Anticoagulants are essential for preventing and treating thromboembolism across a wide range of clinical settings. Yet, they share a narrow therapeutic index that demands a precise understanding of their pharmacodynamic behavior. Thrombin generation provides an integrated measure of anticoagulant effects by capturing the timing, velocity, and total amount of thrombin formed over time. We reviewed the literature to establish a unified theoretical framework, grounded in mechanistic rationale and supported by experimentation, to better define the pharmacodynamics of anticoagulation therapy using thrombin generation as a common language to compare anticoagulant effects across drug classes. Unfractionated and low-molecular-weight heparins and vitamin K antagonists exert broad, multitargeted inhibition that profoundly suppresses peak thrombin and the endogenous thrombin potential. Direct factor Xa inhibitors primarily blunt propagation, direct thrombin inhibitors delay initiation while preserving overall thrombin output, and factor XIa inhibitors act mainly under low tissue factor conditions. Agents that engage multiple components of the coagulation cascade (prothrombinase formation, thrombin feedback activation, or zymogen depletion) produce deeper, cumulative suppression of thrombin generation and maintain efficacy under highly prothrombotic conditions, as seen with mechanical heart valves, antiphospholipid antibody syndrome, and catheter-associated thrombosis. In contrast, selective inhibitors achieve pharmacodynamic predictability but may lose responsiveness in the face of extreme coagulation activation. From a pharmacodynamic perspective, not all anticoagulants are the same. Divergent mechanisms map to unique, reproducible, and informative pharmacodynamic signatures that are characterized using thrombin generation. These signatures help explain why some patients experience breakthrough thrombosis or bleeding despite "on-target" drug levels. Embedding thrombin generation within clinical research allows anticoagulant effects to be interpreted through a mechanistic lens that bridges molecular pharmacology with patient-level variability. This synthesis provides a common language for comparing anticoagulants and lays the foundation for an individualized, pharmacologically informed approach to anticoagulation therapy.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular disorder characterized by mucocutaneous telangiectases and visceral vascular malformations, leading to recurrent bleeding, iron-deficiency anemia, and organ complications. Pulmonary, cerebral, and hepatic involvement are major determinants of morbidity and mortality. Management has traditionally relied on local and interventional approaches, which are largely palliative and do not address underlying disease mechanisms. New insights in HHT pathophysiology, particularly in the dysregulated BMP9-BMP10/ENG/ALK1 pathway, which is fundamental to the angiogenesis process, have enabled the development of targeted systemic therapies. Although no systemic drug is specifically approved for HHT, antifibrinolytics, anti-angiogenic agents, mTOR and AKT inhibitors, and immunomodulatory drugs have shown variable efficacy in selected patients. This review summarizes current evidence on systemic therapies and ongoing clinical trials, highlighting their potential to complement existing strategies and move toward disease-modifying approaches.

Ewing sarcoma breakpoint region 1 (EWSR1):: Fifth Ewing variant (FEV)-positive acute leukemia is exceptionally rare, and its clinicopathological features, molecular profile, and optimal treatment remain poorly defined. Here, we report a case of acute myeloid leukemia (AML) with bone marrow hypocellularity, aberrant lymphoid antigen expression, and an EWSR1::FEV fusion. A 45-year-old man was admitted with a 1-month history of petechiae and fatigue. Complete blood count (CBC) showed pancytopenia. Bone marrow (BM) examination revealed hypocellular marrow, with blasts accounting for 62% of nucleated cells. Flow cytometry (FCM) revealed a predominantly myeloid immunophenotype accompanied by aberrant expression of lymphoid-associated antigens. Conventional karyotyping did not identify a characteristic balanced translocation. Targeted next-generation sequencing (NGS) detected concurrent PTPN11 and NRAS mutations. RNA sequencing (RNA-seq) of the bone marrow sample identified the EWSR1::FEV fusion. Based on these findings, the patient was diagnosed with de novo AML with bone marrow hypocellularity and aberrant lymphoid antigen expression. Given the hypocellular marrow, venetoclax plus azacitidine (VA) was selected as induction therapy. The patient achieved morphological complete remission after one cycle, accompanied by a marked reduction in EWSR1::FEV transcript levels, and remained in morphological remission during approximately 6 months of follow-up after subsequent homoharringtonine combined with venetoclax plus azacitidine (HVA) consolidation. Together with previously reported cases, this case further supports the notion that EWSR1::FEV-positive acute leukemia may represent a distinct molecular subset characterized by lineage ambiguity, fusion-driven biology, and potentially unique therapeutic vulnerabilities. This case also suggests potential activity of venetoclax-based therapy in EWSR1::FEV-positive leukemia and warrants further investigation in additional cases.

