Search Results (538)

Background: The STAG1 gene has been related to a poorly known form of intellectual disability, known as Intellectual Developmental Disorder, Autosomal Dominant 47 (MRD47). Functionally, MRD47 is part of the Cohesinopathies, a small family of rare genetic disorders caused by defective cohesin complex, whose activity is essential for sister chromatid cohesion and therefore for chromatin organization. Chromatin state modulation is an entangled process finely modulated by a large number of actors that, if altered, give rise to the so-called Chromatinopathies. The clinical and biological overlap among these families of conditions on one hand poses significant challenges during diagnostic definition, and, on the other, may help delineate more accurate management guidelines. Methods: Starting from the report of a novel pathogenic variant in the STAG1 gene, we performed a retrospective clinical and molecular review of all previously reported patients affected by this rare disorder. Once clinical and photographic data of all published patients were collected, we used Face2Gene deep learning technology to analyze STAG1 facial phenotype, comparing it to both Chromatinopathy and Cohesinopathy profiles. Results: Our clinical and molecular re-evaluation of reported cases confirms MRD47 as a mainly neurodevelopmental disorder. Through artificial intelligence technology, we were able to first create the gestaltic profile of MRD47. Face2Gene analyses of this composite phenotype, although limited by the tool’s analysis modalities, demonstrates the strong overlap of STAG1 disorder with Chromatinopathies. Conclusions: The present literature review, together with gestaltic analyses of the STAG1-related phenotype, underscores the strong resemblance of MRD47 to epigenetic machinery disorders. The present case brings to light once more the biological and phenotypical entanglement of Cohesinopathies and Chromatinopathies, hinting at STAG1 as the joining chain. Full article

Background: Minimal residual disease (MRD) assessment is an emerging tool for refining the risk of relapse following definitive therapy in non-small-cell lung cancer (NSCLC). However, data regarding its clinical impact on the decision-making process remain limited. We evaluated MRD feasibility and its impact in the real-world setting. Methods: A pooled retrospective analysis of longitudinal MRD data in NSCLC patients (n = 34: Signatera™ (Exome), n = 25, Guardant Reveal™, n = 9) was implemented. Co-primary endpoints: MRD feasibility and clinical impact on management (changes in surveillance intensity or therapy escalation/de-escalation). Secondary endpoints: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy for recurrence detection, and MRD lead time. Results: MRD was feasible in 32/34 patients (94.1%); longitudinal testing included two samples in 15 patients (44.1%) and three samples in 2 patients (5.9%). Signatera™ (Exome) failed in 2/25 (8.0%) due to insufficient tissue. MRD influenced management in 20/34 (58.8%) patients, most commonly supporting therapy de-escalation (15/34, 44.1%), followed by imaging surveillance modification (3/34, 8.8%) and therapy escalation (2/34, 5.9%). In univariable analysis, tumor grade and STAS were associated with MRD-driven management impact, but neither remained significant in multivariable analysis. With a median follow-up of 18.9 months (IQR 8.5–30.7), MRD was positive in 6/32 (18.8%), while recurrence/progression occurred in 10/32 (31.3%) patients. MRD yielded 21 true negatives, five true positives, five false negatives (including two isolated brain recurrences), and one false positive, corresponding to a sensitivity of 50.0%, specificity of 95.5%, PPV of 83.3%, NPV of 80.8%, and an accuracy of 81.3%. The median MRD lead time (n = 5) was 1.31 months (range, 0.46–5.52). Conclusions: In this real-world cohort, MRD testing was feasible and frequently guided clinical decisions, mainly supporting treatment de-escalation. MRD was highly specific but less sensitive. Prospective studies are needed to define optimal testing intervals and validate MRD-guided strategies. Full article

