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Correlation of ten-year survival with cell-free DNA methylation of melanoma patients with asymptomatic brain metastases treated with nivolumab plus ipilimumab: The multicenter phase III NIBIT-M2 trial.
2008 Background: The NIBIT Foundation-sponsored phase III NIBIT-M2 study showed a 41% 7-y OS of melanoma patients (pts) with asymptomatic brain metastases (BM) treated with ipilimumab (I) plus nivolumab (N) (I+N) ( Di Giacomo AM, CCR 2021 and EJC 2024 ). Despite the significant efficacy of I+N therapy in this pts population, no biomarkers predictive of response have been identified yet also due to the accessibility of BM. We here report the 10-y survival and its correlation with cell-free (cf)DNA analyses on serial plasma samples collected from pts enrolled in the NIBIT-M2 study. Methods: The NIBIT-M2 study recruited melanoma pts with active, untreated, asymptomatic BM from 9 Italian Centers, randomized (1:1:1) to receive fotemustine (F) (Arm A), I+F (Arm B), or I+N (Arm C). Primary endpoint was OS. Exploratory analyses were conducted on cfDNA plasma samples collected at baseline and week (W) 12 on therapy. Tumor fraction (TF) was estimated from low pass WGS using IchorCNA. Tumor-specific methylation Score (T-meth Score) was computed as the ratio between the coverage over methylated regions analyzed by cf-methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) and melanoma-specific methylated regions previously identified in the TCGA melanoma cohort. Results: From Jan 2013 to Sept 2018, 80 pts were enrolled: 76 received F (23), I+F (26), or I+N (27). As of December 1, 2025, with a median follow-up of 125 months (mo), median OS was 8.5 (95% CI: 4.8-12.2), 8.2 (95% CI: 2.1-14.3) and 29.2 (95% CI: 0-73.5) mo for Arm A, B, and C, respectively. The 10-y OS rate was 13.0% (95% CI: 0-26.7) in Arm A, 7.7% (95% CI: 0-17.9) in Arm B, and 31.2% (95% CI: 13.0-49.4) in Arm C. The 10-y melanoma specific survival was 13.0% (95% CI: 0-26.7), 7.7% (95% CI: 0-17.9), and 35.1% (95% CI: 16.3-53.9) in Arm A, B and C, respectively. Patients were stratified at baseline according to the median values of TF (n=57; median 0.022) and of T-meth Score (n=53; median 0.096): a significantly higher median OS was observed in pts with TF (22.3 vs 8.2 mo; p=0.033) and T-meth Score (26.3 vs 7.9 mo; p=0.002) below their median values. Of note, low TF and T-meth Score were enriched at baseline in pts from Arm C. Additionally, a decrease in TF (n=29) and T-meth Score (n=24) was observed at W12 in pts with an OS above the median (26.3 mo for TF and 24.0 mo for T-meth Score). Conclusions: The 10-y results of the NIBIT-M2 study, with the longest follow-up available to date in melanoma pts with asymptomatic BM treated with I+N, continue to show persistent long-term therapeutic efficacy of the combination. Plasma-derived TF and T-meth Score may predict long-term survival of melanoma pts with asymptomatic BM treated with I+N. Clinical trial information: NCT02460068 .
Prediction of localized rectal cancer outcomes with ctDNA analysis using a novel ultrasensitive structural variant (SV)-based method.
3619 Background: Rectal cancer has a high risk of recurrence and incidence is rising. Treatment for rectal cancer has moved towards individualization and organ sparing approaches. Selection for treatment is based on radiology, CEA and pathological risk factors, but stronger biomarkers are needed to improve outcomes. Circulating tumor DNA (ctDNA) has shown high prognostic impact on outcome in localized colorectal cancer (CRC), but few patients with rectal cancer have been included in these trials. In this study, we aim to investigate the role of ctDNA in predicting rectal cancer outcomes. Methods: The multicenter CITCCA study included patients with stage I-III CRC planned for curative treatment and investigated prospective, longitudinal ctDNA testing. Neoadjuvant (NAT) and/or adjuvant (ACT) treatment was administered according to local guidelines. All patients underwent surgery. Follow-up was according to Swedish standard-of-care with CT and CEA at 1 and 3 years. Patients were recruited in Sweden, 2020–2024. Sampling of ctDNA occurred before and after surgery at 4-6 weeks, 3 and 6 months,1 and 2 years and was analysed with Pathlight, an ultrasensitive SV-based assay. The primary outcome was recurrence-free interval (RFI). Results: The study included patients with rectal cancer with a median age of 67 years (range 31-81). Ninety-four patients (65%) received upfront surgery and 51 patients (35%) NAT, of which 36 patients (71%) received short-course radiotherapy and 15 (29%) had total neoadjuvant treatment. Fifty-two patients (36%) were (y)pTNM stage I, 45 patients (31%) stage II and 48 patients (33%) stage III. ACT was given to 38 patients (26%). The success rate for assay generation was 96%. At a median follow-up of 35 months (range 2-46), 23 patients recurred or died of rectal cancer. Before surgery, ctDNA was detected in 136 patients (94%). Notably, 92% (55/60) of patients had ctDNA detected prior to surgery, despite NAT. All patients who recurred had positive ctDNA before surgery, regardless of NAT. Postoperatively, at the 4-6 week clinical landmark (CLM), 18 patients (16%) had detectable ctDNA. At the first test after treatment termination, 17 patients (15%) were ctDNA positive and ctDNA detected recurrence ahead of radiology in 13 patients, including 4/4 patients with stage I disease. Positive ctDNA was strongly associated with recurrence (HR: 94; 95% CI: 20-440) and 3-year RFI at CLM was 22% (95% CI: 9%-56%) for ctDNA positive and 95% (95% CI: 90%-100%) for ctDNA negative patients. Conclusions: CtDNA has strong prognostic potential in stage I-III rectal cancer. Using an ultrasensitive SV-based method shows great promise for individualization of treatment in rectal cancer and should be investigated prospectively for organ-sparing selection. Clinical trial information: NCT04726800 .