BackgroundImmune checkpoint inhibitors have reshaped the treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and are increasingly used in perioperative settings. Unlike conventional therapy, immunotherapy may produce atypical response patterns, including delayed response, mixed or dissociated response, pseudoprogression, and hyperprogression.ObjectiveTo summarize current evidence on immunotherapy-related pseudoprogression in HNSCC and propose a practical risk-adapted framework for clinical management.MethodsThis structured narrative review searched PubMed, Web of Science, Embase, Google Scholar, and relevant gray literature from database inception to March 2026. HNSCC-specific studies were prioritized. Evidence from other solid tumors was included only when relevant to general mechanisms, imaging criteria, circulating tumor DNA dynamics, or immune-related response patterns.ResultsPseudoprogression appears uncommon in HNSCC, but its clinical impact is disproportionate because small changes in tumor volume or inflammation may threaten the airway, swallowing tract, tracheostomy site, skin envelope, or carotid artery. Proposed mechanisms include immune-cell infiltration, inflammatory edema, tumor necrosis, increased vascular permeability, and hemorrhage. Low-risk, clinically stable patients may undergo continued immunotherapy with short-interval reassessment. In contrast, laryngeal, hypopharyngeal, tracheostomal, carotid-adjacent, skull-base, cervical esophageal, or rapidly symptomatic disease should be managed as true progression or impending local failure until proven otherwise.ConclusionsPseudoprogression in HNSCC should not be treated as a purely radiologic event. We propose an HNSCC-modified iRECIST approach in which observation is reserved for patients with clinical stability, low-risk anatomy, and feasible short-interval reassessment.

Presacral cysts are rare cystic or cystic-solid masses located between the sacrococcygeal bone and the rectum, and complete surgical resection is the only curative treatment. Due to the complex anatomy of the presacral region, which is adjacent to the rectum, sacrum, and important vessels and nerves, surgical procedures are technically demanding and carry high-risk. Inappropriate surgical approaches and management often lead to complications such as residual cyst wall, recurrence, massive hemorrhage, and pelvic floor dysfunction. To further enhance the clinical understanding of presacral cysts in China, standardize their diagnosis and treatment, and promote standardized management, the Integrated Pelvic Tumor Committee of China Anti-Cancer Association, based om the 2021 and 2024 editions of the "Chinese expert consensus on standardized diagnosis and treatment of presacral cysts", organized multidisciplinary experts from general surgery, gastrointestinal surgery, colorectal and anal surgery, gynecologic oncology, orthopedic soft tissue surgery, neurosurgery, pathology, medical imaging, radiation oncology, epidemiology, and public health. Combining the latest evidence-based research and domestic multicenter clinical experience, and after multiple guideline conferences, they formulated the "Chinese clinical practice guidelines for standardized diagnosis and treatment of presacral cysts (2026 edition)". The guideline aims to provide a Chinese solution for the standardized diagnosis and treatment of presacral cysts. It systematically elaborates on the etiology and pathological types, clinical manifestations and auxiliary examinations, radiological and multidimensional anatomical classification, surgical principles, selection principles for different surgical approaches, perioperative complications and their managements, multidisciplinary treatment strategies, follow-up, and subsequent treatments, and summarizes a total of 20 recommendations. Compared with previous consensus documents, the 2026 guideline proposes a refined and multidimensional anatomical classification based on the position of the sagittal midline, the inferior margin of the S4 vertebra, the number of cyst cavities, and the distance between the cyst and sacrum. It further refines the indications for transperineal, transsacrococcygeal, transabdominal, and combined approaches under the guidance of anatomical classification, enabling individualized surgical plans. It also clarifies reconstructive strategies using gluteus maximus muscle flaps and skin flaps, and provides standardized recommendations for the clinical management of cases complicated with enterocutaneous fistula, anal fistula, sacral variation requiring neuroprotection, recurrent lesions, and suspected malignancy.