Platinum chemistry covers a wide range of applications, including homogeneous and heterogeneous catalysis as well as cancer therapy. Numerous Pt complexes have been synthesized and studied in recent years, with NMR spectroscopy serving as the primary technique for structural characterization. The ¹⁹⁵Pt nucleus has favorable features for NMR studies, being highly sensitive to ligand type and structural environment. From a computational perspective, factors such as solvent effects, relativistic corrections, and the electronic structure of the ligands strongly influence the calculated NMR parameters. Consequently, establishing a general computational protocol for ¹⁹⁵Pt NMR prediction remains a challenging task. In this work, we present a systematic validation and extension of our previously developed computational protocol, originally proposed for Pt(II) complexes, in studying ¹⁹⁵Pt NMR chemical shifts in Pt(II)-Sn(II) complexes. A benchmark set of 100 Pt(II)-Sn(II) complexes was analyzed, yielding good agreement with experimental data (R² = 0.86, MRD = 3.6%, MAD = 163 ppm), which is remarkable given the structural diversity and broad range of chemical shifts covered. Full article

The management of urothelial carcinoma (UC) is undergoing a paradigm shift from static anatomical staging to molecularly guided dynamic approaches that integrate time as a critical therapeutic variable. This evolution is driven by liquid biopsies, particularly circulating tumor DNA, which allow real-time tumor interrogation. We conducted this expert review to synthesize landmark evidence, enabling technologies, and implementation challenges in dynamic precision oncology for UC. In this non-systematic narrative review, we searched PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library for articles published between January 2015 and February 2026. Studies were selected based on their relevance to dynamic precision oncology, clinical actionability, and translational implementation, prioritizing landmark randomized controlled trials providing level 1–2 evidence, large prospective cohorts, and key translational studies. Enfortumab vedotin plus pembrolizumab established the new first-line standard for metastatic UC, achieving a median overall survival of 33.8 months versus 15.9 months (hazard ratio [HR] 0.51, 95% confidence interval 0.43–0.61). Circulating tumor DNA demonstrates robust prognostic value for molecular residual disease (MRD) detection (Level 2a evidence), stratifying recurrence risk with hazard ratios of approximately 4.5. Critically, the IMvigor011 trial has now provided Level 1b evidence that ctDNA-guided adjuvant atezolizumab improves both disease-free survival (DFS) (HR 0.64, p = 0.0047) and OS (HR 0.59, p = 0.0131) in ctDNA(+) patients, while validating treatment de-escalation in ctDNA(−) patients (1-year DFS 95%). Erdafitinib in patients harboring FGFR2/3 alterations (HR 0.64) confirms the value of genomic profiling. Major limitations include the inherent selection bias of this non-systematic approach, substantial platform heterogeneity, and lack of standardization. In conclusion, dynamic precision oncology has transformed UC management, with the IMvigor011 trial establishing ctDNA-guided MRD status as the first phase 3-validated predictive biomarker framework for adjuvant therapy selection in a solid tumor. Implementation requires adherence to established standardization frameworks, cross-platform and cross-agent validations, and tiered implementation strategies to ensure equitable access across diverse resource settings. Full article

Background/Objectives: Minimal residual disease (MRD) negativity is associated with improved outcomes in acute myeloid leukemia (AML) patients. In this retrospective observational real-life case series study, we investigated the efficacy and safety of venetoclax dose adjustment in unfit AML patients and the role of WT1 expression levels as a surrogate marker of MRD monitoring. Methods: A total of 24 consecutive unfit AML patients treated with azacytidine and venetoclax were enrolled in this study, and MRD monitoring was performed by flow cytometry as per international guidelines and by WT1 expression levels assessed by RT-qPCR. Dose adjustment of venetoclax was decided based on MRD status and the onset of grade > 2 neutropenia. Results: The overall response rate was 87.5%, and 16 patients achieved a response already at the first re-evaluation (66.7%). No statistically significant differences were observed between patients who received the standard dose and those with venetoclax dose adjustment in terms of overall survival (19.6 months vs. 30.1 months, respectively; p = 0.9428) and progression-free survival (not reached vs. 22.1 months, respectively; p = 0.3865), although a numerical trend toward lower relapse rates was observed in subjects with late (33.3%) or early and late dose reduction (37.5%) compared to those who had dose adjustment only at the first re-evaluation (75%) (p = 0.3014). The toxicity rate was 33.3% in patients who had early and late dose adjustments, which was lower than that observed with early adjustment (58.3%) and than that reported in the VIALE-A study (84%). Conclusions: Reduced-dose venetoclax regimens (from 28 to 21 days per cycle) in unfit AML patients do not affect response rates or survival and are associated with comparable rates of neutropenia and infectious events, supporting flexible dosing strategies based on patient response and side effects. In addition, WT1 expression could serve as a reliable marker for MRD monitoring. Full article

