been enrolled. No LRM-related DLTs have been observed at 350 mg and 700 mg LRM dosing has commenced. Among six patients with evaluable centrally assessed images all patients thus far have stable disease and remain on study treatment. All patients with available data have shown a numerical reduction in ctDNA by as early as Week 2 (Table) either paralleling or preceding clinical/biomarker improvement (CEA, CA-19-9, liver function tests). Increases in PD-L1 have been observed in CTCs and CAMLs (Table). Conclusions: In the CLOVER trial LRM in combination with TAS-102 plus BEV has been well tolerated with no LRM-related DLTs. Rapid declines in ctDNA have been observed along with stable objective responses, with most patients having baseline liver metastases and RAS-mutant. At the time of abstract submission approximately half of the target number of patients have been enrolled and at the time of presentation the trial is expected to be fully or close to fully enrolled. Observations of increases in PD-L1 on CTCs and/or CAMLs are hypothesis-generating and support investigation of immune checkpoint inhibitor strategies for patients who progress. Clinical trial information: NCT06699836 . Parameter Result CCR5 expression for all pre-screened patients: n/N (%) 64/64 (100%) Age (N=23): median (range) 51 years (31-76 years) Weight (N=23): median (range) 73.8 kg (46.2-112.9) Sex (N=23) Male n=15; female n=8 Change in tumor size: median (range) -10.2% (+12.5 to -28.4%) Change in ctDNA (N=11): median (range) -85% (-9%-99%) PD-L1 increase in CAMLs/CTCs by Week 5 (N=17) 12/17 (70.6%)

Efficacy and safety of enzalutamide (ENZA) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) and cardiometabolic comorbidities (CMDs) and/or related concomitant medications (meds): ARCHES post hoc.

5092 Background: In ARCHES, ENZA improved radiographic progression-free survival (rPFS; primary: data cutoff, Oct 14, 2018) and overall survival (OS; prespecified secondary: data cutoff, May 28, 2021; 5-yr follow-up; data cutoff: Jul 31, 2024) vs placebo (PBO) in mHSPC. Our objective was to evaluate efficacy/safety of ENZA in pts with CMDs on related concomitant meds. Methods: We examined two groups: 1) full CMD (fCMD): pts with CMDs or on concomitant CMD meds; 2) confirmed CMD (cCMD): pts on CMD-related meds + confirmed CMD diagnosis, validated by medical history captured in concomitant med domain. CMDs included hypertension, cardiac disorders, dyslipidemia, diabetes mellitus. Related concomitant meds were diabetes meds, vasoprotectives, cardiac meds, lipid-modifying agents, antithrombotics, antihypertensives. Primary endpoint: rPFS (fCMD population; data cutoff: Oct 14, 2018). Other endpoints: OS, safety (fCMD population; data cutoff: May 28, 2021). Kaplan–Meier used for time-to-event analysis, with treatment (tx)-group comparisons assessed by stratified log-rank test and hazard ratios (HRs) relative to PBO using Cox proportional hazard models. Sensitivity analysis with cCMD population evaluated rPFS and OS, with OS adjusted for crossover with rank-preserved structure failure time model. Results: Of 1150 pts, 938 (82%) were categorized as fCMD and 756 (66%) as cCMD. In the fCMD group, ENZA showed an association with improved rPFS and OS, with similar results for all sensitivity analyses (Table). Similar results also seen in all concomitant med subgroups. At 2021 data cutoff, median tx duration was 41 mo in the ENZA arm, 14 mo in the PBO arm. Tx-emergent adverse event (TEAE) rates (per 100 pt-yr) were similar with ENZA (313.8) and PBO (468.0). TEAEs of special interest rates (per 100 pt-yr) with ENZA vs PBO: fatigue (14.4 vs 18.0); falls (6.2 vs 2.6); fractures (7.3 vs 5.4); select cardiovascular events (2.5 vs 1.6); convulsions (0.2 vs 0.5). No new safety signals were identified. Conclusions: Similar to the overall mHSPC study population, ENZA was efficacious and tolerable in pts with CMD. Optimizing CMD may further enhance outcomes for pts with mHSPC, but ENZA remains a front-line option for all mHSPC pt subgroups. Clinical trial information: NCT02677896 . ENZA, n (%) ENZA, median (mo) (95% CI) PBO a , n (%) PBO a , median(mo) (95% CI) HR (95% CI) a Nominal P value fCMD n = 468 n = 470 rPFS 73 (16) NE (NE–NE) 159 (34) 19.5 (16.6–NE) 0.39 (0.29–0.51) <0.0001 OS 123 (26) NE (NE–NE) 169 (36) NE (49.7–NE) 0.62 (0.49–0.78) <0.001 Crossover adjusted OS b 123 (26) NE (NE–NE) 169 (36) 49.7 (44.5–NE) 0.56 (0.43–0.69) <0.001 cCMD n = 377 n = 379 rPFS b 59 (16) NE (NE–NE) 126 (33%) 19.5 (16.6–NE) 0.41 (0.30–0.56) <0.0001 OS b 98 (26) NE (NE–NE) 137 (36) NE (49.7–NE) 0.62 (0.48–0.80) 0.0002 a Comparator; b Sensitivity analysis. NE, not evaluable.

