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PubMed2026

De-escalation of radiotherapy in HPV-negative non-nasopharyngeal head and neck squamous cell carcinoma: a systematic review.

BACKGROUND: Definitive and postoperative radiotherapy are central components of treatment for head and neck squamous cell carcinoma (HNSCC) but are associated with significant toxicities that can impair long-term function and quality of life. De-escalation strategies, aiming to reduce treatment-related morbidity while maintaining tumor control, have attracted increasing interest. However, most research has focused on HPV-positive oropharyngeal carcinoma. Systematic evidence for HPV-negative disease remains limited. METHODS: PubMed and EMBASE were searched for prospective studies investigating radio(chemo)therapy de-escalation in HPV-negative, HPV-unspecified, or mixed non-nasopharyngeal HNSCC populations. CLINICALTRIALS: gov was searched for ongoing prospective trials. Data extraction and verification were performed independently by three investigators. RESULTS: Screening of 3156 records identified 14 published prospective studies, 10 in the definitive and four in the postoperative setting. Strategies included reduction or omission of elective nodal volumes, dose reduction, and combined approaches. Additionally, 23 ongoing prospective trials were identified. Across studies, elective nodal failure rates were consistently low (0-4.6%), with most recurrences occurring within high-dose volumes rather than de-escalated elective regions. Randomized evidence for elective nodal dose reduction is mixed: two trials maintained regional control and reduced acute toxicity, whereas another was stopped for futility. CONCLUSION: Available evidence on de-escalation in HPV-negative HNSCC is limited, derived primarily from small, heterogeneous phase II studies with mixed HPV populations. Although data are promising in selected settings, notably for elective nodal control, the randomized evidence for elective nodal dose reduction is conflicting, and further adequately designed prospective randomized trials are required.

Humans↗

PubMed2026

Response-adapted surgical de-escalation following neoadjuvant immunotherapy in resectable mucosal HNSCC A systematic review and meta-analysis.

INTRODUCTION: Recent encouraging outcomes with neoadjuvant immune checkpoint inhibitors (ICIs) in mucosal head and neck squamous cell carcinoma (HNSCC) have generated interest in surgical de-escalation. However, the oncologic safety of response-adapted surgery (RAS) and its ability to achieve survival outcomes comparable to baseline-planned surgery (BPS) remain uncertain. METHODS: A systematic search of the PubMed, EMBASE, Cochrane Library, and the Clinical Trials Registry for studies of neoadjuvant ICIs, with or without chemotherapy, in resectable mucosal HNSCC, that explicitly report surgical extent, between 2020-2025 was performed. Two independent reviewers extracted data following PRISMA guidelines. Main outcomes included major pathologic response (MPR), pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS). Study-level proportions were pooled by random effects models. Heterogeneity was assessed by the I2 statistic. RESULTS: The comparative analysis consisted of 4 RAS studies (involving 202 patients) and 11 BPS studies (403 patients). The pooled overall EFS was 83.3% (76.9-88.2) for the former and 82% (75.2-87.2) for the latter (P=.751), and the respective pooled OS was 92.3% (87.5-95.3) and 91.4% (80.3-96.5) (P=.839). The pooled pCR rate was 41.7% (95% CI 5.4-48.4; I2=.0) for RAS and 19.8% (95%CI 13.3-29.6; I2=.62) for BPS (P=.001), while the MPR was not significantly different (59.6%, versus 48.5%, P=.245). RAS was associated with greater organ preservation and reduced need for mandibulectomy and free-flap reconstruction. CONCLUSIONS: RAS following neoadjuvant ICIs in mucosal HNSCC may enable surgical de-escalation with preserved oncologic outcomes and improved function in selected patients. Larger prospective studies are warranted.

Humans↗

PubMed2025

Universal versus targeted chlorhexidine and mupirocin decolonisation and clinical and molecular epidemiology of Staphylococcus epidermidis bloodstream infections in patients in intensive care in Scotland, UK: a controlled time-series and longitudinal genotypic study.