Cr₂O₃-based ceramic coatings are widely used in wear-critical applications; however, their tribological performance under dry sliding conditions can be limited by brittleness and frictional instability. In heavy-duty vehicles, the king pin–bushing contact operates under severe dry sliding conditions, motivating the investigation of composite Cr₂O₃–nTiO₂ coatings as a potential surface engineering solution. In this study, Cr₂O₃–TiO₂ coatings containing 0, 10, 20, 30, and 40 wt% TiO₂ were deposited by atmospheric plasma spraying (APS) from mechanically mixed powders. Phase composition was analyzed by X-ray diffraction using an X’Pert PRO MRD diffractometer, while microstructure and elemental distribution were examined by scanning electron microscopy (SEM) coupled with energy-dispersive X-ray spectroscopy (EDS) on a FEG Quattro C microscope. Mechanical properties were evaluated by Vickers microhardness, instrumented indentation and scratch testing, while dry sliding wear behavior was assessed by pin-on-disc tests performed on a CETR UMT-2 tribometer against a bronze counterbody, with continuous monitoring of the coefficient of friction (COF). The results show that plasma spraying produces lamellar composite coatings with intrinsic porosity and locally modified phase composition. Cr₂O₃-rich coatings exhibit higher hardness (1198 HV2 compared with 877 HV2 for Cr₂O₃–40TiO₂ corresponding to an increase of approximately 36%) and improved resistance to indentation, reflected by lower penetration depths and higher elastic modulus values (134 GPa for S0 compared with 77 GPa for S2). These coatings also exhibit a more stable friction response and reduced material transfer from the bronze counterbody, as confirmed by the lower mass loss of the pins (0.0295 g for S0 compared with 0.0473 g for S4, corresponding to a reduction of about 38%). Increasing TiO₂ content leads to changes in friction stability and wear behavior associated with microstructural heterogeneity. These findings indicate that the sliding wear performance of Cr₂O₃–nTiO₂ coatings is governed by elastic–plastic stability under localized contact loading and support their applicability for dry sliding king pin–bushing systems in heavy-duty vehicles. Full article

Circulating tumour DNA (ctDNA) assays are increasingly applied in haematological malignancies for non-invasive genotyping, quantitative response assessment, measurable residual disease (MRD) detection, and relapse surveillance, often complementing bone marrow-based testing and, in selected scenarios, potentially reducing its frequency. Yet, translating ctDNA results into comparable clinical decisions across laboratories, platforms, and time remains challenging because ctDNA measurements are influenced by the definition of the measurand (for example, variant allele fraction versus mutant molecules per mL), pre-analytical variables, end-to-end workflow losses, and lineage-specific confounders such as clonal haematopoiesis of indeterminate potential (CHIP), therapy-related clonal haematopoiesis, and compartmental disease (marrow, plasma, cerebrospinal fluid, extramedullary sites). This review proposes a harmonisation framework for haematological ctDNA based on three linked concepts—metrological traceability, which connects reported values to reference systems with stated uncertainty, commutability, which ensures that reference materials behave like patient specimens across diverse workflows and fit-for-purpose reference materials that support calibration, and quality control, external quality assessment, and cut-off setting for intended uses such as early molecular response in large B-cell lymphoma, molecular MRD in acute myeloid leukaemia, and deep response monitoring in multiple myeloma. This framework is accompanied by harmonised CHIP-aware reporting rules for settings without matched cellular DNA and practical change-control/bridging strategies to preserve clinical decision thresholds when platforms or bioinformatic pipelines evolve. Full article