Carboplatin-based versus cisplatin-based induction-concurrent chemoradiotherapy with locoregionally advanced nasopharyngeal carcinoma: A multicenter, parallel-group, non-inferiority, randomized, phase 3 trial.

6004 Background: Cisplatin-based chemoradiotherapy has been the standard of care in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, the cisplatin-based chemotherapy is known to the severe side-effects and poor compliance. Carboplatin is the second-generation platinum drug with similar anti-cancer efficacy but less side-effects. The purpose of this study is to investigate whether the carboplatin-based induction-concurrent chemoradiotherapy was non-inferior to the cisplatin-based induction-concurrent chemoradiotherapy in LA-NPC. Methods: We performed a multicentre, parallel-group, non-inferiority, randomized, phase 3 trial at six institutions in China. Patients initially diagonosed with non-keratinizing NPC and stage III-IVa were randomly assigned to carboplatin group or cisplatin group. Patients in the carboplatin or cisplatin group received two cycles carboplatin-based or cisplatin-based induction chemotherapy, followed by concurrent chemoradiotherapy with carboplatin or cisplatin for two or three cycles. Allocation was done by a central randomization system using sequentially numbered, opaque, sealed envelopes. The primary endpoint was 3-year failure-free survival (FFS). Secondary endpoints are overall survival (OS), distant metastasis-free survival (DMFS), loco-regional failure-free survival (LRFFS), and toxic effects. If the upper limit of the 95% CI for the difference in 3-year failure-free survival between the carboplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. This trial is registered with ClinicalTrials.gov, NCT03919552. Results: From Apr 16, 2018 to Aug 7, 2024, a total of 482 patients were enrolled and randomly assigned to carboplatin group (n=241) or cisplatin group (n=241). With a median follow-up of 40.0 months (IQR 21.0-57.0), the 3-year FFS was 84.8% (95%CI 79.5-90.1) in carboplatin group and 86.8% (82.1-91.5) in the cisplatin group (stratified hazard ratio [HR] 1.14, 95% CI: 0.70-1.85, p=0.576), with a difference of 2.0% (95% CI –9.1 to 5.0; p non-inferiority=0.0134). Patients in the cisplatin group had a higher frequency of grade 3 or 4 neutropenia (32% vs 23%, p = 0.04), and anaemia (17% vs 4%, p < 0.001). A significantly higher frequency of any grade nausea (78% vs 58%, p < 0.001), vomiting (40% vs 19%, p < 0.001), and nephrotoxicity (43% vs 18%, p < 0.001). No patients died from treatment-related causes. Conclusions: The primary results indicated that carboplatin-based induction-concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based induction-concurrent chemoradiotherapy for patients with LA-NPC. A longer follow-up is needed to confirm the promising regimen. Clinical trial information: NCT03919552 .