Histological diagnosis of mediastinal tumors can be challenging when safe puncture access is limited by adjacent airway and vascular structures. This technical note describes a 3D Slicer software-based preprocedural planning workflow for transvenous mediastinal biopsy using automated segmentation of normal anatomical structures. In a woman in her 60s with a large mediastinal tumor and superior vena cava (SVC) syndrome, a transpulmonary approach was considered undesirable because of the risk of pneumothorax and hemorrhage, and a transvenous approach was advantageous because biopsy and subsequent endovascular management of SVC syndrome could be incorporated into the same strategy. Contrast-enhanced computed tomography data were imported into 3D Slicer, and critical organs were segmented using artificial intelligence-based tools, and the tumor was manually segmented. With a fixed entry point in the SVC, six candidate puncture trajectories were generated and compared using three-dimensional distance-based metrics. A composite risk score was used to rank the trajectories as a heuristic within-case decision-support tool rather than a validated predictor. The workflow did not automatically determine the puncture direction but provided practical decision support by visualizing and avoiding high-risk trajectories. Transvenous biopsy was successfully performed under biplane fluoroscopic guidance using a transjugular liver biopsy kit without procedural complications.

Percutaneous renal biopsy (PRB) is the gold standard for diagnosing renal diseases. This study aimed to compare the specimen adequacy and safety of three ultrasound-guided PRB techniques: cross-sectional coaxial (Group A), longitudinal coaxial (Group B), and conventional longitudinal noncoaxial technique (Group C). This single-center retrospective study enrolled 184 adult patients who underwent PRB at Anhui Provincial Public Health Clinical Center between January 2019 and December 2025. All procedures were performed by experienced interventional radiologists. Outcomes included total glomerular yield, specimen adequacy, procedural time, and bleeding complications (perinephric hematoma, gross/microscopic hematuria). Baseline characteristics were comparable across groups. Specimen adequacy was 100% in Group A, 97.8% in Group B, and 89.1% in Group C. Group A exhibited significantly superior adequacy compared to Group C (p = 0.016). Group A had the shortest procedural time (1.45 ± 0.20 mins), which was significantly shorter than Group B (2.22 ± 0.35 mins) and Group C (2.61 ± 0.46 mins; all p < 0.001). The incidence of bleeding complications was significantly lower in Group A than in Group C (perinephric hematoma: p < 0.001; gross hematuria: p = 0.002; microscopic hematuria: p = 0.004). A significantly higher incidence of gross hematuria was also noted in Group A compared to Group B (p = 0.004). The cross-sectional coaxial technique for ultrasound-guided PRB provides better specimen adequacy, shorter procedural time, and a lower bleeding risk compared with longitudinal coaxial and conventional non-coaxial techniques. This combined approach may serve as an optimized strategy to improve PRB outcomes, although multicenter randomized trials are needed to confirm its generalizability.