BACKGROUND: There are concerns that biocide skin and mucous membrane decolonisation, which is widely used to prevent health-care-associated infections in intensive care units (ICUs), might select for multidrug-resistant pathogens. We aimed to evaluate the effects of de-escalating from universal to targeted skin and nasal decolonisation on Staphylococcus epidermidis bloodstream infections (SE-BSI). METHODS: We did a retrospective, before-after-control-impact time-series analysis and longitudinal genotypic study in two ICUs with divergent decolonisation practice in tertiary care hospitals of adjacent health boards in Scotland, UK. Participants were aged at least 16 years and admitted between July 1, 2009, and Feb 28, 2022. There were no exclusion criteria for the study. In ICU one (intervention site) universal decolonisation in all admissions was de-escalated to targeted decolonisation of meticillin-resistant Staphylococcus aureus (MRSA) carriers on Feb 1, 2019, while in ICU two (control site) targeted decolonisation was applied throughout. We collected bloodstream infection data from all causes, including clinically significant SE-BSI. Antimicrobial susceptibility testing was used to define meticillin-resistant S epidermidis (MRSE) and chlorhexidine susceptibility. We used multilocus sequence typing to identify sequence types from archived SE-BSI isolates. Whole-genome sequencing was applied to a sample from ICU one. The primary outcomes were incidence densities of all bloodstream infections, SE-BSI, and meticillin-resistant S epidermidis bloodstream infections (MRSE-BSI), and the percentage probability that SE-BSI were MRSE-BSI. The effects of de-escalation on primary outcomes were estimated by differences between the intervention and control sites, before and after de-escalation, using a before-after-control-impact time-series design. Secondary outcomes included the proportion of multidrug resistant sequence types, carriage of mobile genetic elements and genes for multidrug resistance and biofilm production. FINDINGS: Between July 1, 2009, and Feb 28, 2022, S epidermidis was identified in 334 (45%) of 735 bloodstream infections in ICU one, of which 197 occurred before the de-escalation intervention in Feb 1, 2019, and S epidermidis was identified in 167 (60%) of 278 bloodstream infections in ICU two. There was no increase in all bloodstream infection incidence coinciding with de-escalation in ICU one, whereas MRSE-BSI incidence declined significantly from 10·4 cases per 1000 occupied bed days (OBDs; 95% credible interval [CrI] 7·2-15·4) to 4·3 cases per 1000 OBDs (2·5-6·7), as did the percentage probability of MRSE (from 89·2%, 95% CrI 77·8-96·5 to 56·7%, 34·3-77·5%). No significant changes in the primary outcomes were seen in ICU two. MRSE-BSI incidence density was positively associated with chlorhexidine use, but not mupirocin use. De-escalation was associated with a reduced proportion of SE-BSI due to multidrug-resistant sequence types and reduced carriage of mobile genetic elements and genes for multidrug resistance and biofilm production, as observed by multi-locus sequence typing and whole genome sequencing. INTERPRETATION: In ICU settings with low MRSA incidence, the benefits of universal decolonisation should be balanced against the risks of selecting MRSE sequence types adapted for invasive and device-associated infection. FUNDING: National Health Service Grampian Charity.

Humans↗

PubMed2026

Workplace Safety Champions: Strengthening safety culture through nurse engagement.

Workplace violence is a growing concern in health care, disproportionately affecting frontline nurses and nursing assistants. Despite high prevalence, underreporting remains a barrier to effective prevention and response. This article describes the development, implementation, and outcomes of a Workplace Safety Champion program designed to increase reporting of violent incidents and strengthen a culture of safety. A multidisciplinary task force developed an evidence-based Workplace Safety Champion course that emphasizes de-escalation strategies, reporting processes, and staff support. Champions were appointed across inpatient and emergency units and integrated into a hospital-wide Workplace Safety Champion Council. Program evaluation used course completion data and posttraining surveys. The organizational goal of having at least one trained champion in 90% of inpatient and emergency units was exceeded, with 98% of units represented (N = 93 champions). More than 85% of learners reported intent to change their response to workplace violence, and 90% endorsed improved knowledge of resources and de-escalation strategies. The Workplace Safety Champion program successfully improved staff awareness, reporting, and engagement in workplace violence prevention. Embedding champions across units can serve as a sustainable strategy to strengthen safety culture and support frontline health care workers.

Humans↗

PubMed2026

Decluttering chemotherapy agents for HER2+early breast cancer: Do we still need carboplatin?

Over the past two decades, targeted anti-HER2 therapies have transformed management of HER2-positive early breast cancer (HER2 + eBC), enabling chemotherapy de-escalation without compromising efficacy. This review assesses the rationale for incorporating carboplatin into (neo)adjuvant regimens and critically examines its routine use in unselected patient populations with HER2-positive eBC. While initial translational and early clinical studies suggested that adding carboplatin to taxane-based chemotherapy combined with anti-HER2 therapy might be beneficial, more recent randomized trials have failed to demonstrate incremental advantage and have raised concerns about increased toxicity. Emerging prognostic and predictive biomarkers, most notably the HER2DX genomic assay, hold promise for identifying high-risk patient subgroups who may derive meaningful benefit from carboplatin. We conclude that carboplatin should not be routinely added in unselected HER2-positive early breast cancer, but rather, a biomarker-driven, personalized strategy is recommended to enhance patient selection, refine the treatment algorithm, and maximize the cost-to-benefit ratio.