Outcomes of patients with cancer admitted to a dedicated oncology service within a multisite home hospital program.

1504 Background: Home hospital programs deliver acute, inpatient-level care in patients’ homes, and many health systems have adopted these programs after CMS granted a waiver for acute hospital care at home in November 2020. These programs may offer advantages for patients with cancer, including reduced exposure to hospital-associated complications and increased time at home. However, evidence describing outcomes for patients with cancer admitted to home hospital programs remains limited. In March 2025, Mass General Brigham (MGB) launched an oncology service within the system’s multisite home hospital program. Here we describe outcomes among patients with cancer admitted to this service and compared them with outcomes of patients admitted to a brick and mortar (B&M) oncology service. Methods: We conducted a retrospective cohort study of patients with cancer admitted to MGB’s home hospital program between March 1, 2025 and December 31, 2025. Patient demographics, admission diagnosis, length of stay (LOS), the rate of escalations (patients requiring transfer back to a B&M hospital for increased acuity of care), and 30-day readmission rates were collected. Propensity score matching was used to construct a cohort of patients discharged from a B&M oncology service during the year prior to the launch of the home hospital oncology service. Total LOS and 30-day readmission rates were compared between the cohorts using multivariable regression models. Results: There were 137 patients admitted to the home hospital oncology service during the period of analysis. The mean age was 69.7, 53.3% of patients were male, 70.8% were non-Hispanic White, and 87.6% spoke English. The most common admission diagnoses were sepsis (16.1%), skin/soft tissue infections (13.9%), urinary tract infections (10.2%), and renal and electrolyte disorders (10.2%). Twenty patients (14.6%) were admitted directly from an Emergency Department and 85.4% of patients were transferred from inpatient services. The average LOS was 8.9 days, 4.5 days on a B&M service and 4.4 days admitted to home hospital, and the escalation rate was 10.2%. The 30-day readmission rate was 15.8%. When compared to a propensity score matched cohort of patients discharged from a B&M oncology service, the average LOS was not significantly different while the 30-day readmission rate was significantly lower among patients discharged from home hospital. Conclusions: These data show that patients with cancer can be successfully managed in a multisite home hospital program. This dedicated oncology service was able to care for patients with cancer with broad array of admission diagnoses, and the 30-day readmission rate was lower when compared to a cohort of matched patients discharged from a B&M oncology service. Home hospital is a promising model to provide acute care at home for patients with cancer and warrants further study.

PD-L1 upregulation as a reflection of distinct immune contexts in luminal and basal breast cancer.

