julilili42/papers huggingface dataset:
Real-world safety and effectiveness of avelumab in immune-compromised (IC) and non-IC patients with Merkel cell carcinoma (MCC): Results from a prospective German registry (MCC-TRIM).
2025-05-28

9543 Background: MCC is a rare and aggressive form of skin cancer. Avelumab was the first immunotherapy approved for patients with metastatic MCC in Europe. Immunosuppression is an established risk factor for developing MCC, but IC patients have typically been excluded from clinical trials of immunotherapies. We report an analysis of clinical characteristics, survival outcomes, and safety in IC and non-IC patients with MCC treated with avelumab in routine clinical practice in Germany. Methods: This prospective, noninterventional, multicenter, dynamic cohort study (MCC-TRIM; EUPAS25338) enrolled patients with MCC in Germany between April 2019 and September 2023. Primary data from a study-specific electronic case report form and secondary data from the German national skin cancer registry were combined. For this analysis, avelumab-treated patients were grouped as IC or non-IC based on prespecified comorbid conditions and concomitant medications. Survival outcomes with first-line avelumab treatment were assessed using the Kaplan-Meier method. Results: Among 875 patients with MCC (various disease stages) enrolled in the study, 243 were treated with avelumab, of whom 189 (77.8%) were considered non-IC and 54 (22.2%) were considered IC. Patient characteristics are summarized in the Table. At data cutoff (March 2024), median follow-up (IQR) was 14.3 months (6.4-29.4) in the non-IC subgroup and 8.9 (4.2-22.8) in the IC subgroup. In non-IC and IC subgroups, median (95% CI) overall survival from start of first-line avelumab was 38.2 (15.7-not estimable) and 9.9 (4.8-29.8) months, and median progression-free survival was 7.9 (4.0-11.6) and 4.3 (1.0-7.8) months, respectively. The incidence rate of ADRs related to avelumab was 1.01 (95% CI, 0.75-1.34) events per person-year in the non-IC subgroup and 0.71 (95% CI, 0.32-1.45) events per person-year in the IC subgroup. Conclusions: Results from this German nationwide registry showed the safe and effective use of avelumab in routine clinical practice for IC and non-IC patients with MCC. Non-IC (n=189) IC (n=54) Mean age at diagnosis (SD), years 74.8 (10.2) 76.4 (8.1) Male, n (%) 122 (64.6) 35 (64.8) Stage at diagnosis, n (%) Early stage (I, II, or unknown) III IV 38 (20.1)80 (42.3)71 (37.6) 13 (24.1)19 (35.2)22 (40.7) ECOG performance status ≤1, n (%) 153 (81.0) 40 (74.0) Comorbidities, n (%) Diabetes Chronic obstructive pulmonary disease Cerebrovascular disease/stroke Moderate or severe renal disease Ischemic heart disease/myocardial infarction Moderate or severe liver disease Thyroid disorder Inflammatory bowel disease Rheumatoid arthritis 36 (19.0)5 (2.6)2 (1.1)11 (5.8)21 (11.1)3 (1.6)17 (9.0)4 (2.1)5 (2.6) 14 (25.9)4 (7.4)3 (5.6)5 (9.3)8 (14.8)04 (7.4)2 (3.7)5 (9.3)
Treating the untended: Real-world insights into enfortumab vedotin plus pembrolizumab for frail metastatic urothelial carcinoma patients excluded or underrepresented in clinical trials (GUARDIANS).
2025-05-28