Background: Despite well-established treatment and follow-up protocols for the management of colorectal cancer patients, recurrences are frequent. Post curative therapy, ctDNA-based molecular residual disease assessment has the ability to stratify patients into higher and lower risks of recurrence. Large-scale clinical trials are necessary to establish utility at a broad level, but physicians also need real-world evidence and case reports before utilizing MRD testing in routine practice. Methods: We analyzed real-world utilization patterns of Guardant Reveal in patients with CRC across stages by collating information from the test request form after the test was ordered as a part of routine practice in the AMEA region. Results: We report that 92% of the tests were utilized for stage II and stage III patients. The timing of the first MRD test order varies between stages, with a higher proportion of tests being ordered within the first 12 weeks of surgery for stage II (71.8%), while for stage III (50%) and stage IV oligometastatic (72%), the first test was ordered after 12 weeks of surgery. Conclusions: Case reports delineate physicians’ perspectives on actions taken on the basis of MRD test results and outcomes. Full article

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has long constituted a cornerstone of post-remission consolidation therapy for adults with high-risk B-cell acute lymphoblastic leukemia (B-ALL), offering potent graft-versus-leukemia activity at the expense of significant treatment-related toxicity (TRT) and non-relapse mortality (NRM). Over the past two decades, however, outcomes following allo-HSCT have improved substantially. This progress has been driven primarily by a marked reduction in NRM, translating into improved overall survival (OS), as consistently documented by large cooperative group analyses and single-center series. Advances in supportive care, infectious prophylaxis, donor selection, and graft-versus-host disease (GvHD) prevention have contributed substantially to this improvement. In parallel, transplant decision-making has been profoundly reshaped by refined disease biology-based risk stratification and the systematic evaluation of measurable residual disease (MRD). Moreover, the advent of highly effective immunotherapeutic approaches—including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapies—has enabled the achievement of deeper molecular remissions prior to transplantation, both in first and subsequent complete remissions. Taken together, these developments have shifted allo-HSCT from a widely applied strategy to a more individualized, risk-adapted therapeutic approach. This review examines how the indications, timing, and objectives of allo-HSCT are evolving in the contemporary treatment landscape of adult B-ALL, with particular emphasis on Philadelphia chromosome–negative, Philadelphia-like, and Philadelphia chromosome–positive disease subsets. Full article

Background/Objectives: To evaluate margin reflex distance-1 (MRD-1), inter-eyelid symmetry, functional visual parameters, and cosmetic outcomes following Müller Muscle–Conjunctival Resection (MMCR) in selected pediatric patients with mild-to-moderate blepharoptosis, good levator function, and a positive 2.5% phenylephrine test. Methods: This retrospective observational study included pediatric patients (<18 years) who underwent MMCR between 2018 and 2023. Surgical indications were based on functional or developmental criteria, including visual axis obstruction, abnormal head posture, significant eyelid asymmetry, or psychosocial concerns, rather than eyelid height alone. Preoperative and postoperative examinations at 1 week, and at 1, 3, and 6 months, included best-corrected visual acuity (BCVA), MRD-1, eyelid symmetry, levator function, lagophthalmos, and ocular surface findings. Outcomes were analyzed separately for unilateral and bilateral cases. Statistical analyses were performed using non parametric tests, with p < 0.05 considered statistically significant. Results: Fifty patients (55 eyes; mean age 13.16 ± 4.04 years) were included. Mean preoperative MRD-1 increased significantly from 1.83 ± 0.89 mm to 2.97 ± 0.83 mm at 6 months (p < 0.001). Postoperative MRD-1 at 6 months showed a significant correlation with the phenylephrine response. In unilateral cases, excellent or satisfactory postoperative symmetry was achieved in 83.6% of eyes. Bilateral cases demonstrated comparable MRD-1 elevation with satisfactory contour and high patient/parent satisfaction. Transient lagophthalmos improved over time. No overcorrection, exposure keratopathy, or significant ocular surface complications were observed. Revision surgery was required in 8.9% of unilateral cases. Conclusions: MMCR is a safe and effective option for appropriately selected pediatric patients, providing predictable eyelid elevation, good symmetry, and low complication rates when functional indications are present. Full article

