Microangiopathic hemolytic anemia (MAHA) is a form of Coombs-negative hemolysis characterized by mechanical fragmentation of erythrocytes, producing schistocytes on the peripheral blood smear. When accompanied by thrombocytopenia and neurological features, the presentation closely resembles thrombotic thrombocytopenic purpura (TTP), a hematological emergency requiring urgent plasma exchange. However, advanced malignancy can produce an almost identical thrombotic microangiopathy (TMA) that responds poorly to plasma exchange, and for which the definitive treatment is control of the underlying cancer. We report a 77-year-old woman with metastatic breast cancer and extensive osseous metastatic disease who presented with nausea, palpitations, generalized weakness, and transient neurological symptoms. Investigations revealed severe anemia, moderate but rapidly progressive thrombocytopenia, markedly elevated lactate dehydrogenase, elevated indirect bilirubin, undetectable haptoglobin, a negative direct antiglobulin test, and schistocytes on the blood smear. Brain magnetic resonance imaging showed acute bilateral frontal ischemic infarctions. Although early coagulopathy and active cancer yielded an intermediate PLASMIC score, TTP could not be excluded. Empiric plasma exchange and high-dose corticosteroids produced no hematological improvement, and the patient died shortly thereafter. ADAMTS13 testing was delayed by a pre-analytical error. The clinical course and lack of response favored malignancy-associated MAHA with disseminated intravascular coagulation over TTP. This case underscores that in patients with disseminated malignancy, MAHA with thrombocytopenia and neurological signs should raise early suspicion of cancer-associated TMA, even while TTP is treated empirically.

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa); however, current knowledge of its underlying drivers and therapeutic interventions remain limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as a regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach, we demonstrate that EZH2 regulates multilineage cell states and identify the RNA-binding protein Tristetraprolin (TTP) as a contributor to the response to EZH2 therapy through its role in RNA stability and translational regulation. Combined pharmacological inhibition of EZH2 and PI3K/mTORC1 produces superior antitumor activity in murine and human models of phenotypic plasticity, with greatest efficacy observed when combined with castration. Together, these findings identify EZH2-PI3K/mTORC1 signaling as a therapeutic vulnerability in phenotypically plastic PCa and reveal TTP-associated regulatory programs as contributors to targeted therapy response.

Thrombotic thrombocytopenic purpura (TTP) is a rare and rapidly life-threatening thrombotic microangiopathy. Disseminated microvascular thrombosis and resulting ischemia are the critical events determining outcome, if left untreated. The pathogenic hallmark is a severe deficiency of the plasma metalloprotease ADAMTS13, resulting in impaired cleavage of ultra-large von Willebrand factor (vWF) multimers leading to platelet aggregation. The vast majority of TTP cases are acquired and immune-mediated, depleting ADAMTS13 through autoantibodies. In contrast, congenital deficiency of ADAMTS13 affects a minority of patients. Measurement of ADAMTS13 activity is the cornerstone for diagnosis and implementation of treatment. However, clinical prediction scores support early therapeutic decision-making when results are pending. Plasma exchange, immunosuppression and more recently, the anti-vWF nanobody caplacizumab, are the central pillars for treatment of immune-mediated TTP. Caplacizumab prevents microvascular thrombosis during the acute episode but does not address the autoimmune-mediated ADAMTS13 depletion, underscoring the importance of plasma exchange and immunosuppression. Congenital TTP was previously treated using ADAMTS13 replacement through regular plasma infusions, but provision of recombinant ADAMTS13 has recently transformed treatment in these patients. Despite major advances, relapse remains a persistent threat for patients, making structured, long-term follow-up necessary. Diagnostic advances may help improve relapse prediction and corresponding therapeutic management. This review summarizes current concepts in the pathophysiology, diagnosis, clinical management of TTP and highlights recent therapeutic advancements and future challenges.

