TP53-mutated myeloid neoplasms, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), remain among the hardest-to-treat hematologic malignancies, with short survival despite hypomethylating agents +/- venetoclax, and allogeneic transplantation. Despite encouraging early-phase data, Phase 3 trials of mutant-p53 reactivators to date have not yet translated into clear, practice-changing survival benefits, highlighting a need to explore complementary strategies that aim to directly restore wild-type p53 function in the leukemic niche. Building on clinical experience with the adenoviral p53 product (rAd-p53) in solid tumors, where intratumoral rAd-p53 achieves high cumulative response rates with manageable toxicity, we investigate the feasibility of translating p53 replacement into select TP53-mutated myeloid neoplasms using antigen-directed delivery systems. Advances in AML surface proteomics and immunotherapy identify many antigens of interest, in particular, CD33, CD123, and CD209, as internalizing myeloid antigens that are broadly expressed on leukemic blasts and stem/progenitor cells. In parallel, emerging data on in vivo gene delivery via lipid nanoparticles (LNP) and adenovirus platforms that are capable of efficient marrow transduction demonstrate that systemic gene transfer to hematopoietic compartments is feasible. We outline a framework in which CD33-, CD123-, and CD209-directed mRNA/LNP systems or leukemia-adapted rAd-p53 vectors could potentially be used to restore wild-type TP53 in TP53-mutant myeloid clones and discuss key preclinical questions in xenograft models. We acknowledge that the strategy is built on converging but largely indirect lines of evidence rather than direct experimental data in TP53-mutated AML/MDS, and we explicitly discuss key preclinical validation requirements and biological barriers, including dominant-negative stoichiometry, liver sequestration, and by conceivable toxicities, that must be systematically addressed before clinical translation.

To evaluate the predictive value of endometrial and uterine artery blood flow parameters, combined with clinical indicators, for embryo implantation outcomes in PCOS patients undergoing IVF-ET across different BMI categories.

We retrospectively analyzed 129 PCOS patients who underwent IVF-ET at our hospital from June 2022 to June 2025. Participants were stratified into four BMI groups. Transvaginal ultrasound parameters and clinical data were statistically analyzed.

Significant differences were observed in endometrial thickness, morphological patterns, blood flow distribution, and uterine artery blood flow parameters across different BMI groups. The obese group exhibited a tendency toward thinner endometrium, a lower proportion of type A endometrial morphology, reduced endometrial perfusion, and a higher uterine artery resistance index. Logistic regression analysis identified high endometrial blood flow grade, abundant endometrial blood flow, and a greater number of high-quality embryos as protective factors for successful embryo implantation following IVF-ET in patients with PCOS (all P<0.05). Conversely, advanced age was associated with an increased risk of implantation failure (P<0.05). ROC curve analysis demonstrated that a multivariable model incorporating endometrial blood flow grade, endometrial blood flow quantity, number of high-quality embryos, and age had strong predictive performance for implantation success (AUC = 0.917).

Weight management before assisted reproduction is clinically important. Overweight patients should monitor endometrial and uterine artery blood flow parameters and receive targeted interventions to improve pregnancy outcomes.

Intratumoral heterogeneity (ITH) is associated with poor prognosis in various solid tumors. However, its use as a predictive biomarker for immunotherapy in advanced non-small cell lung cancer (NSCLC) is still lacking.

We used Maftools to analyze somatic variants of NSCLC from independent cohorts (POPLAR, OAK, Hellmann2018) including 504 patients with advanced NSCLC. Additionally, 121 patients (in-house cohort) with NSCLC who received radical treatment and underwent 733-panel NGS testing of surgical samples were included. We used Shannon entropy to measure ITH, analyzed correlation with immunogenic markers, and explored ITH's prognostic effect on immunotherapy and its role in predicting postoperative recurrence risk. Using the TCGA cohort, we compared genetic characteristics between low ITH (ITH-L) and high ITH (ITH-H) groups, assessed mutational profiles, and evaluated associations between ITH scores and immune cell populations.