1040 Background: PD-L1 immunohistochemistry (IHC) is an approved biomarker to select patients with metastatic triple-negative breast cancer for immune checkpoint blockade (ICB). However, PD-L1 performs poorly in Luminal breast cancer, suggesting that PD-L1 upregulation may reflect distinct immune contexts across intrinsic subtypes. We hypothesized that PD-L1 expression can arise in either a canonical T-cell–inflamed state or a discordant PD-L1–high, T-cell–non-inflamed state. Discordance between PD-L1 expression and T-cell inflammation highlights the complexity of tumor–immune interactions, and accumulating evidence supports that malignancies can induce immune alterations systemically. To explore these broader immune features with a noninvasive approach, we examined plasma extracellular vesicles (EVs). Methods: We analyzed 1,084 primary invasive breast cancers from TCGA, focusing on Luminal (LumA/LumB) and Basal subtypes (n=867). PD-L1 status was defined using CD274 mRNA tertiles as a transcriptomic proxy for IHC, and a T-cell–inflamed signature (Ayers 18-gene TIS) classified tumors as inflamed (top 20th percentile), consistent with prior transcriptomic studies. Biomarker concordance was defined as the proportion of PD-L1-high tumors that were also TIS-high. Because CD274 is included in the TIS, analyses were interpreted conservatively with planned sensitivity analyses excluding CD274. For translational feasibility, EV profiling workflows were developed using plasma from the PyMT-N mouse model (immune-cold, myeloid-dominant TIME; method-development model, n=1). Plasma EVs from two patients with advanced breast cancer and one healthy control were profiled using proteomic and targeted EV RNA assays. Results: In Basal tumors, PD-L1 expression aligned with T-cell inflammation: 75.6% (65/86) of PD-L1-high tumors were TIS-high. In contrast, Luminal tumors showed reduced concordance, with only 39.4% (80/203) of PD-L1-high tumors classified as TIS-high. Basal PD-L1-high tumors were significantly more likely to be TIS-high than Luminal tumors (OR 4.76; 95% CI 2.70–8.39; p=1.90×10⁻⁸). These findings indicate frequent uncoupling of PD-L1 expression from T-cell inflammation in Luminal breast cancer. In PyMT-N plasma EVs, proteomic profiling detected myeloid-suppressive proteins with minimal T-cell–inflamed signals. In exploratory human plasma EVs, both proteomic and RNA assays captured immune-related signals, supporting EV profiling feasibility. Conclusions: PD-L1 upregulation occurs in distinct immune contexts that differ by intrinsic subtype, with reduced T-cell–inflamed concordance in Luminal breast cancer. This discordance may explain the limited utility of PD-L1 as a stand-alone biomarker in this subtype. Plasma EV profiling may capture systemic immune biology and provide orthogonal information to tumor-based assays, supporting further prospective evaluation.

Real-world comparative outcomes of intensive induction with 7+3 plus midostaurin versus azacitidine, venetoclax, and gilteritinib in FLT3-mutated acute myeloid leukemia.

e18551 Background: FLT3-mutated acute myeloid leukemia (AML) is associated with aggressive disease biology and historically poor outcomes. Although intensive induction with cytarabine, anthracycline, and midostaurin remains a standard frontline approach, lower-intensity regimens incorporating venetoclax and FLT3 inhibitors are gaining progressive usage in clinical practice, particularly among older or medically complex patients. However, comparative real-world survival outcomes between these strategies are limited. We evaluated overall survival (OS) among patients with FLT3-mutated AML treated with intensive versus lower-intensity FLT3-directed regimens. Methods: We conducted a retrospective cohort study using the TriNetX global federated research network, including 113 healthcare organizations. Adult AML patients with primary disease receiving frontline therapy with either intensive induction using cytarabine plus anthracycline and midostaurin only (7+3+Mido) or azacitidine, venetoclax, and gilteritinib (Aza+Ven+Gilt) only were identified, excluding those who received other therapies or stem cell transplants. Treatment initiation served as the index event. Outcomes were assessed from day 1 through 1095 days. Propensity score matching (1:1) was performed based on demographic characteristics and disease stage. The primary endpoint was OS, evaluated using Kaplan-Meier analysis and hazard ratios (HR). Results: A total of 716 patients were identified, including 639 treated with 7+3+Mido and 77 treated with Aza+Ven+Gilt. After propensity score matching, 41 patients were included in each cohort. Mortality occurred in 10 patients (25.0%) treated with 7+3+Mido, compared with 26 (63.4%) treated with Aza+Ven+Gilt. Intensive induction was associated with a significantly lower risk of death (risk ratio 0.39; odds ratio 0.19; p=0.001). Median OS was not reached in the 7+3+Mido cohort, whereas it was 266 days in the Aza+Ven+Gilt cohort. 3-year survival probability was 66.8% vs 20.3%, respectively. Intensive induction was associated with significantly improved OS (HR 0.33; 95% CI 0.16-0.69; log-rank p=0.002). Conclusions: In this real-world analysis of FLT3-mutated AML, frontline intensive induction with 7+3+mido was associated with superior overall survival compared with aza+ven+gilt. These findings support continued use of intensive FLT3-directed induction in appropriate patients and highlight the need for larger studies to better define the role and sequencing of venetoclax-based triplet regimens in FLT3-mutated AML. Overall survival outcomes in FLT3-mutated AML. Outcome 7+3+Mido (n=41) Aza+Ven+Gilt (n=41) Deaths, n(%) 10(25.0%) 26(63.4%) Median OS (days) Not reached 266 3-year survival probability 66.8% 20.3% HR for death (95% CI) 1.00 0.33 (0.16–0.69) OS - Overall survival; HR - Hazard ratio.