e16548 Background: Patients with terminal renal failure (GFR &lt;30 ml/min or dialysis), poor performance status (ECOG ≥2), and/or age ≥80 are often excluded or underrepresented in pivotal clinical trials evaluating enfortumab vedotin and pembrolizumab (EV/P) as first-line (1L) treatment in metastatic urothelial carcinoma (mUC). Consequently, data on safety and efficacy in these populations are limited. This study evaluates EV/P outcomes in this high-risk group. Methods: This multicenter, real-world, retrospective study included mUC patients receiving EV/P as 1L treatment who were underrepresented (age ≥ 80) or ineligible for the EV-302 trial due to GFR &lt;30 ml/min, ECOG ≥2. Endpoints included overall and progression free survival (OS, PFS), objective response rate (ORR), and treatment-related adverse events (AE). Descriptive and survival analyses evaluated safety and efficacy in frail patients. Results: A total of 116 patients from 18 German tertiary care centers were treated between May 2022 and December 2024. The median age was 79 years (IQR 68–83), with 20.7% having a GFR &lt;30 ml/min, 44.8% presenting with ECOG ≥2, and 49.1% aged ≥80. The median age-adjusted Charlson Comorbidity Index was 6 (IQR 4–8), highlighting the high burden of comorbidities in this population. The ORR was 54.1%, including an 8.1% complete response rate. The mPFS was 7.5 months (95% CI 5.9–NR), and the mOS was not reached. Any-grade AEs were reported in 72.2% of patients, with ≥grade 3 AEs in 31.3%. The most common treatment-related AEs were peripheral neuropathy (33.0%) and skin toxicity (23.3%). Among patients aged ≥80, 39% required dose reductions, compared to 31% in the overall cohort, occurring after a median of 68 days (IQR 42–137). Of all patients, 18.1% discontinued treatment due to progressive disease, with only 31.3% of them receiving subsequent anti-cancer therapy. In contrary a total of 26.7% of patients permanently discontinued EV/P due to toxicity or non-specified reasons, with a median treatment duration of 89 days (IQR 40–180). Conclusions: This retrospective real-world analysis suggests that EV/P demonstrates promising oncological efficacy, even in highly frail patients, including those with a GFR &lt;30 ml/min, ECOG ≥2, or aged ≥80 years. However, frequent discontinuations in absence of disease progression underscore the need for prospective studies to evaluate more tolerable regimens and treatment interruptions strategies.
A pooled analysis of clinical outcomes with anti-PD1-based neoadjuvant immunotherapy (NeoIT) in cutaneous squamous cell carcinoma (cSCC).
2025-05-28

9578 Background: Anti-PD1 immunotherapy has shown improved clinical outcomes in patients (pts) with advanced cSCC, and recently, in the neoadjuvant setting for resectable disease. Pathological (path) response is predictive of recurrence in melanoma and recent NeoIT trials suggests the same in cSCC; however, an analysis of clinical outcomes in pts with resectable cSCC treated with intended anti-PD1-based NeoIT in larger datasets remains unknown. Methods: Pts with resectable cSCC treated with intended anti-PD1-based NeoIT from 17 cancer centres globally were included. Baseline patient and disease characteristics, treatment regimen, path response and recurrence-free survival (RFS) or progression-free survival (PFS) were collected and examined. Results: 134 pts with resectable cSCC were treated with intended anti-PD1-based NeoIT. Median age was 75 years old (range, 39-97), 72% (n=97) were male. One fifth (22%, n=29) were immunocompromised and 43% (n=58) had ECOG PS of ≥1. Of 125 (93%) pts with known primary cSCC, 82% (n=102) were from the head &amp; neck. Most pts (79%, n=106) were stage III/IV. The majority had anti-PD1 monotherapy (91%, n=122) and 9% (n=12) had anti-PD1+/-investigational agent. Median follow-up from commencement of NeoIT was 10 months (95% CI, 9 - 12). Nearly half of the pts (49%, n=66) underwent surgery; 37 (56%) pts had major pathological response (MPR; ≤10% viable tumour cells at the surgical specimen; 31 [47%] had complete path response [0% of viable tumour cells] and 6 [9%] had near complete path response [1-10% of viable tumour cells]), 6 (9%) had partial path response (pPR; &gt;10% and ≤50% of viable tumour cells), and 23 (35%) had path non-response (pNR; &gt;50% of viable tumour cells). Of the 66 pts who underwent surgery, 11% (n=7) had recurrence (5 loco-regional and 2 distant recurrence), all non-MPR pts (1 pPR and 6 pNR). 12-months RFS was improved with MPR vs non-MPR (100% vs 79%, p=0.004). 52% (n=34) pts had adjuvant treatment (23 anti-PD1 alone, 7 anti-PD1+/-investigational agent, 2 platinum and 2 cetuximab). Within non-MPR pts, 12 had adjuvant treatment (3 recurred; 25%), while 17 did not have adjuvant treatment (4 recurred; 24%). Fifty-one percent (n=68) of pts did not have surgery; 9 (13%) due to progressive disease (PD) and 53 (78%) due to clinical response. Of the 53 pts with a clinical response, 5 (9%) subsequently progressed. Fourteen (10%) pts have died, 6 (4%) related to cSCC; 2 had surgery (non-MPR) and 4 did not have surgery (all due to PD). Conclusions: Anti-PD1-based NeoIT is an active regimen in resectable stage II-IV cSCC and is associated with high clinical response and MPR rates. No pts with MPR from NeoIT has recurred to date, however, 9% of pts who did not have surgery due to clinical response eventually progressed. These findings highlight the importance of further research to investigate the role of surgery in this subgroup of patients.
Identification of patients at high risk for relapse by Merlin assay (CP-GEP) in an independent cohort of melanoma patients (pts) that did not undergo sentinel lymph node biopsy: An H&N subgroup analysis.
2025-05-28