The traditional clinical paradigm of rare inherited coagulation disorders (RICDs) implies that reduced levels of coagulation factors increase the bleeding tendency, although the relationship between factor activity and clinical phenotype is often variable and disease-related. However, emerging evidence suggests a more complex coagulation balance in RICD, so that a few inherited factor deficiencies predispose patients to arterial thrombosis and venous thromboembolism (VTE). By synthesizing data from international registries, clinical trials and biochemical studies, this review explores the molecular and clinical mechanisms underlying the thrombotic risk in RICDs, including deficiencies of factors II, V, VII, XI, XII, XIII and fibrinogen disorders. We show how some molecular variants disrupt the interplay between procoagulant, anticoagulant, and fibrinolytic pathways. For instance, while FXII and FXI deficiencies are increasingly viewed as protective against thrombosis, in some dysprothrombinemias and dysfibrinogenemias the impairment of anticoagulant regulatory mechanisms lead to increased thrombin generation. In disorders such as FXIII deficiency and afibrinogenemia, mechanical clot instability and loss of thrombin sequestration are proposed as potential mechanisms contributing to an increased risk of thrombotic events. This increased risk is often triggered or exacerbated by replacement therapies, co-inherited thrombophilia, or acquired factors. Understanding the underlying molecular mechanisms is essential to manage patients at risk for both life-threatening hemorrhage and thrombosis. Ultimately, a personalized approach is required to optimize bleeding prophylaxis and as well as episodic treatment.

BackgroundEndobronchial hamartoma and leiomyoma are rare benign airway tumors that may cause significant airway obstruction and require bronchoscopic intervention. However, comparative data on their clinical characteristics and interventional outcomes, particularly according to anatomic location, remain limited.ObjectivesThe objective of this study was to compare the clinical characteristics and bronchoscopic resection outcomes of endobronchial hamartoma and leiomyoma, with a focus on the impact of airway location.DesignThis study was a retrospective observational cohort study conducted over a 21-year period at a single tertiary referral center.MethodsIn this retrospective cohort study, we analyzed 107 patients with benign airway tumors, specifically comparing 56 hamartomas and 51 leiomyomas. Data on clinical presentation, radiologic findings, and bronchoscopic intervention outcomes were collected. A stratified analysis by airway level (trachea to segmental bronchi) was performed.ResultsEndobronchial leiomyomas were predominantly located in the central airways (trachea, 29.4%), while endobronchial hamartomas were more frequent in peripheral bronchi (segmental, 35.7%; P for trend = 0.011). Peripheral tumors showed significantly higher degrees of stenosis (P for trend < 0.001) and more frequent secondary CT findings, such as obstructive pneumonia. The complete resection rate was significantly higher for leiomyomas than for hamartomas (94.1% vs. 80.4%; P = 0.035). However, this difference was driven by anatomic location rather than histology; complete resection rates declined from 100% in the trachea to 64.5% in the segmental bronchi (P for trend < 0.001). Major complications included three pneumothoraxes and one massive hemorrhage during distal airway dissection. No recurrences occurred during a median follow-up of 10 months.ConclusionBronchoscopic resection is highly effective for benign airway tumors. Anatomic location, rather than histological subtype, is the primary determinant of procedural success and technical difficulty. Meticulous preoperative anatomical mapping is essential to identify danger zones near major vessels and optimize therapeutic strategies.

Factor IX (FIX) is a relatively small molecule (55 kDa) that distributes physiologically beyond the plasma pool into the extravascular space. This contrasts with factor VIII, which is confined to the bloodstream as a consequence of its larger size (∼300 kDa) and binding to von Willebrand factor. The extravascular distribution of FIX may be significant in relation to factor replacement therapy in patients with hemophilia B. Given the increasing number of relevant publications over recent years, we critically reviewed and evaluated the experimental and clinical data relating to the extravascular distribution of FIX, considering both the native molecule and therapeutic products generated via biotechnological approaches. Endogenous FIX has an extensive distribution to tissues outside of plasma and is in dynamic equilibrium between plasma and the extravascular compartment. Approximately two-thirds of total FIX exists reversibly bound to type IV collagen in the vessel wall and extravascular space. This may produce an extravascular reservoir of FIX extending the plasma hemostatic role. Consequently, plasma FIX activity alone may not fully reflect the hemostatic potential of FIX prophylactic treatment. Extravascular FIX could be relevant for controlling and preventing both clinical and subclinical bleeds. When used as prophylactic treatment, extended half-life FIX products demonstrate similar annualized bleeding rates, but with a wide range of FIX trough levels and varying extents of extravascular distribution. Clinical implications of variation between FIX products remain to be fully understood; more knowledge is required. Further studies may help to address knowledge gaps, potentially informing treatment optimization.