Search Results (3,234)

Background: Immune checkpoint inhibitors (ICIs) are standard treatment for melanoma and non-small cell lung cancer (NSCLC), yet evidence on their effectiveness in older adults remains limited due to underrepresentation in clinical trials. This study assessed long-term, age-stratified outcomes of ICI treatment in real-world clinical practice. Methods: This nationwide observational study used data from the Netherlands Cancer Registry on patients with synchronous stage IV melanoma or NSCLC who received first-line ICIs between 2018 and 2023. Melanoma treatments included nivolumab plus ipilimumab or anti-PD-1 monotherapy; NSCLC treatments included pembrolizumab with or without chemotherapy. Primary outcomes were five-year overall survival (5-yr OS) and three-year conditional survival (3-yr CS), stratified by age. Results: A total of 11,140 patients were included, consisting of 583 patients with melanoma and 10,557 with NSCLC. In the melanoma population, 5-yr OS was 43.8%. Patients aged ≥ 75 years had a 5-yr OS of 30.8% and a 3-yr CS of 58.7%. In NSCLC treated with pembrolizumab monotherapy, 5-yr OS was 23.1%; among patients aged ≥ 75 years, 5-yr OS was 15.6% and 3-yr CS was 46.6%. Pembrolizumab combined with chemotherapy resulted in a 5-yr OS of 14.6%, with corresponding 5-yr OS of 8.4% and 3-yr CS of 35.5% in patients aged ≥ 75 years. Conclusions: This registry-based analysis suggests that ICI are associated with durable long-term survival in real-world patients with stage IV melanoma or NSCLC, including selected older adults. These findings are in line with outcomes of clinical trials, but further research is needed on predictors of ICI effectiveness in the older population. Full article

Background: Vertebrogenic low back pain (LBP) is a distinct subtype of chronic LBP (cLBP) arising from nociceptive sensitization of the basivertebral nerve (BVN) within pathologically altered vertebral endplates. Modic type 1 and type 2 changes on MRI are primary imaging biomarkers for patient selection. Basivertebral nerve ablation (BVNA), a minimally invasive intraosseous radiofrequency procedure, has emerged as a targeted treatment for this condition. This narrative review aims to synthesize current evidence on the pathophysiology of vertebrogenic LBP, patient selection criteria, procedural outcomes, safety profile, and cost-effectiveness of BVNA. Methods: We conducted this narrative review of the literature, encompassing randomized controlled trials (including the SMART and INTRACEPT studies), prospective registries, and real-world cohort studies evaluating BVNA for vertebrogenic LBP. Clinical and imaging-based selection criteria, procedural techniques, outcome measures, adverse events, opioid utilization, and healthcare utilization data were examined. Results: Evidence demonstrates consistent and durable reductions in pain and disability following BVNA, with a favorable safety profile. Complication rates are low, with vertebral compression fracture and procedure-related radicular pain reported as the most frequent adverse events. BVNA is associated with reduced opioid consumption and decreased overall healthcare utilization. Moreover, emerging data suggest efficacy beyond originally defined inclusion criteria, including cases of osteoporosis, multilevel Modic changes, adult spinal deformity, and complex comorbid presentations. Conclusions: BVNA represents an effective and safe treatment option within the multimodal management of vertebrogenic LBP. Current evidence supports a gradual expansion of procedural indications, with implications for healthcare resource optimization and opioid stewardship. Full article