Poly(ADP-ribose) polymerase inhibitors (PARPi) have reshaped therapy for advanced prostate cancer, yet durable benefit remains concentrated in BRCA1/2-altered tumors, especially BRCA2, and most responders eventually relapse. Here, we frame PARPi response and resistance through a unifying model in which DNA damage response (DDR) rewiring (e.g., homologous recombination repair (HRR) restoration, fork protection, checkpoint tolerance, and altered drug handling) converges with treatment-induced dormancy and quiescent therapy-tolerant residual states that sustain minimal residual disease (MRD) under androgen receptor pathway inhibition (ARPI) and PARP blockade. We synthesize clinical and translational evidence for PARPi monotherapy and PARPi-based combinations across disease states. In first-line metastatic castration-resistant prostate cancer (mCRPC), PARPi plus ARPI consistently prolongs radiographic progression-free survival, with the greatest benefit in HRR-altered tumors, and emerging overall-survival signals in selected subgroups. In later-line settings, monotherapy activity is most robust in BRCA2-mutated disease, whereas non-BRCA HRR alterations show heterogeneous and often modest responses, underscoring the need for biomarkers beyond gene panels. We also discuss combination strategies with DDR-targeting agents, radioligand therapies, and immunotherapy, and summarize ongoing phase III programs in metastatic castration-sensitive prostate cancer (mCSPC). Finally, we outline practical considerations for biomarker-informed patient selection, monitoring, sequencing, and toxicity management, with particular emphasis on intercepting MRD and resistance evolution. Full article

Minimal residual disease (MRD) refers to the persistence of low-level malignant cells or tumor-derived nucleic acids that remain after curative-intent therapy and are undetectable by conventional diagnostic methods. In oncology, MRD has emerged as a powerful biomarker with well-established prognostic value in hematologic malignancies and rapidly expanding relevance in solid tumors. Advances in sensitive detection technologies, including multiparameter flow cytometry, quantitative real-time polymerase chain reaction, next-generation sequencing, and digital polymerase chain reaction, have enabled the identification of residual disease at the molecular level, often preceding clinical or radiological relapse. Beyond its conventional role as a binary indicator of treatment response or cure, MRD is increasingly recognized as a dynamic longitudinal biomarker that supports personalized disease management. Within this evolving paradigm, patient-informed MRD strategies that incorporate tumor-specific molecular profiling and serial monitoring, particularly through circulating tumor DNA, offer the potential to guide treatment adaptation, including escalation, de-escalation, maintenance optimization, and surveillance strategies across both hematologic and solid malignancies. In this review, we summarize the biological basis of MRD, current and emerging detection methodologies, and clinical applications across cancer types, with a focus on patient-informed approaches. We also discuss key limitations, including assay standardization, biological variability in solid tumors, and the lack of clearly defined actionability thresholds. Finally, we highlight future directions for integrating MRD with multi-omics and AI-driven analytical frameworks to enable adaptive, risk-informed cancer management and advanced precision oncology. Full article

Introduction: Myxoid liposarcoma (MLPS) is a rare soft tissue sarcoma comprising 5–10% of adult cases, most often in the thigh. Diagnosis is challenging due to nonspecific imaging findings and resemblance to benign lesions. Case Report: A 42-year-old male presented with a painless, enlarging upper right medial thigh mass. CT and ultrasound suggested a complex solid lesion, possibly benign. Outpatient surgical excision revealed a red, gelatinous, non-encapsulated mass. Frozen section suggested a myxomatous spindle cell tumor. Final pathology confirmed MLPS FNCLCC grade 2 (intermediate grade) with DDIT3 rearrangement on fluorescence in situ hybridization (FISH). Margins were negative but close. Postoperative PET scan and Signatera MRD assay were negative for metastasis. Given the tumor’s size (>10 cm) and known radiosensitivity, adjuvant radiotherapy (60–66 Gy) was initiated. Discussion: MLPS features myxoid stroma, plexiform vasculature, and, in high-grade tumors, a round cell component. The FUS::DDIT3 fusion gene is diagnostic. While MRI offers superior soft tissue characterization, definitive diagnosis requires pathology and molecular testing. Surgical excision with negative margins remains standard, with radiotherapy recommended for large tumors or close margins to reduce recurrence. This case highlights the limitations of preoperative imaging and the value of intraoperative pathology in guiding management. Conclusions: Early recognition, accurate diagnosis, and tailored multimodal treatment are essential for MLPS. Given the potential for recurrence, late extrapulmonary metastases, long-term surveillance with imaging, and molecular assays are critical for optimizing outcomes. Full article