9567 Background: Sentinel lymph node biopsy (SLNB) is still the gold standard for nodal assessment used in the clinical staging of cutaneous melanoma (CM) pts by AJCC v8. Recently, we showed in a small cohort that CP-GEP also has the potential to risk stratify pts who did not undergo SLNB in low and high-risk for recurrence (Amaral et al, EJC 2023). SLNB may be challenging in pts with head and neck (H&amp;N) melanoma, due to the regional course of cranial nerves and lymphatic drainage. Here we focus on the ability of CP-GEP to stratify pts with H&amp;N melanoma in particular those with lentigo maligna, who did not undergo SLNB, for their risk of recurrence. Methods: We analyzed formalin-fixed paraffin-embedded primary tumor samples of 930 pts of which 206 were localized in the H&amp;N region, with stage I/II CM diagnosed between 2000-2017 who did not receive SLNB. The CP-GEP model used combines the expression of 8 genes (SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA) by quantitative reverse transcription polymerase chain reaction with age and Breslow thickness to obtain a binary output: CP-GEP Low- or High-Risk. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and Melanoma Specific Survival (MSS) were evaluated using Kaplan-Meier curves. Results: We included 930 pts (stage IA-IIC) of which 206 pts (22.3%) were diagnosed with H&amp;N melanoma. Patient characteristics: 41% were females, median age was 73-year-old, median Breslow thickness was 0.5 mm and 75.6% were lentigo maligna melanomas. Median follow up was 51 months (RFS). All H&amp;N pts showed the following survival: 5-year RFS 82.5%, DMFS 94.0 and MSS 95.5%. CP-GEP risk stratification identified 17 patients as CP-GEP High-Risk and 188 as CP-GEP Low-Risk. The 5-year RFS rate was 86.7% for CP-GEP Low-Risk and 39.7%% for CP-GEP High-Risk pts (HR 7.85; p&lt;0.001), 5-year DMFS was 96.3% for CP-GEP Low-Risk and 68.9% High-Risk pts (HR 10.26; p&lt;0.001) and the 5-year MSS was 98.5% for CP-GEP Low-Risk pts and 64.7% for CP-GEP High-Risk pts (HR 24.45; p&lt;0.01). Conclusions: Pts with H&amp;N CP-GEP Low-Risk tumors have a good long-term survival compared to High-Risk pts even though SLN status was not assessed. This prognostic information may allow the clinicians to skip SLNB in this difficult anatomic localization and in frail and/or older pts.
Hippocampal-avoidance whole-brain radiotherapy with dose escalation on metastases: A prospective randomized trial (HIPPORAD).
2025-05-28

2038 Background: The HIPPORAD trial aimed to evaluate a new method of whole brain radiation therapy (WBRT) with simultaneous integrated boost (SIB) to the metastases, with versus without hippocampal avoidance in patients with brain metastases. Methods: We conducted a prospective, multicentre, randomised, double-blind trial (DRKS00004598). Patients with 4-10 brain metastases &gt; = 5mm were randomised at 13 centres in Germany 1:1 between WBRT+SIB with hippocampus avoidance (HA-WBRT+SIB) (arm A) and WBRT+SIB (arm B). Patients and assessors of outcome were blinded to the randomised arm. All patients received WBRT with 30 Gy and SIB with 51 Gy or 42 Gy in 12 fractions, 5x/week. The primary endpoint was the change in neurocognitive function (assessed by the Verbal Learning and Memory Test [VLMT]) 3 months after treatment. Secondary endpoints included neurocognitive changes at 9 and 18 months, development of anxiety and depression, quality of life and measures of oncological outcome. Results: Between August 2 nd , 2016 and September 7 th , 2021, 170 patients were recruited and 136 were randomised between HA-WBRT+SIB (n = 67) and WBRT+SIB (n = 69). Of these, 38 patients in arm A and 42 in arm B were known to be alive 3 months after treatment and were included in the primary endpoint analysis. The change in overall learning performance at 3 months was not significantly different between arms (p = 0.83). VLMT-scores decreased after 3 months, but improved at 9 and 18 months, with HA-WBRT+SIB showing an overall superior trend over WBRT+SIB. At 18 months, VLMT-scores improved to values above baseline in both arms. Patients treated with HA-WBRT+SIB had significantly less depression compared to patients treated with WBRT+SIB at 3 (p = 0.047) and 18 months (p = 0.048). The 12-month-tumor control for boosted metastases was 96% in Arm A and 88% in Arm B, while for the WBRT area it was 78% in both arms. Time to hippocampal tumour progression was comparable between arms (p = 0.98). After 12 months, 4% of patients in arm A and 12% in arm B had suffered neurological death. Conclusions: To our knowledge, this is the first prospective trial to show that hippocampal avoidance during WBRT leads to significantly lower rates of depression. The development of VLMT values after HA-WBRT+SIB and WBRT+SIB with 30 Gy in 2.5 Gy-fractions was comparable and a good recovery was observed at 18 months in both arms. The method showed a considerably higher intracerebral tumour control with lower neurological mortality rates compared to historical cohorts. Clinical trial information: DRKS00004598 .
The SURVIVE study: Standard surveillance vs. intensified liquid biopsy-based surveillance in early breast cancer survivors.
2025-05-28