Objective: Glutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy often presents as chronic focal epilepsy, usually with temporal lobe predominance, marked drug resistance, and inconsistent response to first-line immunotherapy. We assembled a large, harmonized, and literature-derived patient-level cohort to examine whether immunotherapy timing and regimen composition were associated with seizure outcome and to identify clinically meaningful prognostic signals. Methods: We performed a literature-derived patient-level analysis of 375 unique published cases linked to 132 contributory source publications from an audited full-text register of 166 reviewed studies. Descriptive analyses used the whole cohort. Treatment-response analyses assessed seizure outcome at the first evaluable post-immunotherapy assessment and at the last follow-up. Good seizure outcome was defined as seizure freedom and/or ≥50% seizure reduction. The primary timing comparison contrasted early treatment, defined as immunotherapy within 6 months of symptom onset, with late treatment, defined as immunotherapy after more than 12 months; four cases treated in the intermediate >6 to ≤12 month window were retained for descriptive timing summaries but excluded from the primary comparison. Statistical testing used the Fisher exact, Chi-square, Mann–Whitney U, and prespecified clustered logistic sensitivity analyses where appropriate. Results: The pooled phenotype was predominantly female, usually temporal-lobe-based, and frequently drug-resistant, with common autoimmune comorbidity and heterogeneous MRI abnormalities. Among timing-evaluable treated cases, earlier immunotherapy showed a class-specific, exploratory signal rather than a uniform regimen-independent effect. In rituximab/CD20-directed regimens, early treatment was associated with a higher rate of good seizure outcome than late treatment at both the first post-immunotherapy assessment and last follow-up (93.8% vs. 50.0%; risk difference [RD]: 43.8 percentage points; 95% CI: 7.7 to 72.7). A similar pattern was observed in the broader escalation group (94.4% vs. 55.6%; RD: 38.9 percentage points; 95% CI: 6.3 to 68.1). By contrast, steroid-containing regimens showed no clear early-versus-late advantage (84.6% vs. 88.2%; RD: −3.6 percentage points; 95% CI: −18.4 to 20.1). Shorter epilepsy duration before immunotherapy and absence of established drug resistance were the most clinically meaningful favorable baseline features. Significance: In GAD65 antibody-associated epilepsy, the therapeutic window may be most relevant for escalation strategies rather than for steroid-containing first-line regimens. However, these class-specific findings are exploratory and hypothesis-generating. They derive from non-randomized, literature-derived data and may reflect treatment intensity, center practice, publication era, and confounding by indication rather than isolated regimen superiority. Prospective collaborative registries with standardized longitudinal seizure outcome measures are needed to validate these observations. Full article

Introduction: Currently, there is an ongoing debate regarding the benefits of kinematic alignment (KA) versus mechanical alignment (MA) in total knee arthroplasty (TKA). Robotic-assisted TKA has been shown to improve implant positioning and precision of the KA technique, enabling successful kinematic alignment. However, its impact on early postoperative and functional outcomes remains unclear. This study aims to examine how imageless, table-mounted, robotic-assisted KA-TKA compares with conventional MA-TKA. Methods: Registry data of all primary TKAs using ATTUNE™ cruciate-retaining implants (January 2021–December 2024) performed by a single, experienced surgeon in a high-volume arthroplasty center were retrospectively reviewed. A total of 64 patients who underwent robotic-assisted KA-TKA were compared to 39 patients who underwent conventional MA-TKA. The mean age was 70.3 ± 7.71 and 69.3 ± 9.47 in the KA-TKA group and the MA-TKA group, respectively, while the male proportion was 32.8% and 30.7%, respectively. Early postoperative outcomes (static/dynamic pain score, ambulation distance, length of stay) and 6-month functional outcomes (range of motion, Knee Society Score, Oxford Knee Score, SF-36, patient expectation/satisfaction scores) were analyzed. Delta changes in outcome scores and proportion of patients attaining a minimum clinically important difference (MCID) were studied. Results: Robotic-assisted KA-TKA displayed benefits in the majority of the early postoperative outcomes, with significant improvements in ambulation distance (23.3 vs. 14.7 m, p = 0.002) compared to conventional MA-TKA. Both groups showed significant improvements in the majority of the functional outcomes at 6 months. Robotic-assisted KA-TKA also shows significant improvements in selected mental health aspects of SF-36, namely vitality (p = 0.001), mental health (p = 0.048), mental component summary (MCS) (p = 0.004), and a larger proportion attaining SF-36 vitality MCID (p = 0.045). Following false discovery rate correction for multiple comparisons, postoperative ambulation distance, SF-36 vitality, and MCS remained statistically significant between groups. No significant differences in KSS, OKS, and satisfaction/expectation fulfillment were noted. Conclusions: Robotic-assisted KA-TKA demonstrated early rehabilitation and select mental health-related quality of life improvements compared to conventional MA-TKA. Further studies are needed to examine its long-term clinical outcomes. Full article