De-escalating neoadjuvant treatments↗

PubMed2026

Thirty years of adjuvant therapy: From treating risk to treating residual disease.

Over the past three decades, adjuvant therapy for solid tumours has evolved from treatment based predominantly on anatomical recurrence risk towards strategies informed by tumour biology, treatment response, and molecular residual disease. Cytotoxic chemotherapy and endocrine therapy established the curative potential of postoperative systemic treatment, while targeted agents and immunotherapy expanded its efficacy across malignancies. However, matching a drug to tumour biology does not establish whether residual cancer remains, and many patients receive treatment despite having been cured by surgery alone. This Perspective examines the transition from empirical risk reduction towards selective intervention against residual disease. Response-adapted perioperative strategies provide a dynamic assessment of treatment sensitivity and support postoperative escalation or omission in defined settings. Circulating tumour DNA offers a complementary approach, but its strong prognostic value must be distinguished from evidence that biomarker-directed treatment improves outcomes. Contrasting findings from randomised trials demonstrate that neither de-escalation after a negative result nor escalation after a positive result can be generalised across clinical contexts. Future studies should integrate anatomical risk, tumour genomics, pathological response, and longitudinal molecular assessment while prioritising absolute benefit, mature survival outcomes, irreversible toxicity, patient-reported outcomes, and equitable access. They should also distinguish durable eradication from temporary suppression and evaluate treatment omission with the same rigour as intensification. Progress in adjuvant oncology should ultimately be measured by additional cures achieved with less avoidable harm, through the smallest effective intervention supported by validated evidence.

Adjuvant therapy↗

PubMed2026

Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab for Stage II to III, ERBB2-Positive Breast Cancer: A Secondary Analysis of the DAPHNe Trial.

IMPORTANCE: The neoadjuvant combination of paclitaxel, trastuzumab, and pertuzumab (THP) represents a promising abbreviated regimen for early-stage ERBB2-positive breast cancer, but long-term outcomes and the role of ultrasensitive circulating tumor DNA (ctDNA) monitoring remain incompletely defined. OBJECTIVE: To assess 5-year outcomes and characterize ctDNA dynamics with an ultrasensitive assay in patients with ERBB2-positive breast cancer receiving neoadjuvant THP. DESIGN, SETTING, AND PARTICIPANTS: This study was a prespecified secondary analysis of the prospective, single-arm, investigator-initiated phase 2 DAPHNe nonrandomized clinical trial. Patients were enrolled in the DAPHNe trial from November 2018 to January 2020. The trial took place at a multicenter academic cancer center and affiliated community practices. Participants included patients with stage II to III ERBB2-positive breast cancer receiving neoadjuvant THP for 12 weeks. Ultrasensitive ctDNA analyses were performed in patients with available tumor tissue and serial plasma samples. The secondary analysis was conducted between between March 2023 and April 2025. INTERVENTIONS: Neoadjuvant THP administered for 12 weeks, followed by surgery and adjuvant therapy guided by pathologic response. MAIN OUTCOMES AND MEASURES: Main outcomes included 5-year event-free survival, recurrence-free interval (RFI), distant RFI, and overall survival. ctDNA detection and clearance were assessed using a whole-genome-based, tumor-informed ultrasensitive assay at 4 predefined time points (baseline, preoperative, postoperative, and late adjuvant). RESULTS: The overall trial cohort included 98 patients (median [IQR] age, 49.5 years [24.0-78.0 years]; 97 female patients [99.0%]; 1 male patient [1.0%]), with mostly stage 2 disease (91 patients [92.9%]) and hormone receptor-positive tumors (65 patients [66.3%]). With a median (IQR) follow-up of 5.2 (5.0-5.4) years, the 5-year event-free survival was 99% (95% CI, 97%-100%), the 5-year RFI was 98% (95% CI, 93%-100%), the 5-year distant RFI was 100% (95% CI, 100%-100%), and the 5-year overall survival was 99% (95% CI, 97%-100%). Among 57 patients included in ctDNA analyses, baseline ctDNA was detected in 51 individuals (89.5%). After neoadjuvant therapy, ctDNA clearance occurred in 49 of 51 patients (96.1%), with only 2 individuals (3.9%) remaining ctDNA-positive preoperatively; detectability remained low (<10%) during postoperative follow-up. One single patient experienced a local recurrence, with ctDNA detected at time of recurrence and cleared following surgical resection. CONCLUSIONS AND RELEVANCE: In this secondary analysis of the DAPHNe nonrandomized clinical trial, neoadjuvant THP was associated with excellent long-term outcomes in patients with early-stage ERBB2-positive breast cancer. Ultrasensitive ctDNA analyses demonstrated high baseline detection rates and near-universal clearance after abbreviated neoadjuvant therapy, supporting further investigation of ctDNA-guided de-escalation strategies in this setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03716180.