Mammogram energy use: Metering to map optimization strategies.
e12714 Background: Mammography is a critical component of screening and diagnosis in breastcancer. A key component of cancer prevention also involves mitigation and avoidance of environmental risk factors. Radiology is an energy-intensive field, with opportunities to impact multifactorial patient wellbeing – providing necessary cancer screening and diagnosis while optimizing clinical operations to reduce energy consumption and minimize associated environmental risks. Methods: We conducted prospective metering of two digital breast tomosynthesis (DBT)machines at a large academic medical center. Unit 1 was metered for 16 days, while Unit 2 was metered for 24 days, from April–May 2025. Scanning volume during the study period was 7-10 scans/device/weekday, with no scans on weekends. Power was measured in kilowatts (kW), and energy was calculated as kilowatt-hours (kWh). DBT units operated in four power modes – ready-to-scan, scan, low-power, and off – defined by EnergyStar and COCIR standards. Usingthe time and power associated with each mode, we calculated the contribution of each mode to total DBT energy consumption. Results: While scan mode consumed the most energy and power in both DBT units, the greatest share of energy consumption for both units over the study period came from ready-to-scan mode (68% Unit 1, 45% Unit 2). The biggest discrepancy between time spent across modes for the two units was low-power mode, with Unit 2 spending 66% of time in low-power (24.61 kWh) and Unit 1 spending 18% (1.58 kWh). Extrapolating to annual energy consumption, Units 1 and 2 were estimated to consume 892.88 and 1,641.97 kWh, respectively (Table 1). Conclusions: These findings reveal opportunities for actionable changes at the oncology practice level to reduce non-productive mammography energy consumption. Downstream, this may both reduce the health impacts of energy-associated pollutant emissions and liberate financial resources for improving patient care. Energy optimization strategies could include reducing turnover time between patients, decreasing duration in energy-intensive ready-to-scan mode, andpowering off machines overnight and on weekends. Future quality improvement studies should evaluate the environmental and cost savings of such interventions. DBT Unit Mode Power (mean kW +/- SD) Power (median kW) Duration (minutes (% of total)) Energy Consumption (kWh (% of total)) Annual Projected Energy Consumption (kWh) Total (Unit 1) - - 23,040 (100%) 40.8 (100%) 892.9 Scan 0.57 ± 0.12 0.58 1190 (5%) 11.4 (28%) 250.9 Ready-to-Scan 0.30 ± 0.013 0.3 5369 (23%) 26.9 (68%) 606.5 Low-Power 0.023 ± 0.057 0.0059 4214 (18%) 1.6 (4%) 35.6 Total (Unit 2) - - 34,560 (100%) 91.3 (100%) 1,642.0 Scan 0.57 ± 0.099 0.5 2005 (6%) 18.5 (18%) 300.2 Ready-to-Scan 0.42 ± 0.046 0.4 6951 (20%) 48.2 (45%) 743.2 Low-Power 0.10 ± 0.018 0.1 22724 (66%) 24.6 (36%) 598.6
Comparative effectiveness of adjuvant TACE versus HAIC after curative resection for high-risk BCLC 0–B hepatocellular carcinoma: A three-center retrospective study.
e16253 Background: Recurrence remains a major challenge following curative resection for early-to-intermediate stage hepatocellular carcinoma (HCC), particularly in patients with high-risk pathologic features. While postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) is widely used, postoperative adjuvant hepatic arterial infusion chemotherapy (PA-HAIC) may provide sustained intrahepatic drug exposure and superior micrometastatic control. We compared oncologic outcomes of PA-TACE and PA-HAIC in BCLC stage 0–B HCC patients at high recurrence risk. Methods: We retrospectively analyzed consecutive HCC patients undergoing curative hepatic resection at two centers (January 2019–December 2024). Patients were categorized into three cohorts: resection alone (LR), PA-TACE, or PA-HAIC. The primary endpoint was recurrence-free survival (RFS); overall survival (OS) was the key secondary endpoint. Propensity score matching (PSM) balanced baseline covariates. Subgroup analyses were performed by microvascular invasion (MVI), tumor size, and multiplicity. A prognostic nomogram for RFS was developed and internally validated. Results: A total of 372 high-risk patients were included. After PSM, both adjuvant strategies significantly improved RFS and OS compared with LR alone. Median RFS was 17.2 months (95% CI, 14.8–19.6) for LR, 38.5 months (95% CI, 32.1–44.9) for PA-TACE, and 46.3 months (95% CI, 39.7–52.9) for PA-HAIC. Median OS was 54.1 months for LR and 67.2 months for PA-TACE; median OS was not reached in the PA-HAIC group. PA-HAIC demonstrated superior disease control over PA-TACE, with higher 1-year (78.6% vs 71.2%), 2-year (62.4% vs 54.8%), and 4-year (41.3% vs 32.6%) RFS rates. The 4-year OS rate was 72.8% for PA-HAIC versus 61.5% for PA-TACE. The RFS nomogram showed good discrimination (C-index: 0.80 training; 0.79 validation). Subgroup analyses revealed PA-HAIC's RFS advantage over PA-TACE was most pronounced in patients with MVI (HR, 0.58; 95% CI, 0.44–0.76), tumor diameter ≥5 cm (HR, 0.61; 95% CI, 0.47–0.79), or multifocal disease (HR, 0.63; 95% CI, 0.48–0.83). Benefits were attenuated in lower-risk subsets. Conclusions: In this PSM-adjusted retrospective study, both PA-TACE and PA-HAIC improved outcomes versus resection alone in high-risk BCLC 0–B HCC patients. PA-HAIC showed superior RFS benefit over PA-TACE, particularly in patients with MVI, larger tumors (≥5 cm), or multifocal disease. Prospective trials are warranted to confirm optimal adjuvant selection and identify patients most likely to benefit.
A retrospective real-world study on the efficacy and safety of anlotinib in combination with immunotherapy as maintenance therapy after standard immunochemotherapy for extensive-stage small cell lung cancer (ALTER-L059).