Background/Objectives: Adult patients supported with extracorporeal membrane oxygenation (ECMO) frequently require invasive diagnostic, therapeutic, surgical, or bedside procedures during ongoing extracorporeal support. These procedures are clinically challenging because ECMO-related anticoagulation, platelet dysfunction, acquired coagulopathy, and circuit-related coagulation activation may increase both bleeding and thrombotic risks. This systematic review evaluated the safety of invasive procedures performed during adult ECMO support, excluding tracheostomy/tracheotomy because this procedure has recently been addressed in a dedicated systematic review. Methods: A systematic search of PubMed/MEDLINE and Scopus was performed. The final bibliographic data collection was completed in April 2026. Studies were eligible if they included adult ECMO or extracorporeal life support patients undergoing invasive procedures during ongoing ECMO support, or with ECMO used as procedural support, and reported at least one procedure-specific safety outcome. Primary outcomes were procedure-related complications, bleeding, major bleeding, and transfusion requirements. Secondary outcomes included thrombotic and circuit-related complications, oxygenator exchange, reintervention, reoperation, procedural failure, ECMO duration, intensive care unit and hospital length of stay, and mortality. Results: The final qualitative synthesis included 46 studies, comprising 26 studies from PubMed/MEDLINE and 20 additional unique studies from Scopus. Included procedures were grouped into six domains: airway, bronchoscopic, and tracheobronchial procedures; thoracic surgery and lung resections; abdominal surgery, gastrointestinal endoscopy, and decompressive laparotomy; lung transplantation and perioperative extracorporeal life support; cardiovascular, vascular, pulmonary embolism-related, and mechanical circulatory support-related procedures; and mixed non-cardiac surgery. Airway and bronchoscopic procedures generally showed high procedural success in selected cohorts, although registry-level tracheal procedure data reported hemorrhagic complications in 26.0% and surgical-site bleeding in 13.0%. Emergency thoracic and abdominal procedures carried the highest bleeding, transfusion, reintervention, and mortality burden. Lung transplantation studies showed that ECMO can be integrated into perioperative pathways, but hemothorax, transfusion, thromboembolism, and anticoagulation strategy remained central safety issues. Conclusions: Invasive procedures during adult ECMO are feasible in selected patients and experienced centers, but procedural safety varies markedly by procedure type, urgency, baseline disease severity, and anticoagulation strategy. A procedure-centered, multidisciplinary approach with individualized anticoagulation management and careful planning is essential. Full article

Background/Objectives: Immunotherapy has emerged as an important field of research in non-small-cell lung cancer (NSCLC) and has demonstrated promising results in clinical practice. In recent years, multiple studies have been conducted, increasing the amount of available data. Therefore, the aim of this systematic review is to assess the combination of perioperative immunotherapy with chemotherapy compared to chemotherapy only in patients with resectable NSCLC in terms of survival, pathological response, and adverse events. Methods: The clinical databases PubMed, Cochrane Library, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) were systematically searched, up to March 2026. A two-step selection process served as the screening for eligibility, in which the assessment was based on pre-defined inclusion and exclusion criteria. This process was visualized via a PRISMA diagram. For each included study, the risk of bias was assessed with the help of the Cochrane Risk of Bias 2.0 tool and the Newcastle Ottawa Scale. A narrative synthesis was performed due to heterogeneity. Data were extracted into tables. Results: A total of 16 studies, involving 4646 patients in total, met the eligibility criteria, and their data on study population, intervention, comparison, and outcome were extracted into tabular form. Survival and pathological response rates are continuously higher in patients treated with immunochemotherapy. Findings on adverse events differed across the individual studies, though the results indicate an increased risk of treatment-related adverse events (TRAEs) in patients undergoing the combined treatment approach. Discussion/Conclusions: Chemoimmunotherapy leads to superior clinical outcomes in terms of survival and pathological response rates, though the trend towards a higher incidence and severity of TRAEs warrants further research. The interpretation of findings is limited by differences in study characteristics, mechanism of conduct, and endpoints between the individual studies. Full article

Background: Following a stroke, body and brain temperatures are closely linked. Elevated temperature may reflect the severity of brain injury rather than infection. The significance of admission temperature remains unclear, and hypothermia treatment lacks proven efficacy and safety. Administering paracetamol (acetaminophen) above 36.5 °C is considered safe, though its clinical benefit is modest. This study aimed to examine how admission temperature, peak temperature in the first 24 h, and temperature fluctuations affect three-month functional outcomes. Methods: We conducted a retrospective study using data from a prospective stroke registry, including 5883 patients (4830 with ischemic stroke [IS] and 1053 with hemorrhagic stroke [HS]). Temperature at admission, maximum temperature within the first 24 h, and the temperature increase during the first day were assessed. Patients with a temperature ≥ 37.5 °C received 3 g of paracetamol per day until normothermia was achieved. Results: Baseline temperature was not associated with 3-month functional outcomes. In IS patients, an increasing temperature during the first 24 h was associated with a 10-fold higher risk of poor functional outcome (sensitivity 81%, specificity 64%); whereas in HS, the risk increased sevenfold (sensitivity 88%, specificity 53%). The most reliable predictor of therapeutic response was the temperature increase on the first day, with sensitivities of 89% and 83%, and specificities of 84% and 71%, for IS and HS, respectively. Conclusions: An increase in temperature during the first 24 h, rather than a single measurement, is the most reliable temperature-based biomarker for predicting poor functional outcomes and guiding the initiation of antihyperthermic treatment. Full article