In the Hellmann2018 cohort, ITH-L correlated with higher durable clinical benefit (DCB) rate, objective response rate (ORR), and median progression-free survival (mPFS), highlighting ITH-L as a potential positive predictor for ICI therapy. Combining ITH with TMB revealed that ITH-L/TMB-H patients had significantly better DCB, ORR, and mPFS, supporting the potential predictive value of ITH when evaluated together with TMB. Validation in POPLAR/OAK cohorts supported the association of ITH, alone or combined with TMB, with immunotherapy outcomes. ITH-L patients exhibited higher DCB, ORR, longer mPFS, and median overall survival (mOS). Combining ITH and circulating tumor DNA validated these findings. In early-stage surgical NSCLC patients, ITH-L was associated with significantly higher median recurrence-free survival (mRFS). Mechanistically, the ITH-L group showed elevated TMB, neoantigen (SNV), and subclonal genome fraction, alongside reduced HRD scores and CNV burden. Mutational analysis identified XIRP2 as the most frequently altered gene, enriched in the ITH-L group, while SHOX2 was the only gene with higher frequency in the ITH-H group. Immune infiltration analysis revealed significant differences in M1 macrophages, activated memory CD4+ T cells, and naive CD4+ T cells between groups.

ITH may serve as a potential biomarker associated with immunotherapy outcomes in advanced NSCLC and postoperative recurrence risk in early-stage surgical patients.

Volumetric modulated arc therapy (VMAT) is increasingly used for breast and chest wall (CW) treatment with regional nodal irradiation (RNI) because of its ability to sculpt dose around complex target volumes. However, VMAT can increase low-dose radiation to surrounding normal tissues and particularly increase cardiac dose.

To evaluate the dosimetric impact of a strategic aperture-restricted beam geometry, compared with traditional open-field geometry in VMAT planning for comprehensive left-sided breast/CW irradiation with RNI across three linac platforms. The impact of convergence mode settings was also investigated.

Fourteen patients with left-sided breast/CW irradiation including comprehensive RNI were retrospectively included. For each patient, a patient-specific optimization template with a prescription of 40.05 Gy in 15 fractions was applied across three linac platforms (Varian TrueBeam, Varian Halcyon, and Elekta Versa HD), using two beam geometries: an open-field approach, in which field sizes fully encompassed the targets, and an aperture-restricted approach, in which the deep field border was limited to reduce beam entry to the heart and ipsilateral lung. Jaw tracking was enabled on the TrueBeam and Versa HD linacs. Each plan was also evaluated across three convergence modes ("Off," "On," and "Extended"), resulting in 18 plans per patient. All plans were normalized such that 95% of the breast/CW planning target volume received 95% of the prescription dose. Dosimetric endpoints include mean heart dose, ipsilateral lung V17Gy, contralateral lung V4Gy, and contralateral breast/CW V5Gy. Total monitor units (MUs) were evaluated, and patient-specific quality assurance (PSQA) was performed for the three highest-MU plans on each linac platform. Paired tests were used to compare across plans.

Target coverage was maintained after plan normalization. Aperture-restricted VMAT significantly reduced mean heart dose compared with open-field geometry across all linac platforms and convergence modes. The proportion of plans exceeding mean heart dose of 4 Gy was substantially lower with aperture-restricted geometry compared to open-field plans (2.4% vs 26.2%). The largest reduction in mean heart dose was observed with the "Off" convergence mode, decreasing from 4.20 to 2.71 Gy on TrueBeam, 3.32 to 2.58 Gy on Halcyon, and 3.97 to 2.84 Gy on Versa HD. Ipsilateral lung V17Gy was also significantly reduced with aperture-restricted beam geometry, with only one exception on Halcyon using the "Extended" mode. No significant differences were observed in contralateral lung V4Gy, although contralateral breast/CW V5Gy increased significantly, representing a dosimetric tradeoff associated with the aperture-restricted geometry. Aperture-restricted beam geometry significantly increased MUs; however, PSQA passed for the three highest-MU plans on each linac platform according to our clinical criteria. Additionally, more extensive convergence modes were associated with improved plan quality, particularly in reducing hotspot dose (D0.1cc) and enhancing cardiac and ipsilateral lung sparing.

Aperture-restricted beam geometry significantly reduced mean heart dose and ipsilateral lung dose while maintaining target coverage across all three linac platforms, supporting its potential clinical value in VMAT planning for comprehensive left-sided breast/CW irradiation with RNI, albeit with increased contralateral breast/CW dose. When combined with a more extensive convergence mode, overall plan quality was further improved.

Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene. Patients report substantial pain, stiffness, and declining physical function; those whose disease is not amenable to surgery require systemic therapy. Vimseltinib is an oral, switch-control kinase inhibitor of the CSF1 receptor (CSF1R). Here, the authors report safety and efficacy of vimseltinib in patients with TGCT based on prior treatment. Cohort A included patients who did not receive prior specific anti-CSF1/CSF1R agents (n = 46; prior imatinib/nilotinib allowed), and cohort B included patients who received prior specific agents (n = 20).

The phase 2 (expansion) portion of this ongoing, multicenter, open-label, phase 1/2 study (NCT03069469) enrolled adults (≥18 years) with histologically-confirmed TGCT not amenable to surgery. Patients received vimseltinib 30 mg twice weekly (recommended phase 2 dose). The primary objectives were to assess safety and antitumor activity; secondary objectives included assessment of active range of motion (ROM) and patient-reported outcomes.

Most treatment-emergent adverse events were grade 1/2, and there was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. Best overall response rates were 64% (29 of 45) and 37% (7 of 19) for cohorts A and B after mean follow-up of 23 and 19 months, respectively. Most patients experienced meaningful improvements in active ROM and patient-reported physical function, stiffness, health status, and pain.

Vimseltinib had a manageable safety profile, demonstrated durable antitumor activity, and provided functional and symptomatic improvements in patients with TGCT, offering an effective treatment option regardless of previous treatment with anti-CSF1/CSF1R agents.

This study aimed to evaluate the efficacy and safety of concurrent versus sequential stereotactic radiotherapy (SRT) and immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients with multiple brain metastases (BM).

We retrospectively analyzed 198 NSCLC patients with BM who underwent SRT and ICIs treatment between 2017 and 2024. Of 136 eligible patients, were assigned to two cohorts and subcohorts through propensity score matching. The concurrent cohort consisted of 68 patients receiving ICIs within 14 days of SRT (post-SRT 34 cases and pre-SRT 34 cases). The sequential cohort included another 68 patients undergoing sequential treatment > 14 days apart (post-SRT1 31 cases and pre-SRT1 37 cases). Overall survival (OS) and intracranial progression-free survival (iPFS) were the primary endpoints. Secondary endpoints were intracranial objective response rate (iORR), disease control rate (DCR) and adverse events (AEs).

Concurrent group achieved significantly superior median OS (24.5 months vs. 18.3 months, HR = 0.68, 95% CI 0.49-0.94, p = 0.001) and median iPFS (14.2 months vs. 9.8 months, HR = 0.62, 95% CI 0.45-0.86, p < 0.001) compared to the sequential group. Subgroup analysis, the post-SRT group showed significantly improved median OS (27.1 months vs. 17.2, 19.2, 13.2 months, p < 0.05) and median iPFS (20.1 months vs. 10.5, 12.1, 5.3 months, p < 0.05) compared to the other three groups (pre-SRT, post-SRT1 and pre-SRT1). Multivariate analysis revealed that a treatment interval ≤ 14 days was an independent protective factor for both iPFS (p = 0.004) and OS (p = 0.019). Subgroup analysis demonstrated that a treatment interval ≤ 7 days was superior to an interval of 8-14 days or > 14 days. Furthermore, ICIs following SRT was associated with improved OS (p = 0.003) and iPFS (p < 0.001). No significant differences were observed in radionecrosis (RN) and AEs.

Concurrent SRT with ICI, especially ICIs following SRT, provides superior survival outcomes for NSCLC patients with multiple BM, without increasing AEs. The timing of therapy is a critical factor influencing the efficacy of the combined regimen.

The incidence of thyroid cancer (TC) has significantly increased over the past decades due to a few recognised risk factors. Although the relationship between dietary factors and TC is still not fully understood, emerging evidence suggests that certain dietary habits may influence the risk of developing this type of cancer. This systematic review (PROSPERO ID: CRD42023463802) investigated the association between dietary patterns and TC risk using the available evidence.

Five databases were searched (PubMed/Medline, Embase, Scopus, Web of Science and LILACS) for observational studies in adults comparing unhealthy and healthy dietary patterns among individuals diagnosed with TC-between September 2023 and January 2025, without restrictions on language or publication year. Three independent reviewers conducted study selection and data extraction.