Humans↗

PubMed2026

Clinical Variable-Based Machine Learning for Predicting Early mCRPC Using Exclusively Clinical Variables: Development and Multicenter External Validation.

BACKGROUND AND OBJECTIVE: Metastatic hormone-sensitive prostate cancer (mHSPC) exhibits heterogeneous progression patterns, with early progression to metastatic castration-resistant prostate cancer (mCRPC) within 12 months indicating aggressive tumor biology and poor prognosis. Current risk stratification tools (CHAARTED, LATITUDE) offer limited individualized prediction. Machine learning approaches are increasingly applied to predict prostate cancer progression, but most models show modest performance (AUC 0.68-0.72), limited external validation, or require genomic variables unavailable in routine practice. This study aimed to develop and externally validate a novel RINH algorithm for predicting early mCRPC progression (≤ 12 months) using exclusively clinical variables, positioning it as a superior alternative to conventional ML classifiers. METHODS: This multicenter study enrolled 412 patients with de novo mHSPC from seven Spanish academic centers using mixed retrospective-prospective data collection. Twenty clinical variables were recorded, including demographics, PSA, ISUP grade, metastatic localization, CHAARTED/LATITUDE classifications, and treatment modalities. Following RINH-based outlier exclusion (55 patients), 357 patients (29 with early progression, 8.1%) were used to train six ML algorithms: RINH, Logistic Regression, Linear Discriminant, Support Vector Machine, Random Forest, and Subspace Discriminant. A two-tiered validation strategy integrated stratified fivefold cross-validation across all centers and formal external validation using center 1 (n = 121, 19 events) for training and centers 2-7 (n = 207, 10 events) for independent testing. Performance metrics included AUC, sensitivity, specificity, accuracy, and F1-score. KEY FINDINGS AND LIMITATIONS: Artificial intelligence and machine learning (ML) are transforming oncology, promising personalized risk stratification beyond traditional clinical criteria. In metastatic hormone-sensitive prostate cancer (mHSPC), early progression to castration resistance (mCRPC) within 12 months signals aggressive biology and poor prognosis, yet current tools (CHAARTED, LATITUDE) offer limited individualized prediction. Multiple ML models have been proposed with variable success: most achieve modest performance (AUC 0.68-0.72), lack robust external validation, or rely on genomic variables inaccessible in routine practice. We propose a novel approach using the Rivality Index Neighborhood (RINH) algorithm, demonstrating superior predictive capacity in an initial multicenter validation with exclusively clinical variables. This study provides rigorous multicenter external validation, advancing toward implementable precision oncology tools. CONCLUSIONS AND CLINICAL IMPLICATIONS: The RINH algorithm achieves superior predictive performance for early mCRPC progression using exclusively clinical variables, representing a significant advance toward implementable risk stratification. However, low reliability scores in external validation underscore that excellent performance metrics alone do not guarantee stability. Before clinical deployment, validation in substantially larger cohorts with higher progression events is essential. If validated, this model could enable personalized, risk-adapted therapeutic strategies, refining patient selection for treatment intensification or de-escalation.

Humans↗

PubMed2026

The 21st International ``Ponte di Legno'' Childhood Acute Lymphoblastic Leukemia Workshop Report: Progress and Emerging Opportunities.