8080 Background: Although immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the standard first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), the use of immunotherapy as a maintenance strategy remains challenging. This study aims to evaluate the efficacy and safety of anlotinib combined with ICIs as first-line maintenance treatment for ES-SCLC. Methods: ALTER-L059 was a retrospective, multicenter study conducted at 9 hospitals in China. Eligible patients were 18 years or older with histologically or cytologically confirmed ES-SCLC and had completed 4–6 cycles of first-line immunochemotherapy as induction therapy without disease progression. They subsequently received maintenance therapy with immunotherapy combined with anlotinib. The primary endpoint was progression-free survival from the start of maintenance therapy (PFS2). Secondary endpoints included progression-free survival from the start of induction therapy (PFS), overall survival from the start of maintenance therapy (OS2), overall survival from the start of induction therapy (OS) and safety. Results: Between January 2022 and December 2024, a total of 100 patients were enrolled. By the data cutoff date on November 11, 2025, the median follow-up duration was 16.92 months (95% CI: 15.81-18.03). The median PFS2 was 6.05 months (95% CI: 4.83-7.59), and the median PFS was 9.53 months (95% CI: 8.31-11.93). The median OS2 was 17.74 months (95% CI: 15.24-19.71), and the median OS was 21.26 months (95% CI: 18.60-22.60). The incidence of grade 3 or higher treatment-related adverse events (TRAEs) was 30.0%. The most common TRAEs (incidence ≥20%) were hypertension (33.0%), hand-foot syndrome (23.0%), proteinuria (21.0%), and hypertriglyceridemia (20.0%). Conclusions: Patients who had been diagnosed with ES-SCLC and had completed 4–6 cycles of immunochemotherapy as induction therapy without disease progression subsequently received maintenance therapy with immunotherapy combined with anlotinib, demonstrating favorable survival outcomes and manageable toxicity. Clinical trial information: NCT06982287 .
Early circulating tumor DNA dynamics as a prognostic and predictive biomarker in solid tumors treated with immune checkpoint inhibitors: A systematic review and meta-analysis.
e15091 Background: Early identification of patients likely to benefit from immune checkpoint inhibitors (ICIs) remains a major challenge across solid tumors. Circulating tumor DNA (ctDNA) kinetics have emerged as a promising noninvasive biomarker, yet results across studies are heterogeneous. We conducted a systematic review and meta-analysis to evaluate the prognostic and predictive value of early ctDNA reduction in patients receiving ICIs. Methods: A systematic search of PubMed, Embase, Web of Science, and Cochrane Library was conducted from inception through March 2025 following PRISMA guidelines. Studies evaluating early ctDNA dynamics (≤8 weeks after ICI initiation) in adult patients with solid tumors were included. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR). Random-effects models were used to pool hazard ratios (HRs) and odds ratios (ORs). Heterogeneity was assessed using I² statistics, and publication bias was evaluated with funnel plots and Egger’s test. Results: A total of 27 studies encompassing 3,842 patients across lung, melanoma, breast, gastrointestinal, and genitourinary malignancies met inclusion criteria. Early ctDNA reduction (defined as ≥50–90% decline or complete clearance, study-specific) was associated with significantly improved PFS (pooled HR 0.45; 95% CI 0.38–0.53; I² = 41%) and OS (pooled HR 0.40; 95% CI 0.32–0.49; I² = 36%). Patients demonstrating early ctDNA reduction had a markedly higher ORR (pooled OR 4.92; 95% CI 3.71–6.53; I² = 29%). Subgroup analyses showed consistent benefit across tumor types and ICI regimens. Early ctDNA dynamics outperformed baseline PD-L1 expression and tumor mutational burden in predicting treatment response. No significant publication bias was detected. Conclusions: Early ctDNA kinetics are a robust, tumor-agnostic biomarker associated with improved survival and treatment response in patients receiving ICIs. These findings support the integration of ctDNA monitoring into early treatment assessment and clinical trial design. Prospective trials are warranted to validate ctDNA-guided immunotherapy strategies.
Single‐Atom/Nanocluster Synergistic Electrode Derived From Phthalocyanine Salts for Efficient Electroreduction of Nitrate to Ammonia
ABSTRACT Electrochemical nitrate reduction reactions to ammonia represent a promising route to close the global nitrogen cycle, but their practical implementation is hindered by the low conversion efficiency of existing electrocatalysts. Herein, we develop a multiscale regulation strategy to construct a copper‐cobalt co‐modified carbon‐nanofiber‐based self‐supporting electrode (CuCo‐CNF), in which Cu nanoclusters and Co single atoms are selectively anchored using phthalocyanine salts as precursors. Benefiting from the synergistic interaction between dual active sites, the CuCo‐CNF electrode exhibits an outstanding NH 3 yield rate of 11.3 mg h −1 cm −2 with a Faradaic efficiency of 95.84% at −0.7 V versus RHE, outperforming carbon‐nanofiber‐based electrodes. It has been demonstrated that Cu nanoclusters significantly enhance NO 3 − adsorption, reducing the adsorption energy from 0.66 eV on isolated Cu atoms to −1.34 eV, thereby accelerating the initial NO 3 RR kinetics. Moreover, the free‐energy barrier of the rate‐limiting step is substantially lower on Cu nanoclusters (*NO 2 → *NO 2 H, +0.59 eV) than on Cu single atoms (*NO → *NOH, +1.02 eV). Meanwhile, the incorporation of cobalt heteroatoms further promotes active hydrogen generation, further enhancing both reaction rate and NH 3 selectivity. This work establishes an effective strategy for constructing self‐supporting electrodes and offers valuable mechanistic insights into efficient and selective electrocatalytic nitrate‐to‐ammonia conversion.