Forty-five studies were included (two cross-sectional, thirteen cohort and thirty case-control). A posteriori patterns rich in vegetables, fruits, fish, lean meat, dairy products and unsaturated fats were significantly associated with reduced TC risk, whereas starchy foods, seafood, seaweed, processed meats, instant foods, fast food and Western patterns increased risk. A priori patterns with higher inflammatory potential were also positively associated with TC risk. Most studies demonstrated good methodological quality, according to NOS assessment.

This systematic review suggests that dietary patterns may be associated with TC risk. Although healthier dietary patterns tended to be associated with a lower risk and pro-inflammatory or Western-style dietary patterns with a higher risk, the current evidence remains observational and heterogeneous. Further prospective studies are needed to clarify the biological mechanisms underlying these associations.

Overdiagnosis is a major challenge in screening, leading to healthy individuals being diagnosed and treated for conditions that would never have caused harm. While evidence on overdiagnosis is growing, little is known about how health professionals (HPs) understand and engage with this phenomenon in practice. This study examines health professionals' awareness, understanding and approaches to overdiagnosis in breast, lung, and prostate cancer screening.

This is a qualitative study with semi-structured interviews, using Positioning Theory as an analytical lens, among HPs involved in breast, prostate, or lung cancer screening in Flanders, Belgium, both in public health settings and in individual clinical care. 34 HPs, of whom 21 were purposively invited, because of their professional role, research background or public advocacy related to screening. In addition, 13 clinicians were randomly recruited from a list of registered physicians (GPs, gynaecologists, urologists and pneumologists).

Few participants spontaneously mentioned overdiagnosis as a harm of screening, although most recognised it, primarily in relation to prostate cancer screening. Some HPs demonstrated a thorough understanding of overdiagnosis, but did not necessarily perceive it as a relevant harm. HPs' perceptions and corresponding approaches depended primarily on their overall position regarding screening. The participating HPs articulated three different storylines to motivate their positions: (1) routine screening, where HPs accept screening as self-evident and are largely unaware of overdiagnosis, (2) determined screening, where HPs emphasise the evidence-based benefits of screening and acknowledge overdiagnosis, which they try to mitigate, but also de-problematise, and (3) cautious screening, where HPs question the evidence base and benefits of screening and consider overdiagnosis one of the reasons for adopting a reluctant position towards screening.

Participants rarely identify overdiagnosis as a harm of screening, despite being (passively) aware of it. HPs' broader position on screening shapes how they understand, interpret, and respond to overdiagnosis and is primarily based on their knowledge of screening benefits, and influenced by professional contexts and personal characteristics. Regardless of their level of enthusiasm for screening, HPs with a more comprehensive understanding of its benefits and harms tend to adopt more deliberate and carefully considered - albeit divergent- approaches to overdiagnosis.

Not applicable.

Multiple myeloma, a malignant plasma cell disorder, has undergone remarkable therapeutic advancement. The lenalidomide-bortezomib-dexamethasone (VRd) regimen has been firmly established as one of the standard induction therapies for newly diagnosed multiple myeloma (NDMM) patients, owing to its substantial clinical benefits. Despite its superiority in achieving good responses, VRd harbors intrinsic limitations in high relapse risk, and treatment-related toxicities. Dara (Daratumumab)-containing regimens are prioritized as frontline treatment options per international guidelines. While the quadruplet Dara-VRd combination further improves clinical efficacy, it carries notable safety and tolerability burdens and is suboptimal for vulnerable patient subgroups: it is poorly tolerated by elderly or frail individuals, requires complicated dose modifications for patients with renal impairment, and impairs hematopoietic stem cell mobilization in transplant-eligible candidates. The triplet daratumumab-bortezomib-dexamethasone (DVd) regimen has yielded encouraging anti-tumor activity in patients with relapsed/refractory multiple myeloma (RRMM), which motivated us to explore its clinical performance in the frontline setting. The present study aimed to compare the efficacy and safety of frontline DVd versus VRd induction, to generate real-world clinical evidence guiding individualized treatment decision-making for NDMM.

To compare the efficacy, safety and real-world applicability of DVd versus VRd in NDMM patients.

This multicenter prospective study enrolled 206 NDMM patients (DVd: n = 98; VRd: n = 108) from 12 Chinese centers (March 2023-March 2025). Propensity score matching (PSM; covariates: age, serum creatinine, Durie-Salmon stage, ISS stage) generated a balanced cohort (70 patients/group). Key endpoints: overall response rate (ORR), renal response rate (RRR), time to renal recovery (TTRR), progression-free survival (PFS), duration of response (DOR), and adverse events (AEs; NCI CTCAE v5.0).