Chronotherapy in metastatic melanoma: Retrospective outcomes of immunotherapy administration timing in a community practice.

e21580 Background: Circadian rhythms influence immune cell trafficking and PD-1/PD-L1 signaling, suggesting a potential relationship between timing of immune checkpoint inhibitor (ICI) administration and therapeutic response. Although prior studies have reported improved outcomes with morning ICI administration, findings remain inconsistent. This study evaluates whether ICI infusion timing is associated with differences in clinical outcomes among patients with metastatic melanoma treated at a community oncology practice, providing real-world data on chronotherapy in routine care. Methods: A retrospective cohort study of 69 patients diagnosed between 2020 and 2025 with stage IV melanoma was conducted at the Cancer Center of Kansas. Patients were categorized based on timing of their treatments: AM (8:00–12:00) or PM (12:00–17:00). Baseline characteristics, comorbidities, melanoma subtype, and metastatic burden were compared using χ² and Mann–Whitney U tests. Survival outcomes, including progression-free survival (PFS) and time to next treatment (TTNT), were our primary endpoints. Kaplan–Meier estimates with log-rank testing and multivariable Cox proportional hazards models were performed adjusting for age, sex, ECOG performance status, BRAF mutation, and metastatic burden. Treatment-related toxicities (CTCAE v5.0) were analyzed by timing group. Results: Sixty-nine patients were included (AM: n=33; PM: n=36). Median age was higher in the AM group (75 vs. 66 years; p=0.04), while sex, BRAF mutation, and comorbidities were generally balanced. Cutaneous melanoma predominated (AM: 84.8%; PM: 97.1%). Median PFS was numerically longer in the AM group (30.0 vs. 25.5 months; log-rank p=0.859), as was median TTNT (29.0 vs. 14.3 months; p=0.752), though neither difference reached statistical significance. Toxicity rates were comparable (AM: 45.5% vs. PM: 33.3%; p=0.303). On multivariable Cox regression, ECOG PS (HR 5.72 for poor PS; p=0.005) and higher metastatic burden (≥4 sites: HR 9.5–13.0; p<0.01) remained dominant prognostic factors for shorter PFS, whereas infusion timing was not independently associated with outcome after adjustment. Conclusions: Despite biologically plausible circadian effects, morning ICI administration showed a numerical but not statistically significant improvement in PFS and TTNT in our modest-sized community-based cohort. These findings complement and partially contrast with selected prior studies reporting morning infusion advantages. A larger, ongoing multi-center study across additional practices in Kansas is currently expanding the sample size with the goal of improving statistical power and better defining the impact of chronotherapy on melanoma outcomes.

Sonrotoclax (BGB-11417) + zanubrutinib (SZ) vs venetoclax + acalabrutinib (AV) in treatment-naive chronic lymphocytic leukemia (TN CLL): A phase 3 randomized trial design (CELESTIAL-TNCLL-2).