Photonic Intrinsic Chiral Flatband With Tailorable Quality Factor and Circular Dichroism
ABSTRACT Engineering spin‐selective light‐matter interactions in photonic systems requires precise control of the radiative loss, optical chirality, and dispersion of resonant modes; however, these properties are intricately dependent on the structural parameters, making their independent tuning challenging. Herein, a partially etched dielectric metasurface supporting an intrinsic chiral quasi‐guided mode (QGM) with flatband dispersion is proposed, for which the quality (Q) factor and circular dichroism (CD) can be independently modulated. The QGM is generated via Brillouin zone folding, with its flatband dispersion remaining robust against structural variations within a certain range. The radiative loss and spin‐dependent coupling strength of the QGM can be independently engineered by adjusting the scaling ratio and rotation angle of individual nanostructures, enabling decoupled control of Q factor and CD while maintaining the flatband dispersion. Experimental measurements of the chiral QGM confirm the independent tunability of Q factor and CD, demonstrating angle‐insensitive linear and nonlinear CD. Our work establishes a general physical mechanism for realizing flatband QGMs with independently tunable Q factor and CD, providing a versatile platform for next‐generation functional chiral metasurfaces with potential applications in chiral emission, harmonic generation, and ultrasensitive optical sensing.
Carbon Quantum Dot‐Enabled Microcrystalline Domain Engineering for Selective Four‐Electron Oxygen Reduction
ABSTRACT Engineering carbon‐based electrocatalysts with well‐defined microcrystalline domains remain a central challenge for achieving efficient and durable oxygen reduction reaction (ORR) without relying on noble metals. Here, a carbon quantum dot (CQD)‐enabled microcrystalline domain engineering strategy that regulates graphitic ordering, electronic structure, and active‐site distribution in carbon catalysts is reported. The incorporation of CQDs during carbonization promotes the formation of spatially distributed microcrystalline domains, together with enriched B‐N coordination and optimized charge density. This structural configuration enhances O 2 activation and *O adsorption while suppressing peroxide pathways, thereby favoring a selective four‐electron ORR process. As a result, the optimized catalyst delivers a half‐wave potential approaching that of commercial Pt/C, together with a near four‐electron transfer pathway. When applied as the air cathode in zinc‐air batteries, it exhibits high power densities of 153 mW cm −2 in liquid cells and 123.8 mW cm −2 in flexible devices, along with stable operation over 1200 h. This work establishes CQD‐enabled microcrystalline domain engineering as an effective strategy for regulating structure‐property relationships in carbon electrocatalysts and provides design insights for high‐performance energy conversion devices.
Freeform Manufacturing of Plant‐Based Structural Colors for Scalable Photonic and Mechanochromic Devices
ABSTRACT Plant‐based, iridescent, and dynamically tunable structural colored materials are highly attractive for sustainable photonic devices. However, fabricating complex architectures at the decimeter‐scale with optical fidelity using plant‐derived materials remains challenging, limiting their use in photonic devices and adaptive actuation. Here, we introduce an aqueous two‐phase freeform fabrication strategy for vibrantly colored hydroxypropyl cellulose (HPC), where a robust immiscible aqueous environment is developed to preserve HPC cholesteric structures with < 3% shift in peak reflection wavelength over three days, enabling stable processing of large‐scale structural colored materials. Our technique involves a food‐grade support medium with low interfacial tension, allowing for embedded 3D printing of photonic structures and post‐extrusion recovery of the HPC cholesteric domains. Intricate constructs, including interlocking chainmail, with feature sizes down to ∼50 µm and color consistency over lengths exceeding ten centimeters, can be achieved. Additionally, this approach can be utilized to create non‐planar, mechanochromic hydrogel actuators with programmable multicolor designs, as demonstrated in an octopus‐inspired hydrogel actuator and a color‐shifting display for information encryption, camouflage, and human–machine interaction. Our green, freeform manufacturing approach provides new design possibilities for sustainable photonic devices and can be applied to industrially relevant applications.
Qualitative assessment of barriers and facilitators of vagina dilator use after pelvic radiotherapy in a tertiary cancer centre in Nigeria.
e23262 Background: Pelvic radiotherapy (PRT) is an essential component of curative treatment for many gynaecological cancers. Still, it can also result in late side effects (SE) that impact long-term quality of life. SE include vaginal wall atrophy, bleeding, stenosis, and decreased vaginal length, which can lead to sexual dysfunction and difficulty with future pelvic exams. The late SEs are among the most distressing survivorship concerns for patients treated for gynaecological cancers. Vaginal dilator therapy (VDT) is commonly recommended following a course of PRT to prevent vaginal stenosis. However, many patients, especially older women, remain apprehensive about VDT, despite receiving counselling. The underlying reasons for non-use remain poorly understood. This study aimed to assess the barriers and facilitators to vaginal dilator use among women who receive PRT in Nigeria. Methods: Semi-structured telephone interviews were conducted with 16 women who had previously undergone PRT for gynaecological cancers at a tertiary cancer centre in Nigeria from 2024 to 2026. Interviews were analysed using inductive thematic analysis following Braun and Clarke’s methodology, followed by deductive mapping of identified factors onto the Consolidated Framework for Implementation Research (CFIR). Data collection and analysis were conducted concurrently until thematic saturation was reached. Results: Participants’ use of vaginal dilators was influenced by multiple factors across CFIR domains. At the individual level, perceptions of vaginal dilators as either medically necessary or sexually oriented influenced initiation and continued use. Pain/discomfort, bleeding, and vaginal discharge were commonly cited as reasons for discontinuation. Sociocultural and religious beliefs reportedly did not support the use of vaginal dilators but were overridden by perceived medical necessity. Family and spousal support facilitated adherence. Health system factors, including quality and timing-sensitive education, strongly influenced uptake, while inadequate follow-up limited sustained use. Conclusions: Barriers to vaginal dilator use after pelvic radiotherapy extend beyond individual patient factors and reflect broader sociocultural and health system influences. Implementation strategies that emphasise clear medical framing, patient-centred education delivered at appropriate time points, and follow-up may enhance sustained use.