Both groups had high completion rates after induction (95.9% [94/98] vs. 94.4% [102/108], p = 0.623). ORR was comparable in the original cohort (DVd 97.9% vs. VRd 94.1%, p = 0.282), but DVd achieved faster response (median time to response: 1.85 vs. 2.27 months, p = 0.002), despite worse baseline characteristics. In the propensity score-matched cohort, the two groups also had similar ORR (DVd 97.1% vs. VRd 97.0%, p = 1.00) with comparable deep remission rates (MRD negativity: 4.3% vs. 7.3%; sCR/CR: 30.4% vs. 32.3%). Renal response: Despite lower mean baseline eGFR in DVd group (23.7 vs. 32.7 mL/min, p < 0.001), magnitude of eGFR improvement was comparable (ΔeGFR: 15.2 vs. 12.7 mL/min, p = 0.48) in the original cohort. In the propensity score-matched cohort, 78.6% (22/28) in DVd and 95.0% (19/20) in VRd achieved response (renal-CR: 50.0% vs. 70.0%; renal-PR: 7.1% vs. 15.0%; renal-MR: 21.4% vs. 10.0%, p = 0.207). PFS: In the original cohort, the 12-month PFS rate was 92.8% in the DVd group and 79% in the VRd group. In the propensity score-matched cohort, the 12-month PFS rate in DVd and VRd group was 91.9% vs. 84%. Subgroup analyses confirmed PFS benefits in patients with high-risk genetics, ISS stage III, and transplant-eligible patients. DOR: In the original cohort, the 12-month DOR rate was 92.5% in the DVd group and 74.6% in the VRd group. In the propensity score-matched cohort cohort, the 12-month DOR rate in DVd and VRd group was 91.9% vs. 84%. Subgroup analyses confirmed DOR benefits in patients with high cytogenetic risk, ISS stage III, and transplant-eligible patients.

Across both the original and PSM cohorts, the DVd regimen had relatively fewer severe adverse reactions than the VRd regimen with no statistical significance. After PSM, the patients in DVd group vs. VRd group: grade 3-4 neutropenia (5.71% vs. 10%, p = 0.346) and thrombocytopenia (10% vs. 14.29%, p = 0.438), grade 3-4 ALT elevation (7.14% vs. 10%, p = 0.546).

DVd demonstrates faster response, superior PFS and DOR, accompanying with relatively less toxicity in NDMM patients. These real-world data support DVd as a frontline option for NDMM patients.

Preoperative risk stratification for radical prostatectomy is crucial, yet predicting the wide range of postoperative outcomes remains a significant challenge. While machine learning (ML) shows promise, "black box" models limit clinical translatability. This study aimed to predict postoperative parameters using ML and employ explainable AI (XAI) to identify their key clinical drivers. In a retrospective study of 326 patients (224 robot-assisted [RARP], 102 open [ORP]), we developed predictive models for twelve outcomes, including length of stay and pathological ISUP grade. Four ML algorithms (Random Forest, Gradient Boosting, SVM, Neural Network) were evaluated via nested 5-fold cross-validation. A custom permutation-based Shapley sampling framework SHAP (SHapley Additive exPlanations) was applied to the best-performing models to quantify the predictive importance of preoperative features. ML models outperformed baseline heuristics for a subset of the prespecified outcomes, with strongest performance for postoperative hemoglobin (R² up to 0.57) and the decision to perform frozen sections (AUC up to 0.89). Not all outcomes proved equally amenable to prediction, consistent with the heterogeneous nature of postoperative recovery. SHAP analysis revealed a clear dichotomy: procedural parameters, such as catheter dwell time and hospital stay, were almost exclusively predicted by the surgical approach (RARP vs. ORP). In contrast, pathological outcomes like ISUP grade were predominantly driven by preoperative tumor characteristics. Preoperative hemoglobin was identified as a strong predictive feature for postoperative anemia within this dataset, ranking above non-modifiable factors such as age. Explainable AI can deconstruct the complex interplay of factors influencing surgical success, providing a data-driven basis for hypothesis generation and clinical pathway optimization. As a single-centre proof-of-concept study without external validation, these findings require prospective confirmation in independent multi-centre cohorts before clinical translation can be considered.