Head and neck squamous cell carcinoma (HNSCC) is biologically and clinically dichotomous according to HPV status, a distinction that fundamentally dictates the design, implementation, and interpretation of liquid biopsy strategies. Conventional anatomical imaging lacks sufficient sensitivity for minimal residual disease (MRD) detection, contributing significantly to treatment failure and suboptimal clinical outcomes. This review provides a critical, evidence-based synthesis of the three principal circulating analytes, circulating tumor DNA (ctDNA), exosomes, and circulating tumor cells (CTCs), and their evolving roles in real-time, non-invasive molecular monitoring. Critically, the clinical readiness of these analytes differs substantially: while ctDNA, particularly HPV-related ctDNA, is approaching clinical validation for MRD detection and recurrence surveillance in HPV-positive HNSCC, exosomes and CTCs remain investigational tools hindered by ongoing technical challenges including lack of standardized assays, limited reproducibility across platforms, and insufficient prospective validation. We review how the presence of a clonal, virally derived DNA target in HPV-positive HNSCC contrasts with the heterogeneous somatic mutational landscape of HPV-negative tumors, necessitating divergent analytical platforms and yielding distinct clinical utility profiles for MRD detection and recurrence surveillance. We further outline a pragmatic translational pathway focused on assay standardization, particularly for exosomes and CTCs where this foundational work is most urgently needed, integration of complementary multimodal liquid biopsy approaches, and rigorously designed prospective interventional clinical trials to establish clinical utility. Collectively, these efforts aim to transition HNSCC management from reactive, anatomy-based surveillance to proactive, molecularly guided precision oncology, with the potential to improve therapeutic decision-making and patient outcomes. Full article

Background: Liquid biopsy using circulating tumor DNA (ctDNA) is rapidly reshaping gastrointestinal (GI) oncology. The highest-impact applications are molecular residual disease (mRD) detection after curative-intent therapy and early recognition of progression or resistance during systemic treatment. Methods: We performed a structured, clinically oriented narrative synthesis by using explicit search, eligibility, evidence prioritization, and clinical interpretation rules, integrating landmark prospective cohorts, randomized ctDNA-guided strategy trials where available, meta-analyses, key methodological research (e.g., pre-analytics, assay design, and clonal hematopoiesis (CH)/clonal hematopoiesis of indeterminate potential (CHIP)), and selected trial registries. Results: In resected colorectal cancer (CRC), postoperative ctDNA positivity is among the strongest known biomarkers of recurrence risk; large prospective studies demonstrate clear separation of disease-free survival (DFS)/overall survival (OS) between mRD+ and mRD− patients. In stage II colon cancer, randomized data (DYNAMIC) show that a ctDNA-guided strategy reduces adjuvant chemotherapy exposure without compromising long-term outcomes. In metastatic CRC, ctDNA supports early response monitoring and resistance tracking; ctDNA-selected anti-EGFR rechallenge provides a model of biomarker-driven actionability (CHRONOS). In gastroesophageal cancers, longitudinal ctDNA dynamics correlate with relapse risk and treatment efficacy, and in esophageal squamous cell carcinoma, ctDNA after neoadjuvant chemoradiotherapy informs residual disease risk and adjuvant stratification. In pancreatic ductal adenocarcinoma and hepatobiliary malignancies, sensitivity is constrained by low shedding and background cell-free DNA (cfDNA), yet ctDNA positivity remains clinically meaningful, and emerging data in resected extrahepatic cholangiocarcinoma (STAMP-linked analyses) show that ctDNA dynamics during adjuvant therapy predict recurrence. Conclusions: ctDNA is a clinically validated biomarker for mRD in CRC, whereas in other GI cancers, it remains a promising but methodologically heterogeneous tool whose clinical utility is tumor- and context-dependent. The next phase requires interventional trials demonstrating outcome improvement, harmonized sampling and reporting standards, and rigorous control of confounders (notably CH/CHIP). Full article