TPS621 Background: Current breast cancer (BC) follow-up relies on clinical examinations and breast imaging, as studies from the 1980s demonstrated no survival benefit from distant metastasis screening. However, with advancements in treatment strategies and the diagnostic potential of liquid biopsies, this approach warrants re-evaluation. To enable pre-symptomatic detection of distant relapse, we propose assessing a liquid biopsy-guided surveillance strategy incorporating tumor markers (CA 27.29, CA 125, CEA), circulating tumor cells (CTCs), and circulating tumor DNA (ctDNA). Methods: The SURVIVE study (NCT05658172) is the first large-scale, multicenter, partially double-blinded randomized controlled trial comparing intensified and standard surveillance in 3,500 survivors of medium- to high-risk early breast cancer (eBC). All subtypes are eligible. High risk includes (neo-)adjuvant chemotherapy, tumor size &gt;50 mm, positive lymph nodes (≥pN1mi), or high grade (≥G3). Patients are randomized 1:1 to standard or liquid biopsy-guided intensified follow-up. Primary therapy (surgery, adjuvant chemo- or radiotherapy) completion is required, while adjuvant endocrine, antibody, or targeted therapy is permitted. Enrollment is allowed up to 24 months post-primary therapy for TNBC/HER2+ eBC and 60 months for HR+/HER2- eBC. In both arms, guideline-based follow-up is performed, with additional blood samples collected longitudinally (years 1–3 every 3 months; years 4–5 every 6 months). In the intervention arm, these samples are analyzed for tumor markers, CTCs, and ctDNA (RaDaR assay). Abnormal findings indicating minimal residual disease (MRD) trigger full staging. Recurrence is treated per national guidelines. In the case of M0 status, liquid biopsy testing and staging continue, with the option for inclusion in interventional trials, if applicable. The study is recruiting, with the first patient enrolled in December 2022. By January 2025, 812 patients were randomized across 78 centers. Final enrollment is scheduled for 2026 but may occur earlier due to accelerated recruitment. Statistics: The two primary objectives are to evaluate the lead time effect obtained by liquid biopsy marker testing in the intensified follow-up arm and to test whether intensified, liquid biopsy-guided surveillance improves overall survival (OS) compared to standard follow-up. OS will be analyzed in the ITT population using Kaplan-Meier and Cox regression, while the lead-time effect is assessed descriptively. Secondary endpoints include IDFS, DDFS, DRFS, BCSS, and QoL as well as biomarker sensitivities and specificities obtained in the intensified follow-up arm. Aims: We aim to determine whether liquid biopsy-guided follow-up enables earlier, sensitive, and specific detection of distant (oligo-)metastases, facilitating timely intervention and improving OS. Clinical trial information: NCT05658172 .
Timely Intervention: Navigating Ethical Challenges in OTOF-Gene Therapy Trials
2025-05-28

<i>OTOF</i>-gene therapy for profound deafness in children has entered clinical trials. Given that there is an approved alternative therapy with cochlear implants, it is imperative to scrutinize the risks, while also highlighting the novel benefits, of this experimental gene therapy. Since the untreated inner ear subsequently degenerates in this form of inherited deafness, the <i>OTOF</i>-gene therapy will be most effective in young children. Moreover, the best outcome in terms of hearing and speech comprehension is expected when the gene therapy is applied before the age of 3 years. Given such "earlier the better" considerations, the optimal time for these clinical trials and this particular therapy is at an age when children are too young to give informed consent. Enrolling children, which are a vulnerable category of persons, in clinical trials where the balance of benefits and risks is uncertain, raises a series of ethical considerations. In this article, we outline how this research can be pursued in an ethically responsible manner.
A multiscale in situ time-resolved study of the nano- to millisecond structural dynamics during protein crystallization
2025-05-29