Pembrolizumab in combination with bevacizumab and oral cyclophosphamide in recurrent platinum-resistant ovarian cancer: A real-world study.
e17595 Background: The role of immunotherapy in ovarian cancer remains poorly defined, with limited activity observed for immune checkpoint inhibitors as monotherapy. However, emerging data suggest that combination strategies may enhance efficacy; notably, the addition of pembrolizumab to weekly paclitaxel has recently demonstrated a survival benefit in patients with platinum-resistant disease. We evaluated the efficacy and safety of pembrolizumab combined with bevacizumab and oral cyclophosphamide in patients with recurrent epithelial ovarian cancer. Methods: This retrospective study included all patients with recurrent, platinum-resistant, heavily pre-treated epithelial ovarian cancer who received pembrolizumab in combination with bevacizumab and oral cyclophosphamide at the Oncology Unit of Alexandra University Hospital from January 2021 onward. Clinical characteristics, treatment exposure, and outcomes were extracted from institutional records. Results: Forty-eight patients were included. Median age at diagnosis was 57.9 years (IQR 45.9–63.8). Histology was predominantly high-grade serous ovarian carcinoma (44/48), with two patients each having high-grade endometrioid and clear-cell carcinoma. Most patients (44/48, 91.6%) presented with stage III/IV disease; 32 underwent primary debulking surgery and 11 interval debulking. ECOG performance status was 0–1 in 43 patients, and 7 patients carried BRCA1/2 mutations. Patients were heavily pre-treated, with a median of five prior systemic therapy lines (range 4–9). All patients progressed on first-line platinum-based chemotherapy, with a median progression-free survival (PFS) of 15.0 months (95% CI 9.8–20.1). Patients received a median of four cycles of pembrolizumab–bevacizumab–cyclophosphamide (range 2–35). Overall response rate was 31.3% (15/48), and disease control rate was 45.9% (22/48). Median PFS on pembrolizumab–bevacizumab–cyclophosphamide was 3.7 months (95% CI 2.7–4.8). Twelve patients experienced PFS longer than 6 months; prolonged benefit was not associated with histology, ECOG performance status, BRCA mutation status, or platinum-free interval following first-line therapy. No new safety signals were observed. Conclusions: In a heavily pre-treated, platinum-resistant ovarian cancer population, the combination of pembrolizumab, bevacizumab, and oral cyclophosphamide demonstrated clinically meaningful activity with manageable toxicity. These real-world findings support further exploration of immunotherapy-based combinations in ovarian cancer, particularly in settings where treatment options remain limited.
Post-progression treatment (tx) analyses of evERA Breast Cancer (BC): A phase III trial of giredestrant (GIRE) + everolimus (E) in patients (pts) with estrogen receptor–positive, HER2-negative advanced BC (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i).
1016 Background: evERA BC (NCT05306340) is the first Phase III trial to demonstrate a statistically significant and clinically meaningful improvement in investigator-assessed progression-free survival (INV-PFS) with an all-oral, selective ER degrader and full ER antagonist combination (GIRE + E) compared with standard-of-care endocrine therapy combinations (SOC ET + E) in pts with ER+, HER2– aBC post-CDK4/6i + ET (Mayer ESMO 2025). Improvement in INV-PFS was seen in all pts (hazard ratio [HR], 0.56) and in pts whose tumors had a detectable ESR1 mutation ( ESR1 m; HR, 0.38), with no unexpected safety findings. We report exploratory post-progression tx analyses. Methods: Pts with ER+, HER2– aBC who had disease progression (PD) or relapse during/post-CDK4/6i + ET were randomized 1:1 to once-daily oral 30 mg GIRE + 10 mg E or SOC ET (exemestane/ fulvestrant/tamoxifen) + E until PD/unacceptable toxicity. Exploratory analyses included PFS2 (time from randomization to PD on next-line tx, or death), chemotherapy-free survival (CFS; time to first subsequent chemotherapy and/or antibody–drug conjugate [ADC], or death), and types of cancer tx following discontinuation from study tx. Results: Median PFS2 and CFS were longer with GIRE + E vs SOC ET + E in all pts (PFS2 HR, 0.69; CFS HR, 0.61), including in the ESR1 m (PFS2, 0.61; CFS, 0.46) and ESR1 m not detected populations (PFS2, 0.77; CFS, 0.80; Table). Of those receiving follow-up cancer therapy in all pts, and in the ESR1 m and ESR1 m not detected populations, 69.1%, 63.3%, and 73.8%, respectively, received chemotherapy in the GIRE + E arm vs 71.5%, 65.3%, and 79.0% in the SOC ET + E arm; 24.5%, 18.4%, and 29.5% received an ADC in the GIRE + E arm vs 31.4%, 25.3%, and 38.7% in the SOC ET + E arm. Conclusions: Delaying chemotherapy improves clinical and quality of life outcomes in ER+ aBC. These analyses further support the superior INV-PFS of GIRE + E over SOC ET + E observed in all pts and in the ESR1 m population. Improvements in PFS2 and CFS, regardless of ESR1 m status, suggest that the clinical benefit of GIRE + E is sustained beyond initial progression. Clinical trial information: NCT05306340 . All pts ESR1 m ESR1 m not detected GIRE + E (n = 183) SOC ET + E (n = 190) GIRE + E (n = 102) SOC ET + E (n = 105) GIRE + E (n = 81) SOC ET + E (n = 85) PFS2 Event, n (%) 81 (44.3) 108 (56.8) 39 (38.2) 57 (54.3) 42 (51.9) 51 (60.0) Median, mo (95% CI) 19.0(15.5, not evaluable [NE]) 13.2 (11.7, 15.9) 19.0 (15.5, NE) 12.9 (11.8, 17.6) 17.3(13.0, NE) 12.9 (9.8, 20.8) Stratified HR (95% CI) 0.69 (0.51, 0.92) 0.61 (0.40, 0.93) 0.77 (0.51, 1.17) CFS Event, n (%) 111 (60.7) 146 (76.8) 51 (50.0) 78 (74.3) 60 (74.1) 68 (80.0) Median, mo (95% CI) 11.1(9.6, 12.7) 7.9 (6.9, 9.5) 12.6 (10.9, 18.7) 8.5 (7.1, 10.0) 9.5 (7.4, 11.6) 7.2(6.1, 9.5) Stratified HR (95% CI) 0.61 (0.47, 0.78) 0.46 (0.32, 0.66) 0.80 (0.57, 1.14)
Cost-effectiveness analysis of first-line (1L) therapies for advanced urothelial carcinoma (aUC) from a U.S. payer perspective.