Urea cycle disorders (UCDs) are rare inherited metabolic diseases associated with toxic hyperammonemia, leading to severe neurological damage and early mortality. Early diagnosis of distal UCDs through newborn screening (NBS) enables presymptomatic intervention; however, comparative real-world outcome data remain limited. We conducted a retrospective, multicenter study using data from the Spanish UCD Registry to describe the clinical characteristics and compare health outcomes between patients diagnosed through NBS (n = 40) and those diagnosed after clinical presentation (n = 53). Patients identified by NBS showed a markedly more favorable clinical prognosis, with a mortality rate of 2.5% compared with 15.1% in the unscreened cohort, as well as significantly lower rates of neurological involvement, fewer hospital admissions due to metabolic decompensation, and a reduced need for liver transplantation. Screening also identified a high prevalence of argininosuccinate synthetase deficiency (ASS1D) cases with attenuated biochemical profiles, highlighting the relevance of sensitive screening cutoffs. These findings provide real-world evidence that presymptomatic diagnosis through NBS is associated with improved survival and long-term neurological outcomes in patients with distal UCDs. Full article

Non-ST-segment elevation myocardial infarction (NSTEMI) has become the predominant form of acute coronary syndrome (ACS) and is frequently associated with multivessel coronary artery disease (MVD). Patients presenting with NSTEMI and MVD represent a particularly high-risk population characterized by advanced age, comorbidities, and an increased atherosclerotic burden. Although advances in pharmacological therapy and early invasive management have improved prognosis, the optimal revascularization strategy in this setting remains uncertain. In contrast to ST-segment elevation myocardial infarction (STEMI), where randomized controlled trials consistently support complete revascularization, evidence in NSTEMI with MVD is limited and is largely derived from observational studies and registry data. This has generated ongoing debate regarding whether complete revascularization offers superior outcomes compared with culprit-only percutaneous coronary intervention (PCI), and whether non-culprit lesions should be treated during the index procedure (immediate strategy) or in a staged manner. Current data suggest that complete PCI is generally associated with reduced recurrent ischemia, reinfarction, and repeat revascularization, with potential long-term survival benefits. However, patient comorbidities, lesion complexity, and procedural risk continue to influence outcomes, highlighting the importance of individualized decision-making. This narrative review synthesizes contemporary evidence on PCI-based revascularization strategies in NSTEMI with MVD, focusing on two central aspects: the extent of revascularization (complete versus incomplete) and the timing of intervention (single-stage versus staged). By integrating findings from registries, randomized trials and guideline recommendations, the review identifies areas of consensus, persisting uncertainties, and key evidence gaps. Ultimately, it underscores the need for large, dedicated trials to guide practice and optimize outcomes for NSTEMI patients with multivessel coronary disease. Full article

Individuals with Duchenne muscular dystrophy (DMD) are prone to nutritional imbalances, and zinc deficiency may contribute to impaired bone health. This study evaluated serum zinc status and the effects of oral supplementation on bone parameters in DMD. In this quasi-experimental before-and-after study, 34 patients were assessed at three time points over eight months. Eligible participants who met the inclusion criteria and agreed to participate received the proposed interventions during routine follow-up at the Neurology outpatient clinic. Anthropometry, dietary intake, bone mineral density (BMD), bone mineral content (BMC), and serum zinc were measured; supplementation (5–15 mg/day) was provided for four months. Baseline zinc deficiency was observed in 36.7% of participants. No significant overall changes were detected. Stratified analyses revealed a modest increase in total body BMD among individuals with adequate baseline BMD (p = 0.02). As this finding emerged from a subgroup analysis, it should be interpreted cautiously, and the potential contribution of physiological growth to the observed change cannot be excluded. In addition, zinc-deficient participants showed a significant rise in serum zinc levels (p = 0.008). These findings suggest that the response to zinc supplementation may vary according to baseline nutritional and skeletal status and underscore the relevance of micronutrient monitoring in individuals with DMD. Trial registration: The trial was also registered in the Brazilian Registry of Clinical Trials under the code RBR-7cfdxm, approved on 14 June 2018. Full article