The 21st Ponte di Legno Working Group meeting convened in Orlando, USA, on December 4-5, 2025, bringing together leading childhood acute lymphoblastic leukemia (ALL) investigators from major global consortia. In response to the transformative advances in childhood ALL treatment, particularly the integration of immunotherapy into frontline therapy, the group revisited and updated its mission statement. The revised mission emphasizes collaborative studies on rare leukemia subsets, harmonized toxicity reporting, particularly for immunotherapy-related toxicities, and unrestricted worldwide collaboration. In addition, sharing data and strategies for integrating novel agents will be integral to optimizing future trial design. Key scientific topics included rare genetic subgroups, T-cell ALL genomics, treatment-related toxicity benchmarking, and central nervous system (CNS) disease management challenges. A major focus was immunotherapy integration into frontline therapy, particularly blinatumomab as an emerging standard of care and inotuzumab ozogamicin as an investigational agent, and their potential to enable chemotherapy de-escalation. Additional discussions addressed immunotherapy-specific toxicities. The integration of immunotherapy into frontline ALL therapy represents a paradigm shift with potential to improve outcomes while reducing treatment burden. However, careful attention to CNS disease control, emerging toxicities, and preservation of the remarkable achievements in childhood ALL therapy remains essential as the field advances.

Blinatumomab↗

PubMed2026

Personalizing endometrial cancer care beyond histology: clinical applications and limits of molecular classification.

Endometrial cancer is a biologically heterogeneous disease whose management has been reshaped by molecular classification. This review summarizes the current evidence supporting the integration of molecular subgroups into prognostic assessment and treatment personalization across stages of disease. The Cancer Genome Atlas classification and its clinically applicable surrogates identify four major molecular categories: POLE-mutated, mismatch repair-deficient, p53-abnormal, and no specific molecular profile tumors. These groups differ substantially in biology, prognosis, treatment sensitivity, and areas of unmet need. POLE-mutated tumors have an excellent prognosis and represent the clearest candidates for adjuvant treatment de-escalation, particularly in early-stage disease. Mismatch repair-deficient tumors show intermediate prognosis but strong sensitivity to immune checkpoint inhibition, which has transformed the management of advanced and recurrent disease and is now being tested in earlier settings. p53-abnormal tumors represent the highest-risk subgroup, requiring multimodal treatment and offering opportunities for biomarker-driven strategies including HER2-directed therapy and DNA damage repair targeting. No specific molecular profile tumors remain the most heterogeneous category, increasingly refined by estrogen receptor status, grade, L1 cell adhesion molecule overexpression, and other biomarkers. Mismatch repair-proficient advanced/recurrent disease should be interpreted as a composite clinical trial population rather than a molecular class. Molecular classification should be integrated with traditional clinicopathologic factors, emerging biomarkers, and local implementation strategies to support equitable, biologically informed treatment selection in endometrial cancer.

Humans↗

PubMed2025

Rapid pan-microbial metagenomics for pathogen detection and personalised therapy in the intensive care unit: a single-centre prospective observational study.

BACKGROUND: Most clinical metagenomic studies do not provide rapid results, detect pathogens from all microbial kingdoms, or measure clinical impacts. We aimed to evaluate the feasibility, performance, and clinical impacts of a rapid pan-microbial respiratory metagenomic service for patients admitted to intensive care units (ICUs). METHODS: This was a single-centre observational study of a rapid metagenomics service that tests respiratory samples from ICU patients at Guy's and St Thomas' hospitals, London, UK, between Dec 5, 2023, and April 12, 2024. Testing used a previously published pan-microbial metagenomics workflow, which simultaneously detects bacteria, fungi, and DNA and RNA viruses; provides same-day preliminary results after 2 h; and provides final results after 24 h. Patients were included if they were aged 18 years or older, admitted to the ICU, had confirmed respiratory failure requiring supplemental oxygen or advanced airway support, and had at least one of the following: (1) clinical suspicion of lower respiratory tract infection based on clinical, biochemical, or radiological findings, (2) sepsis of unknown origin, and (3) concern from an intensive care physician regarding inflammatory pathology. Patients with a suspected or confirmed containment level three organism were excluded. The outcome was performance characteristics of the metagenomic test compared with routine diagnostic testing, detection of additional pathogens by metagenomics, change in antimicrobial prescribing within 24 h of testing, and initiation of immunomodulation. FINDINGS: We processed 114 samples (1-5 per day) from 74 patients (39 [53%] female and 35 [47%] male). 107 (94%) of 114 samples passed quality control, of which 101 (94%) provided same-day preliminary results. Bacteria were detected in 45 (43%) of 104 tested specimens, fungal organisms in 17 (16%) of 104 tested specimens, and viruses in 28 (34%) of 83 tested specimens. Sensitivity in lower respiratory tract samples after 24 h was 97% (95% CI 87-100) for bacteria, 89% (65-99) for fungi, and 89% (71-98) for viruses, with only one false positive for bacteria. Metagenomics identified 42 pathogens not detected by other tests in 32 (30%) of 107 samples. Antimicrobial therapy was changed after metagenomic results from 30 (28%) of 107 samples: 22 (21%) were de-escalated and eight (7%) were escalated. Metagenomics contributed to the initiation of immunomodulation in 15 (20%) of 74 patients for a range of inflammatory conditions. Pathogens with clinical significance to local infection control or national public health were found in ten (14%) of 74 patients, including three invasive Group A streptococci, two parvovirus B19, and one each of HIV-1, measles virus, Mycobacterium tuberculosis, Neisseria meningitidis, and Mycoplasma pneumoniae. INTERPRETATION: Respiratory metagenomics for ICU patients showed good performance and turnaround time, and diverse clinical and public health benefits. This ability to inform both personalised patient therapy and infectious disease surveillance needs evaluation in multicentre studies. FUNDING: None.