4589 Background: Recent years have seen a shift in aUC management following approval of enfortumab vedotin–pembrolizumab (EV-P) and gemcitabine/cisplatin plus nivolumab (GC-NIVO) as first-line therapies. Despite improved clinical outcomes, their relative economic value remains uncertain. Herein, we conducted a cost-effectiveness analysis of current 1L regimens in aUC from a U.S. payer perspective using 2026 pricing. Methods: A partitioned survival model with three health states (progression-free [PF], progressed disease [PD], and death) was developed over a 10-year horizon from a U.S. payer perspective. Analyses focused on cisplatin-eligible patients. Survival data were reconstructed from published Kaplan–Meier curves and extrapolated using parametric survival models. Treatment dosing, schedules, and duration were modeled according to trial protocols. Patients receiving gemcitabine/cisplatin without progression were modeled to receive avelumab maintenance (GC→AVEL). Subsequent-line therapy costs were applied at incident progression, and grade ≥3 adverse event costs and disutilities were applied as one-time events. Drug acquisition costs (2026 USD) were based on average sales prices from the Centers for Medicare & Medicaid Services. Costs and quality-adjusted life years (QALYs) were discounted at 3% annually. Incremental cost-effectiveness ratios (ICERs) and net monetary benefit (NMB) were evaluated at willingness-to-pay (WTP) thresholds of $100,000, $150,000, and $200,000 per QALY. Parameter uncertainty was characterized using probabilistic sensitivity analysis. Results: In the base-case analysis, total discounted costs and QALYs were $90,269 and 1.62 for GC→AVEL, $131,836 and 2.09 for GC-NIVO, and $1,451,885 and 2.77 for EV-P. Compared with GC→AVEL, GC-NIVO gained 0.46 QALYs at an incremental cost of $41,567, resulting in an ICER of $89,501 per QALY and positive NMB across all evaluated WTP thresholds. Compared with GC→AVEL, EV-P gained 1.15 QALYs at an incremental cost of $1.36 million (ICER $1.19 million per QALY). Compared with GC-NIVO, EV-P gained 0.68 QALYs at an incremental cost of $1.32 million (ICER $1.93 million per QALY), exceeding all evaluated WTP thresholds. In a scenario analysis limiting EV-P to 10 treatment cycles, total costs decreased to $287,360, with ICERs of $172,000/QALY versus GC→AVEL and $225,000/QALY versus GC-NIVO, remaining above the $150,000/QALY threshold. Conclusions: Using updated 2026 pricing, GC-NIVO is likely to be the most cost-effective first-line regimen for cisplatin-eligible patients with aUC. EV-P offers the greatest clinical benefit but is not cost-effective at current prices. A major limitation of this study is cross-trial variability in study populations and design, limiting the validity of head-to-head economic comparisons.
Dual immune checkpoint inhibition vs anti–PD-1 monotherapy in metastatic <i>BRAF</i> wild-type/undetermined melanoma: Ethnicity-based benchmarking of treatment endpoints in 2,659 patients.
e21512 Background: Immunotherapy is the mainstay for metastatic melanoma (MM), yet ethnic differences in treatment outcomes remain underexplored courtesy due to inconsistent reporting. Our systematic review and meta-analysis assessed overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) among BRAF wild-type/undetermined MM patients receiving anti-PD1 monotherapy (nivolumab or pembrolizumab) or dual immune checkpoint inhibition (nivolumab plus ipilimumab), focusing on ethnicity based benchmarking. Methods: PubMed, Embase, and Cochrane Central were searched for real world studies reporting outcomes in adults with BRAF wild-type or undetermined MM treated with first-line anti-PD1 monotherapy or dual checkpoint inhibition. Meta-analysis using a random-effects model was conducted for the aforesaid treatment endpoints. Results: 2,659 patients from 8 studies were included for analysis. Median ages ranged from 62 to 75 years. Majority of patients had good performance status (ECOG 0-1). OS and PFS were summarised qualitatively due to limited hazard ratio data. Median OS for anti-PD1 monotherapy (n=595) was 31.5 months, with Asians demonstrating lower survival (28.1 months) compared with White patients (32.5 months). Dual checkpoint inhibition (n=417) was associated with a longer median OS (58.3 months), although markedly shorter among Asians (12 months) relative to Whites (59.2 months). Median PFS followed a similar pattern, with anti-PD1 monotherapy yielding 7.6 months overall (Asians 6.1; Whites 8.2) and dual therapy 17.8 months overall (Asians 8.2; Whites 18.8). Meta-analysis of ORR included 1,757 patients, demonstrating a higher pooled response for dual therapy (52%) than for monotherapy (36%). Among White patients, dual therapy achieved higher ORR (57.2%) (n=682) than monotherapy (36.9%) (n=902), whereas Asians had comparable responses to either regimen [(37.5% for dual (n=40); 35.3% for monotherapy (n=144)]. Differences between ethnic subgroups did not reach statistical significance. No eligible studies reported outcomes for Black or mixed-ethnicity populations, precluding quantitative or qualitative analyses in these groups. Conclusions: Dual checkpoint inhibition confers superior ORR compared with anti-PD1 monotherapy, particularly in White patients, whereas response among Asian patients appears similar across treatments. Across included studies, dual therapy was associated with a longer median OS of 58.3 months versus a median OS of 31.5 months with anti-PD1 monotherapy, dual therapy also demonstrates improved PFS of 17.8 months as compared to 7.6 months shown with monotherapy. Limited data on Black and Mixed ethnicities highlights the need for larger, ethnically diverse studies to guide optimised, personalised treatment.