TPS7099 Background: Inhibition of B-cell lymphoma 2 (BCL2) and Bruton tyrosine kinase (BTK) has emerged as an effective fixed-duration treatment (tx) strategy that can induce high rates of undetectable minimal residual disease (uMRD) in patients (pts) with TN CLL. AV is approved in the EU as a first-line fixed-duration tx for TN CLL. Sonrotoclax, a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. Zanubrutinib is a highly potent next-generation BTK inhibitor that is approved in the US/EU for CLL. In an ongoing phase 1/1b trial (NCT04277637), SZ has had promising efficacy, with a 100% ORR (n=135) and high rates of blood uMRD at 10 -4 sensitivity (uMRD4) in pts with TN CLL, including those with high-risk disease features. SZ is generally well tolerated, with neutropenia as the most common grade ≥3 TEAE and no laboratory or clinical TLS events occurred. The phase 3 trial BGB-11417-304 (NCT07277231) was designed to directly compare fixed-duration SZ vs AV in TN CLL to investigate whether SZ compared with AV, may improve efficacy in terms of achieved uMRD rate after completing treatment and PFS and potentially improve tolerability and safety. Methods: BGB-11417-304 is a global phase 3, open-label, randomized study. Eligible adults have a confirmed diagnosis of previously untreated CLL requiring tx per iwCLL 2018 criteria, adequate hematologic and organ function, ECOG PS 0-2, and measurable disease confirmed by CT/MRI. Exclusion criteria include prior systemic tx for CLL; diagnosis of prolymphocytic leukemia or Richter transformation; known central nervous system involvement; history of confirmed progressive multifocal leukoencephalopathy; or uncontrolled hypertension or clinically significant cardiovascular disease. Approximately 500 pts will be enrolled and randomized 1:1 to arm A (3 lead-in cycles of oral zanubrutinib monotherapy followed by 12 cycles of oral SZ) or arm B (2 lead-in cycles of oral acalabrutinib monotherapy followed by 12 cycles of oral AV). Randomization will be stratified by age (<65 y vs ≥65 y), IGHV mutation status, and presence of del(17p) and/or TP53 mutations. The primary endpoint is PFS in arm A vs arm B, as determined by independent review committee (IRC), with an intermediate endpoint of uMRD4 rate in blood and bone marrow in arm A vs arm B, assessed by next-generation sequencing (clonoSEQ) at the first post-tx follow-up visit. Key secondary endpoints are PFS-IRC in high-risk subgroups and OS. Other secondary endpoints are ORR and complete response assessed by IRC and investigator (INV), uMRD5 rate (clonoSEQ), PFS-INV, duration of response by IRC and INV, time to next tx, pt-reported outcomes, and safety/tolerability. Enrollment in BGB-11417-304 is currently ongoing. Clinical trial information: NCT04277637 .

Aspiration pneumonitis and inpatient outcomes in adult cancer hospitalizations: A 2018–2022 National Inpatient Sample analysis.

e23217 Background: Aspiration pneumonitis is frequently conflated with infectious pneumonia in hospitalized oncology populations despite potentially distinct patterns of clinical deterioration and need for intensive care. We compared mortality and indicators of higher-acuity care, including intensive care–level interventions, across aspiration and pneumonia phenotypes in adult cancer hospitalizations. Methods: A serial cross-sectional study of adult hospitalizations with a principal diagnosis of malignancy in the 2018–2022 Healthcare Cost and Utilization Project National Inpatient Sample was performed. Aspiration pneumonitis was identified using any-diagnosis ICD-10-CM codes J69*, and infectious pneumonia using J12–J18. Hospitalizations were categorized using a mutually exclusive exposure variable: (1) neither aspiration nor pneumonia, (2) aspiration pneumonitis only, (3) infectious pneumonia only, and (4) aspiration with infectious pneumonia. Outcomes included in-hospital mortality (primary), mechanical ventilation and shock as escalation-associated endpoints, length of stay (LOS), and hospitalization cost derived using cost-to-charge ratios. Analyses generated national estimates using survey weights with stratification. Multivariable survey-weighted logistic regression was performed to estimate adjusted mortality differences, limited to aspiration-only versus pneumonia-only hospitalizations. Results: Among an estimated 4.81 million cancer hospitalizations that we analyzed, 1.41% were complicated by aspiration pneumonitis alone, 6.04% by infectious pneumonia alone, and 0.22% by combined aspiration and infectious pneumonia. In-hospital mortality differed across phenotypes: 23.97% in aspiration-only hospitalizations, 14.95% in infectious pneumonia alone, and 3.32% in hospitalizations without aspiration or pneumonia. Mechanical ventilation was required in 24.21% of aspiration-only admissions compared with 10.86% in infectious pneumonia, while shock occurred in 7.07% and 3.46%, respectively. Aspiration pneumonitis was associated with longer LOS (16.05 vs 12.39 days) and higher mean cost ($64770 vs $49121) compared with infectious pneumonia. In adjusted analyses comparing aspiration-only with pneumonia-only hospitalizations, aspiration pneumonitis remained independently associated with higher in-hospital mortality (adjusted OR 1.27; 95% CI 1.14–1.42; p < 0.001). Conclusions: Aspiration pneumonitis identifies pulmonary complications among hospitalized adults with cancer, characterized by higher mortality and intensive care–level interventions than infectious pneumonia. Distinguishing aspiration-related events from infectious pneumonia may support earlier risk recognition, targeted airway protection strategies, and proactive planning for higher-acuity care.