Humans↗

PubMed2026

Radiomics as a spatial context for treatment decision-making in head and neck cancer.

Radiomics has been widely explored as a non-invasive biomarker in head and neck squamous cell carcinoma (HNSCC), yet its clinical role remains unclear. Tissue-based biomarkers differ in their susceptibility to spatial sampling. Biomarkers such as PD-L1 expression, immune-cell infiltration, necrosis, and immune exclusion may exhibit substantial spatial heterogeneity, whereas HPV/p16 status and some genomic alterations are generally more stable across the tumor. Nevertheless, localized sampling may incompletely capture heterogeneity in selected clinical contexts. This mismatch becomes clinically relevant when treatment decisions, particularly for chemoradiotherapy, immunotherapy, or de-escalation, are based on potentially non-representative biopsy findings. In this narrative review, we argue that the role of radiomics is not to outperform established biomarkers, but to contextualize them by capturing spatial heterogeneity related to hypoxia, necrosis, stromal architecture, and immune exclusion. We synthesize current evidence linking radiomic features to these biological processes and map them to specific clinical decision points, including larynx preservation, immunotherapy stratification, and recurrence assessment. Rather than serving as a standalone predictor, radiomics may provide complementary spatial information that helps identify situations in which biopsy-derived biomarkers should be interpreted with caution. Although current evidence is largely retrospective, radiomics offers a pragmatic framework for integrating spatial information into biomarker-guided clinical workflows.

Journal Article↗

PubMed2026

Swab Testing to Optimize Pneumonia Treatment With Empiric Vancomycin: A Randomized Controlled Trial.

BACKGROUND: Fear of methicillin-resistant Staphylococcus aureus (MRSA) as a cause of community-acquired pneumonia (CAP) frequently leads to empiric vancomycin coverage. Data evaluating the use of MRSA polymerase chain reaction (PCR) nasal swab testing to guide vancomycin de-escalation is limited for patients in the intensive care unit (ICU). METHODS: Swab Testing to Optimize Pneumonia Treatment With Empiric Vancomycin (STOP-Vanc) is a pragmatic, prospective, single-center, non-blinded randomized trial in which adult ICU patients with suspicion of CAP were randomized 1:1 to receive usual care either with (intervention) or without (control) the addition of MRSA nares PCR testing following ICU admission. The primary outcome was vancomycin-free hours alive, defined as the expected number of hours alive and free of vancomycin use within the first 7 days of trial enrollment as estimated using a longitudinal proportional odds state transition model adjusted for baseline covariates. RESULTS: A total of 277 adult ICU patients were randomized. Methicillin-resistant Staphylococcus aureus PCR nasal swab testing had a negative predictive value (NPV) of 98.9% in the intervention arm. The primary endpoint, vancomycin-free hours alive, was 105.7 in the control arm and 109.7 in the intervention arm (adjusted difference, 4 hours; 95% CI, -9.5-18.2; P = .458). CONCLUSIONS: Despite MRSA PCR nasal swab testing demonstrating a high NPV in this critically ill population, MRSA PCR nasal swab testing did not decrease the duration of vancomycin use or 30-day mortality among ICU patients with suspected CAP. Additional clinician education and antimicrobial stewardship interventions might be needed to reduce vancomycin use in this patient population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT06272994 (STOP-Vanc).

Humans↗

PubMed2026

Genomic and Transcriptomic Correlates of Deep PSA Response in Patients with Metastatic Androgen Pathway Modulation-Sensitive Prostate Cancer.