Burden and survival outcome of secondary malignancies in Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL): A population-based analysis using Surveillance, Epidemiology, and End Results (SEER 2000-2022).
e19094 Background: WM/LPL is an indolent B-cell Non-Hodgkin Lymphoma with prolonged survival and predisposition to secondary malignancies (SM) influencing clinical outcomes and survivorship care. We evaluated the incidence, demography, treatment utilization, and outcomes of SM in patients with WM/LPL using population-based data. Methods: SEER-22 database was used to identify patients with LPL/WM diagnosed between 2000–2022 and stratified by SM. Overall survival (OS) was analyzed using Kaplan–Meier survival analysis and propensity score matched Cox regression was used to assess mortality risk. Hazard ratios were reported, with p<0.05 deemed significant. Results: 22,170 patients with WM/LPL were identified, with a median age of 71 years (IQR 16); the cohort was predominantly male (59.0%), White (84.0%), had a median household income of $50,000–$75,000 (48.9%), and resided primarily in urban areas (89.5%). Among all WM/LPL patients, 20.8% (n=4,615) developed a SM. Patients who developed SM were older than those without (median age 75 vs 70 years, p<0.0001) with 45.2% alive at predefined follow-up. The most common solid organ SM were gastrointestinal adenocarcinoma (16%), prostate cancer (14%), and lung adenocarcinoma (9%), while the leading hematologic SM were plasma cell myeloma (6%), diffuse large B-cell lymphoma (5%), and myelodysplastic syndrome (2%). 35.3% of the cohort received chemotherapy, while 0.1% received cancer-related surgery or radiation. On multivariable analysis, older age (OR 0.82, 95% CI 0.81–0.83), male sex (OR 0.59, 95% CI 0.44–0.80), urban residence (OR 1.99, 95% CI 1.24–3.18), and higher income (OR 2.16, 95% CI 1.13–4.15) were significantly associated with SM diagnosis. Kaplan–Meier analysis demonstrated inferior survival among patients with SM (54.8% vs 45.2%, p<0.0001), with shorter median OS (9 vs 14 years, log-rank p<0.001). Similarly, Propensity-matched analysis revealed worse OS in patients with SM (HR 1.15, 95% CI 1.09–1.22, p<0.001). Median OS varied substantially by SM site (see Table). Conclusions: Our study demonstrates a substantial burden of SMs among patients with WM/LPL and are associated with substantially inferior survival despite the indolent nature of the disease. The marked heterogeneity in SM types and outcomes highlights the need for risk-adapted surveillance, survivorship-focused care, and equitable strategies to address disparities and improve long-term outcomes in this population. SM Site Median OS (years) IQR p-value Hepatopancreatobiliary 1 0 <0.05 CNS 3.5 9 <0.05 Breast 3 6 <0.05 Colorectal 4 3.5 <0.05 Lymph Node 5 8 <0.05 Blood 6 7 <0.05 Lung 7 9 <0.05 Head & Neck 6.5 8.5 <0.05 Melanoma 9 10 <0.05 Urogenital 10.5 7 <0.05
Sex-stratified risk of second malignancies in Hodgkin lymphoma survivors: A retrospective study.
e19041 Background: Hodgkin lymphoma (HL) survivors are at increased risk of second primary malignancies (SPMs), often related to treatment exposures such as radiation and chemotherapy. Understanding sex-specific and time-dependent patterns of SPMs is essential to guide survivorship care and improve long-term outcomes. Methods: Using SEER 12 Registries (1992–2021), we identified patients diagnosed with HL as a first primary malignancy. We applied SEER*Stat multiple primary–standardized incidence ratio (MP-SIR) sessions to calculate expected and observed cases of second malignancies. Outcomes were stratified by cancer type (solid vs hematologic), sex, and latency interval (<1 year, 1–5 years, 5–10 years, >10 years). We reported standardized incidence ratios (SIRs, O/E) with statistical significance determined by 95% confidence intervals. Results: Among HL survivors, the overall SIR for second malignancies was elevated across both sexes, with variation by cancer type and latency. Notably, Non-Hodgkin lymphoma exhibited persistently elevated and statistically significant observed-to-expected (O/E) ratios in both sexes across all latency periods, with particularly high risk within the first year post-Hodgkin lymphoma (M: 21.98, F: 26.51). Respiratory system cancers also showed consistently elevated risks (e.g., M: 2.44, F: 6.26 at & <1 year), remaining significant across all latency intervals. Thyroid cancer demonstrated striking early excess risk, especially among males (M: 15.67, F: 9.75 at <1 year), which sharply declined over time. Acute myeloid leukemia followed a similar latency-driven pattern, with the highest risk observed in early latency (M: 14.94, F: 15.67 at 1–5 years) and a gradual decline thereafter. Breast cancer, as a female-specific malignancy, showed a latency-dependent increase, with significant elevation only at >10 years (F: 1.80). Sex-specific differences were evident in several cancers, including urinary system, melanoma, and thyroid, where females generally exhibited higher O/E ratios. These findings highlight the importance of both latency and sex in tailoring surveillance strategies for Hodgkin lymphoma survivors. Conclusions: This analysis highlights the importance of sex- and latency-specific surveillance strategies in HL survivorship care. Early vigilance for hematologic malignancies and long-term screening for radiation-associated solid tumors, is warranted. These findings support risk-adapted follow-up and inform guideline development for survivorship clinics.
Clinical efficacy of laparoscopic hybrid surgery versus total open surgery for simultaneous resection of colorectal cancer liver metastases (CHLH trial).