Background: Background breast features are frequently noted in pathology reports alongside invasive breast cancer but rarely factor into prognosis or treatment decisions. Their relationship to tumor characteristics and patient outcomes remains incompletely characterized. Methods: We conducted a retrospective cohort study of 7603 patients with Stage I–III invasive breast cancer (diagnosed 1991–2022, age < 80 years) from the Joint Breast Cancer Registry in Singapore. Natural language processing (NLP) was applied to 9754 free-text pathology reports to extract co-existing background breast features, with accuracy validated by dual-reviewer assessment of 200 reports. Because background features are most reliably assessed on excision specimens, the primary analytic cohort comprised 3988 patients with available excision pathology reports. Unsupervised hierarchical clustering grouped extracted features into three categories. Associations with tumor characteristics were assessed with multinomial logistic regression and ten-year overall survival by Cox proportional hazards models (median follow-up 9.6 years; 620 deaths). Results: Here, we show that NLP-based extraction of background breast features from routine pathology reports achieves an accuracy of over 90% across features. Lobular neoplasia and benign proliferative changes are associated with less aggressive tumor characteristics, whereas early neoplastic and papillary lesions are more prevalent in HER2-enriched and luminal B tumor subtypes. Benign proliferative changes are associated with better survival in age- and year-adjusted models (hazard ratio 0.91, 95% CI 0.86–0.97), but this association is attenuated after adjustment for stage and subtype. Conclusions: NLP-enabled extraction of background breast features from pathology text is feasible at scale. These features reflect tumor biology but do not independently add prognostic information beyond established clinical variables. Full article

Background: Chronic myeloid leukemia (CML) is a rare disease in children and adolescents. Discrepancies have been reported regarding the outcomes of adolescents, most of whom have been studied with younger or older patients not separately. Methods: The International Registry of Pediatric CML (I-CML-Ped Study) retrospectively and prospectively enrolled 614 patients less than 18 years old. Data from adolescents (15–18 years) with CML in chronic phase (CML-CP) were analyzed and compared to data from children less than 15 years old enrolled during the same period. Results: In total, 132 out of 144 adolescents presented with CML-CP: palpable spleen was reported in 67%, and the median leukocyte count was 181 G/L [interquartile range, 70–327]. Responses to treatment and outcome were analyzed in 124 adolescents with imatinib as first-line treatment: the cumulative incidence of major molecular responses (MMR) at months 12 and 36 was 33.4% (95% confidence interval CI, 24.9–41.9) and 79.8% (95% CI, 71.8–87.7), respectively. With a median follow-up of 4 years (95% CI: 3.5–4.9), 49 (40%) of these 124 patients were switched to another treatment, 11 (9%) patients progressed to the advanced phase, and the five-year overall survival rate was 95.2% (95% CI, 90.8–99.9%). We did not find significant statistical differences between these adolescents and younger children receiving imatinib in terms of response (complete cytogenetic response, MMR) and outcome (progression-free survival, overall survival). Conclusions: Response to treatment and outcomes in adolescents with CML-CP in the tyrosine kinase inhibitor era are satisfying without statistically significant difference from results observed in younger children. Full article

Background and Objectives: The COVID-19 pandemic disrupted cancer diagnosis and treatment pathways worldwide. Glioblastoma is an aggressive primary brain malignancy requiring timely multimodal care. This study evaluated survival outcomes among glioblastoma patients diagnosed before and during the COVID-19 pandemic and prepared a dataset for machine learning-based prediction of 12-month mortality. Materials and Methods: Patients aged ≥20 years diagnosed with glioblastoma between 2018 and 2021 were identified from the SEER database using ICD-O-3 histology codes 9440/3, 9441/3, and 9442/3. Patients were categorized as pre-COVID period (2018–2019) or COVID period (2020–2021). OS and CSS were evaluated using Kaplan–Meier curves, log-rank tests, and Cox regression models. Machine learning models predicted 12-month all-cause mortality using registry variables. Results: The final cohort included 9914 patients; 4819 were diagnosed pre-COVID and 5095 during COVID. Median OS was 11 months pre-COVID and 10 months during COVID; 12-month OS was 44.3% and 41.2%, respectively. Median CSS was 11 months in both periods; 12-month CSS was 46.9% and 44.1%, respectively. COVID-period diagnosis was modestly associated with poorer OS (adjusted HR 1.050, 95% CI 1.006–1.095, p = 0.025) and CSS (adjusted HR 1.048, 95% CI 1.003–1.095, p = 0.035). Machine learning models showed moderate discrimination for 12-month mortality prediction. Conclusions: Glioblastoma patients diagnosed during the COVID period had modestly poorer OS and CSS in conventional survival analyses; however, competing-risk analysis did not show a significant association with cancer-specific death. Registry-based machine learning models provided moderate 12-month mortality prediction, supporting their potential utility for population-level prognostic assessment. Full article