BACKGROUND: Despite advances in metastatic androgen pathway modulation-sensitive prostate cancer (mAPMS) treatment, outcomes remain heterogeneous. Achieving a post-treatment undetectable prostate specific antigen (PSA) is a strong prognostic marker. We aimed to identify genomic and transcriptomic determinants of PSA response in a real-world clinical-genomic cohort. PATIENTS AND METHODS: Patients with mAPMS who underwent DNA (Tempus xT) and, in a subset, RNA (Tempus xR) sequencing were identified from the Tempus Lens database. Inclusion required stage IV disease within 90 days of sample collection and samples obtained within 12 months before or 3 months after treatment initiation. Patients with PSA at 6 months (n = 525) were classified as PSA-low (<0.1 ng/mL, n = 240) or PSA-high (≥0.1 ng/mL, n = 285). Overall survival (OS) was assessed by 6-month landmark analysis with delayed-entry adjustment. Logistic and Cox models were adjusted for clinical variables. Sensitivity analyses used a relative definition of > 95% PSA decline from baseline. RESULTS: Baseline PSA was lower in PSA-low versus PSA-high patients (24 vs 36 ng/mL, p = 0.01). SPOP (17% vs 11%) and ZFHX3 (2.5% vs 6%) alterations differed between groups, but neither persisted after adjustment. Using the relative definition, ZMYM3 and JAK1 alterations were independently associated with failure to achieve a deep PSA response. Expression of PSMA, TROP2, B7-H3, and STEAP1 did not differ between groups. PSA-low status was independently associated with improved OS, as was deep relative response. CONCLUSION: Deep PSA response at 6 months correlates with improved OS in mAPMS. Integrating molecular markers with PSA response may inform treatment intensification or de-escalation strategies.

Biomarkers↗

PubMed2026

The next-generation biomarkers in early-stage triple negative breast cancer.

PURPOSE OF REVIEW: Despite maximal neoadjuvant chemoimmunotherapy, nearly 40% of early-stage triple-negative breast cancer (TNBC) patients fail to achieve pathological complete response, underscoring an urgent need for biomarkers capable of guiding treatment modulation. This review summarizes recent advances in tumor-infiltrating lymphocytes (TILs), circulating tumor DNA (ctDNA), and genomic signatures, exploring their potential integration into clinical decision-making. RECENT FINDINGS: TILs remain the most validated, cost-effective prognostic biomarker, although standardized scoring is still needed to overcome interobserver variability. ctDNA has emerged as a dynamic, real-time prognostic tool, with postneoadjuvant detection strongly predicting relapse and worse outcomes. Nonetheless, optimal sampling timing remains undefined. Genomic signatures, particularly TNBC-DX, provide standardized, reproducible prognostic information by integrating immune and proliferative gene expression. Emerging data suggest that combining these biomarkers may offer a complementary and synergistic effect. SUMMARY: Multibiomarker integration, supported by prospective validation and automated models, represents a promising approach to personalize treatment algorithms in early-stage TNBC, balancing efficacy and toxicity while guiding escalation and de-escalation strategies.

artificial intelligence↗

PubMed2026

Decoding age-stratified clinical and molecular heterogeneity in male breast cancer through multiomic profiling.

OBJECTIVE: Age-associated molecular heterogeneity is well described in female breast cancer but remains insufficiently characterized in male breast cancer (MBC). We profiled age-stratified clinical and molecular differences between younger (≤55 years) male breast cancer (YMBC) and older (>55 years) male breast cancer (OMBC). METHODS: We retrospectively analyzed 347 patients with MBC diagnosed at Fudan University Shanghai Cancer Center by integrating clinicopathological data, RNA sequencing, and whole-exome sequencing (WES). Survival, differential expression, and mutational signature analyses were performed. Tumor microenvironment features were inferred using xCell and ESTIMATE, and weighted gene co-expression network analysis (WGCNA) was conducted to identify age-associated co-expression modules. Candidate therapeutics were prioritized using the Genomics of Drug Sensitivity in Cancer (GDSC) resource and evaluated using patient-derived organoids (PDOs). RESULTS: Compared with OMBC, YMBC more frequently had human epidermal growth factor receptor 2 (HER2)-positive status (14.91% vs. 4.02%) and triple-negative tumors (4.92% vs. 1.78%), and had worse 5-year recurrence-free survival (hazard ratio=2.19, P=0.018). Transcriptomic analyses indicated enrichment of neural-related programs and reduced immune-related signaling in YMBC, and xCell/ESTIMATE supported lower immune infiltration. Consistently, WGCNA identified age-associated modules linking neural-related programs with reduced immune infiltration. Immunohistochemistry supported increased perineural invasion and lower CD8+ T cell infiltration in YMBC. GDSC-guided prioritization with PDO testing nominated sepantronium bromide (YM155) as a candidate vulnerability in YMBC. WES showed a higher NBPF10 mutation frequency in YMBC (54.5% vs. 14.3%, P<0.05). CONCLUSIONS: Integrated multi-omics profiling revealed age-stratified clinical and molecular heterogeneity in MBC. YMBC patients demonstrated inferior recurrence-free survival, neural signaling enrichment, an immune-cold microenvironment, and enriched NBPF10 mutations. These findings support age as a meaningful stratification variable in MBC risk assessment and treatment planning, and highlight the need for caution when considering treatment de-escalation in younger patients, while nominating YM155 as a candidate agent for prospective evaluation.