3587 Background: Despite widespread adoption of simultaneous resection for colorectal liver metastases, the clinical efficacy varies among different approaches, and the optimal surgical strategy remains controversial. This study aims to evaluate the efficacy and safety of laparoscopic hybrid surgery (LHS) versus total open surgery (TOS) in the simultaneous resection of CRLM. Methods: This is a prospective cohort study (NCT06550700) conducted at a tertiary medical center, enrolling 266 patients who underwent simultaneous resection for CRLM from January 2017 to June 2021. The surgical approach is selected by colorectal surgeons and hepatobiliary surgeons based on their experience with either TOS or LHS. The primary outcomes were the incidence of complications and postoperative recovery-related outcomes. The secondary outcomes were 5-year overall survival (OS) and disease-free survival (DFS). Results: This study ultimately enrolled 144 patients in the LHS group and 122 patients in the TOS group. The complication rate was significantly lower in the LHS group than in the TOS group (10.4% vs. 20.5%, p = 0.022). Compared with the TOS group, patients in the LHS group had shorter postoperative hospital stay [8.00 (6.00, 10.00) vs. 9.00 (8.00, 12.00) days, p < 0.001], earlier resumption of liquid intake [3.00 (3.00, 3.00) vs. 4.00 (3.00, 4.00) days, p < 0.001], and less intraoperative blood loss [300.00 (200.00, 400.00) vs. 500.00 (500.00, 700.00) mL, p < 0.001]. However, the LHS group was associated with longer operative time [260.00 (236.00, 320.00) vs. 240.00 (195.00, 269.00) min, p < 0.001]. No significant differences were observed between the two groups in overall survival (p = 0.464) or disease-free survival (p = 0.838). Conclusions: Compared with TOS, applying LHS for simultaneous resection for CRLM results in faster postoperative recovery, lower complication rates, and similar survival outcomes. Clinical trial information: NCT06550700 .
Trends in early-onset colorectal cancer incidence (2000–2022) among Black Americans and Sub-Saharan African populations.
e15692 Background: Early-onset (age < 50) colorectal cancer (CRC) incidence is rising in low- and middle-income countries even as rates plateau in high-income countries. Black Americans have among the highest early-onset CRC rates in the U.S., whereas historically sub-Saharan Africa (SSA) has had very low rates. We compared 2000–2022 CRC incidence trends in these two populations with shared ancestry to isolate environmental and healthcare system influences from genetic predisposition. Methods: Annual age-standardized CRC incidence rates (per 100,000; ages 15–49) for U.S. Black Americans (2000–2022) were obtained from SEER. Corresponding incidence data for SSA were derived from Global Burden of Disease. Five-year CRC prevalence in SSA was also assessed to gauge survivor trends. Annual percent change (APC) was used to evaluate temporal trends. Results: Among U.S. Black Americans, early-onset CRC incidence increased by ~40% from 2000 to 2022 (10.9→15.2 per 100,000), with APC ≈1.5% per year. In SSA, incidence roughly doubled over the same period (~2.5→4.0 per 100,000), though rates there remain about 3–5-fold lower than in U.S. Blacks. Within SSA, all four subregions experienced upward incidence trends. Central SSA showed the steepest increase, from 1.9 per 100,000 in 2000 to 4.2 in 2022 (APC 3.7%). Eastern SSA had the highest early-onset CRC rate by 2022, climbing from 3.5 to 5.1 per 100,000 (APC 1.8%). Incidence in Southern and Western SSA rose more moderately, reaching 3.5 and 3.0 per 100,000 respectively by 2022 (APCs 1.7% and 2.0%). Moreover, the 5-year CRC prevalence in SSA almost doubled (from ~10 to ~17 per 100,000), indicating an increase in young CRC survivors. Conclusions: Early-onset CRC has risen in both Black Americans and SSA. However, the substantially higher rates in U.S. Blacks – despite shared ancestry – highlight predominantly environmental/lifestyle factors (e.g., Westernized diet, obesity) and differences in detection rather than genetic causes. The recent rise in SSA likely stems from Westernization and improved cancer detection in the absence of widespread screening. These findings underscore the need for interventions targeting modifiable risk factors and improved surveillance to curb early-onset CRC in SSA. Additionally, the disproportionately high early-onset CRC burden among U.S. Black Americans warrants earlier screening, targeted lifestyle interventions, and greater awareness to reduce this disparity.
First-in-human evaluation and preclinical mechanistic studies of targeted hyperthermia therapy.
2595 Background: Photothermal conversion of near-infrared (NIR) light using specifically tuned, directly delivered gold nanorods produces controllable hyperthermia in tumor microenvironments. Precisely controlled, targeted hyperthermia therapy (THT) induces immunogenic cell death (ICD) and remodels the tumor microenvironment, promoting immune activation in otherwise poorly inflamed tumors. Here, we report an early clinical evaluation of THT integrated with mechanistic preclinical analyses. Preclinical studies: In B16F10 melanoma and CT26 colorectal models, controlled thermal dosing induced a 24–48 h ICD response marked by calreticulin and HSP70 exposure, chemokine and complement activation, and early T-cell receptor remodeling. Transcriptomic analyses revealed a dose-dependent transition from innate immune activation to a coordinated tissue repair program involving extracellular matrix remodeling. Lower thermal doses in the hyperthermic window decreased regulatory pathways and induced antigen presentation. Modulation of myeloid signaling limited macrophage accumulation, prevented tumor regrowth, and sustained antitumor inflammation. Methods: In a first-in-human, open-label, early feasibility study (NCT06894407), ten patients with stage IIIc/IIId/IV M1 cutaneous metastatic melanoma progressing on checkpoint inhibitor therapy received intratumoral gold nanorods (Sona Nanotech Inc.) followed by NIR-mediated heating on days 1 and 8. Up to four lesions per patient were treated, with intratumoral temperatures maintained at 42–48 °C for 5 minutes. Safety, feasibility, and early biological activity were assessed through adverse-event monitoring, clinical photography, and tumor biopsies obtained on days 15 and 29. Results: Clinical: THT was well tolerated, with no treatment-related serious adverse events observed. By day 15, 8 of 10 patients demonstrated regression in treated lesions. Histologic assessment showed complete tumor clearance in 6 patients, partial regression in 2 patients, and no response in 2 patients. Conclusions: THT-induced ICD progresses through temporally regulated immune states, including a reparative myeloid-associated phase that limits durability. Defined thermal-dose parameters provide a framework for rational integration of THT with macrophage-modulating and checkpoint-based immunotherapies. THT is safe, feasible, and biologically active in immunotherapy-refractory metastatic melanoma. Further clinical studies are needed to evaluate the efficacy of THT in immune-refractory cancers. Clinical trial information: NCT06894407 .