Universal adipogenic and immunologic remodeling in the recurrent myeloid leukemia microenvironment of recurrent versus primary myeloid leukemias: An age-stratified analysis.

6596 Background: Disease recurrence is the primary cause of mortality in myeloid leukemias. While molecular studies suggest leukemic cells actively reprogram marrow stroma to create a self-reinforcing niche, natural age-related adiposity confounds whether this remodeling is disease-intrinsic or a byproduct of aging. We sought to validate the "disease-intrinsic" hypothesis by delineating the landscape of recurrent disease across a large-scale transcriptomic cohort, rigorously distinguishing leukemic reprogramming from physiologic aging. Methods: We analyzed 2,378 myeloid leukemia samples (2,007 primary, 371 recurrent) from NCI genomic datasets via xCell computational deconvolution. To control for ontogenic marrow changes, the cohort was stratified into Pediatric (<18 years, n = 2,071) and Adult (≥ 18 years, n = 307) subgroups. Demographic analysis confirmed balanced gender and race distributions (p > 0.05); age disparity was explicitly corrected via the stratified design. Differences in tumor microenvironment (TME) composition were assessed using Mann-Whitney U tests, with Bonferroni-corrected p-values (Padj) calculated to ensure statistical rigor. Results: Recurrent tumors exhibited a profound, convergent stromal remodeling independent of age. The 'adipogenic shift' via Preadipocyte enrichment was observed in both Pediatric (P < 10⁻⁴⁸) and Adult (P < 10⁻⁴) recurrences. Conversely, vascular collapse was universal, characterized by a significant reduction of Pericytes in both Pediatric (P < 10⁻⁷²) and Adult (P < 10⁻⁸) cohorts. Immunologically, CD4+ Memory T cells were consistently enriched in both Pediatric (P < 10⁻²⁶) and Adult (P < 10⁻⁴) groups, suggesting a convergent mechanism of adaptive immune persistence in the relapsed setting. Conclusions: We demonstrate that recurrent myeloid leukemia drives a convergent microenvironmental evolution characterized by vascular collapse, pathologic adiposity, and immune persistence, independent of patient age. These findings corroborate that stromal remodeling is a dominant, disease-intrinsic program actively driven by leukemic cells rather than a passive reflection of aging. Validating this "adipogenic shift" as a universal resistance mechanism identifies the adipogenic and vascular niches as priority targets for therapeutic intervention across the spectrum of myeloid malignancies. Differential enrichment of microenvironmental populations in recurrent vs. primary myeloid neoplasms. Cohort Cell Type Direction Mean Diff (Rec - Pri) Padj Pediatric (<18y) Preadipocytes Recurrence- High +0.064 p < 0.05 Pericytes Primary- High -0.085 p < 0.05 CD4+ Memory T-cells Recurrence- High +0.849 p < 0.05 Adult (≥18y) Preadipocytes Recurrence- High +0.056 p < 0.05 Pericytes Primary- High -0.078 p < 0.05 CD4+ Memory T-cells Recurrence- High +1.184 p < 0.05