Male breast cancer↗

PubMed2026

Circulating Tumor DNA in Bladder Cancer: Current Clinical Evidence and Emerging Multi-Omics Perspectives-A Narrative Review.

Background: Circulating tumor DNA (ctDNA) analysis has emerged as a promising tool for real-time disease monitoring in muscle-invasive bladder cancer (MIBC). This narrative review summarizes current clinical evidence regarding ctDNA across disease stages. Methods: We examine recent translational and clinical findings, incorporating key prospective data from practice-changing trials, as well as insights into minimal residual disease (MRD) detection, treatment escalation and de-escalation strategies, and systemic barriers to adoption. Results: Postoperative ctDNA positivity consistently identifies patients with molecular residual disease (MRD) who face a substantially higher risk of recurrence and mortality, frequently preceding radiographic relapse by several months. Prospective evidence now validates ctDNA as a predictive biomarker to guide adjuvant immunotherapy escalation, while sustained ctDNA negativity correlates with high long-term disease-free survival. Beyond plasma ctDNA, emerging multi-compartment liquid biopsies-integrating urinary tumor DNA (utDNA)-demonstrate enhanced sensitivity, particularly in bladder-sparing and local surveillance settings. Furthermore, integrating genomic ctDNA profiling with novel post-transcriptional layers like epitranscriptomics offers a functional framework to capture tumor adaptation under therapeutic pressure. However, clinical translation remains constrained by a lack of assay harmonization, variable analytical sensitivity, and the need for standardized intervention thresholds. Conclusions: Longitudinal liquid biopsies are rapidly shifting MIBC management from static, stage-based paradigms toward dynamic, molecularly informed precision oncology. While ctDNA-guided strategies show robust clinical utility, prospective interventional validation and technical standardization are required before widespread routine integration.

biomarkers↗

PubMed2026

Primary Tumor Epigenetic and Transcriptomic Alterations Associated with Nodal Burden and Metastatic Risk in ER+/HER2- Breast Cancer.

De-escalation of axillary surgery has resulted in the loss of pathologic nodal information, yet the extent of lymph node involvement remains an important determinant of treatment decisions in estrogen receptor-positive (ER+)/HER2- disease. We examined whether primary tumors differed molecularly according to the extent of this regional dissemination. Genome-wide DNA methylation profiling of primary ER+/HER2- tumors from 47 patients with pN1 (n = 29) vs. >pN1 (n = 18) disease showed differences concentrated at promoters of developmental and cell-adhesion genes. By integrating methylomes with transcriptomes from the TCGA-BRCA cohort (n = 148) and clinical outcomes from KM Plotter (RFS, n = 1154; OS, n = 442; DMFS, n = 423), we identified four genes (ARL10, RIC3, CXCL14, KCNH2) showing concordant molecular and clinical associations, from which we derived the Lymph-node Involvement Outcome Numerator (LION) score. Lower LION scores were observed in metastatic lesions from the AURORA US cohort (n = 45). In SCAN-B (n = 3969), lower scores were associated with shorter distant recurrence-free intervals (HR = 0.38; 95% CI 0.23-0.62); this association persisted after adjustment for age, nodal and tumor category but was lost after adjustment for histological grade (HR = 0.83; 95% CI 0.48-1.44), indicating that the score and grade capture overlapping biology. These findings suggest that primary tumors already display coordinated epigenetic and transcriptional alterations associated with the extent of metastatic dissemination.

Humans↗