Protein crystallization is key to determining the structure of proteins at atomic resolution. It can occur naturally, including in pathological pathways, for instance with aquaporin and γ-crystallin proteins. A fundamental understanding of the underlying crystallization process is both technologically and biologically relevant. A multitechnique approach is employed here to investigate protein crystallization in situ , allowing us to assess the evolution of the liquid suspension and crystallite structure as well as protein diffusion during the crystallization process. The wide range of methods probe the sample on ångström to millimetre length scales, accessing nanosecond to millisecond dynamics information while acquiring data with minute-timescale kinetic resolution during crystallization. This process takes several hours from an initial state of monomers or small clusters until the presence of large crystallites. Employing neutron spectroscopy allows us to distinguish different crystallization pathways and to reveal the presence of coexisting clusters during the entire crystallization process. We demonstrate the multitechnique approach on human serum albumin (HSA) proteins crystallized from aqueous solution in the presence of LaCl 3 . For this system, the crystallization kinetics can be consistently described by a sigmoid function across all methods, and the kinetics can be controlled by the salt concentration. Moreover, we compare the HSA–LaCl 3 model system with the crystallization behavior of β-lactoglobulin–CdCl 2 , which includes a metastable intermediate state.
Key lessons from the first international treatment eligibility committee: the case of metachromatic leukodystrophy
2025-05-29

The MLD treatment eligibility panel demonstrates how international expert advice can be streamlined across Europe for a rare disease like MLD, where disease-specific guidelines are still in development. By balancing complex clinical, social, and ethical parameters, the panel aids in encouraging appropriate use of innovative and costly therapies and guarantees accessibility to expert advice irrespective of country of origin.
Smooth Muscle Cell‐Derived Fibronectin Promotes an Atheroprotective Smooth Muscle Cell Phenotype Associated With Altered NO‐cGMP Signaling
2025-05-29

Background Coronary artery disease due to atherosclerosis is the leading cause of death worldwide. Recent studies revealed an important role of smooth muscle cell (SMC) phenotypic switching in atherogenesis. How the extracellular matrix affects SMC phenotype in atherosclerotic lesions is not well understood. Fibronectin (Fn1) is an abundant component of the extracellular matrix in plaques and has been linked to coronary artery disease risk in humans. Methods We used mouse genetics combined with single‐cell analyses, cell lineage tracing, and immunostaining of murine and human atherosclerotic lesions. Results Genetic ablation of SMC‐derived Fn1 in mice led to a decrease of alpha smooth muscle actin‐positive cells in atherosclerotic lesions and a reduced collagen content in the fibrous cap indicative of decreased plaque stability. Plaques lacking SMC‐derived Fn1 contained more modulated SMCs with relatively low collagen expression. Interestingly, a subset of the modulated SMCs showed high expression of NO‐sensitive guanylyl cyclase (NO‐GC). NO‐GC is a major cGMP generator in SMCs and like Fn1 has been implicated in coronary artery disease. Fn1 knockout SMCs showed increased cell growth and activity of the NO‐cGMP pathway. Expression of Fn1 and NO‐GC was also detected in modulated SMCs of human atherosclerotic lesions. Conclusions SMC‐derived Fn1 promotes plaque stability through suppression of SMC phenotypes with low alpha smooth muscle actin and collagen expression. This atheroprotective effect might be mediated, at least in part, by a crosstalk between Fn1 and the NO‐cGMP axis in SMCs. Our study identifies a mechanistic link between 2 coronary artery disease risk genes, Fn1 and NO‐GC, which explains how the extracellular matrix regulates SMC phenotype and plaque stability.
Metagenomic analysis of heavy water-adapted bacterial communities
2025-05-29

Micro-organisms can survive and thrive in unusual and extreme environments. Here, we present a metagenomic analysis of living bacteria found in highly pure, deleterious heavy water (&gt;99% D 2 O), stored in sealed plastic containers for more than 30 years, without any external supply. Deep DNA sequencing analyses have revealed that the most abundant genetic signatures were primarily associated with Pseudomonadota and Bacteroidota . These bacteria exhibited shorter gene lengths and depletion of polar and metabolically costly amino acids compared to the related species from light water environments. Genes related to DNA transposition, repair and modification were notably abundant, particularly mutant forms of the IS3 transposable elements family. We also explore potential carbon and energy sources and discuss the evolutionary implications of bacteria capable of surviving in such an extreme human-made environment.