Background/Objectives: Tezepelumab targets thymic stromal lymphopoietin and has broad efficacy in severe asthma, yet real-world evidence on patient-reported trigger burden remains limited. We assessed 12-month outcomes after tezepelumab, focusing on clinical remission, biomarkers, and trigger profiling as complementary dimensions of response. Methods: In this multicenter longitudinal real-world observational cohort based on routine clinical follow-up and Severe Asthma Network in Italy (SANI) registry data, 43 adults with severe asthma treated with tezepelumab at four Italian SANI reference centers were evaluated at baseline and, when available, after 1, 3, 6, and 12 months. Outcomes included exacerbations, lung function, type 2 biomarkers, the Asthma Control Test, SNOT-22, trigger categories, Asthma Trigger Inventory (ATI) scores, and SANI-defined clinical remission. Results: Among 22 patients with 12-month follow-up data, mean annualized exacerbations decreased from 4.30 ± 2.77 to 0.36 ± 0.49 (p < 0.001), and 14/22 (63.6%) were exacerbation-free. Asthma control improved, whereas FEV1 remained stable. FeNO and blood eosinophils decreased at selected time points. The number of reported trigger categories was lower at 6 months (p < 0.001), and physical exertion, smoke, irritants, and infection-related ATI domains improved longitudinally. Complete clinical remission was achieved in 5/22 patients (22.7%). Conclusions: Tezepelumab was associated with reduced exacerbations, improved asthma control, and lower patient-reported trigger burden. Structured trigger profiling may provide an exploratory patient-centered dimension for assessing treatment response in severe asthma. Full article

Background: Rule-based multi-agent system (MAS) architectures for healthcare coordination rely on hardcoded decision trees that cannot generalise to novel clinical scenarios or self-correct reasoning errors. These limitations are acute in surgical continuum care, where patients traverse presurgical risk stratification, intraoperative monitoring, postsurgical ICU, ward care, and remote rehabilitation over days to weeks—a complexity no fixed-policy agent architecture can address without prohibitive rule engineering. Objective: We present the first agentic large language model (LLM) framework for autonomous end-to-end surgical continuum monitoring, superseding the prior rule-based MAS Digital Twin. Six ReAct-driven tool-use agents replace fixed-policy agents with dynamic reasoning, multi-hop evidence retrieval, and Reflexion self-correction while maintaining mandatory confidence-gated Human-in-the-Loop (HITL) gating at every care-pathway-modifying decision. Methods: The framework is grounded in the ReAct paradigm and Reflexion self-evaluation, embedded within the DETER Digital Twin state engine S(t). Each agent is specified by a ReAct loop signature, a ten-function clinical tool registry, and confidence-gated HITL escalation logic. Inter-agent coordination replaces the rule-based Priority Queue Manager with an LLM-mediated Coordination Supervisor Agent reasoning over competing resource requests. Results: The framework delivers: (i) six formally specified ReAct-loop agents with explicit tool registries and authorisation boundaries; (ii) a confidence-gated HITL architecture that reduces alert fatigue while preserving safety for ambiguous clinical scenarios; (iii) an extended conflict resolution function P(p,t,context) incorporating surgical phase and DETER deterioration trajectory gradient; (iv) Reflexion self-correction with a formal N_max = 2 termination condition and Clinical Factuality Verification Layer; and (v) a multi-phase Digital Twin state engine extending S(t) to the full surgical continuum. Conclusions: The proposed framework represents a fundamental architectural departure from rule-based clinical AI—from hardcoded policies to dynamic reasoning, from static retrieval to multi-hop tool-use chains, and from fixed escalation thresholds to confidence-gated self-evaluation—providing a formally specified, clinically deployable foundation for next-generation autonomous surgical care coordination. Full article