Intracranial hypertension (IH) is a frequent and serious complication of acute brain injury, strongly influencing morbidity and mortality. While invasive intracranial pressure (ICP) monitoring is standard, it has limitations. Intracranial compliance (ICC) offers additional insight into the brain's ability to handle changes in volume. Noninvasive ICP waveform analysis, such as the peak 2 (P2)/peak 1 (P1) ratio and time to peak (TTP), shows promise in evaluating ICC and detecting IH. The brain4care (B4C) system provides continuous, noninvasive monitoring for neurocritical care. We systematically reviewed studies comparing B4C with invasive ICP monitoring, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. MEDLINE, Embase, and the Scientific Electronic Library Online were searched for clinical studies from 2016 to May 2025 reporting quantitative B4C parameters in patients undergoing invasive ICP monitoring. Two reviewers evaluated studies, extracted data, and assessed quality using the Newcastle-Ottawa Scale. Sixteen studies involving 826 patients with acute brain injury were reviewed. The P2/P1 ratio, frequently assessed, showed high sensitivity (26.8-100%) and variable specificity (45.5-96.5%) for IH, with moderate to good accuracy (area under the curve [AUC] 0.71-0.83). TTP was less consistent, although a 0.3 threshold gave 92% specificity in the largest study. All studies demonstrated qualitative morphological concordance between B4C-derived and invasive ICP waveforms. The overall methodological quality was moderate, with frequent limitations related to comparability, confounder adjustment, and follow-up. B4C noninvasive monitoring provides reliable reflections of ICC and shows strong correlation with IH, consistently aligning with invasive ICP waveform patterns. This approach is well tolerated as an adjunct for dynamic, physiology-driven neurocritical care. Further prospective, multicenter studies are necessary to clearly define its clinical utility and support safe integration into standard practice.

Circulating tumor DNA (ctDNA) serves as a non-invasive liquid biopsy technique, offering potential utility in the prognostic evaluation of multiple myeloma (MM). In this study, we performed a systematic review and updated meta-analysis to analyze the association between ctDNA and the prognosis of patients diagnosed with MM. A comprehensive literature search was performed across PubMed, Embase, Web of Science, and the Cochrane Library to retrieve relevant literature published up to May 29, 2025, assessing the impact of ctDNA on survival outcomes in patients with MM. The survival outcomes included overall survival (OS), progression-free survival (PFS), and time to progression (TTP). A total of 948 MM patients from 14 studies were included in the analysis. Patients with detectable ctDNA exhibited a significantly increased risk of aggressive disease progression (hazard ratio [HR], 3.21; 95% confidence interval [CI], 1.98-5.18) and reduced OS (HR, 3.97; 95% CI, 2.24-7.04). Subgroup analyses consistently indicated that ctDNA positivity was associated with accelerated disease progression, irrespective of race, disease status, treatment, or ctDNA detection method. In subgroups defined by relapsed or refractory MM (RRMM) and Oceanian or Caucasian race, ctDNA positivity was significantly correlated with poorer OS. However, the associations were not significant in newly diagnosed MM (NDMM) or among Asian patients. Therefore, we conclude that ctDNA is a potential predictor of inferior survival outcomes in MM patients.

Two client-owned Lionhead rabbits underwent median sternotomy for mediastinal mass excision. Premedication included methadone, dexmedetomidine, and midazolam, with ketamine added for one rabbit. Anesthesia was maintained with isoflurane in oxygen and a ketamine infusion. Bilateral ultrasound-guided TTP blocks were performed at the level of the second and fifth intercostal spaces using a linear transducer and a spinal needle advanced in-plane in a lateromedial direction. Bupivacaine 0.5% was injected at a total dose of 2 mg/kg per rabbit, divided equally among four injection sites (total volumes of 0.9 mL and 1.0 mL for the first and second rabbits, respectively). Only one rabbit exhibited a brief intraoperative nociceptive response. The second rabbit developed severe postoperative respiratory compromise related to inadequate thoracic drain function and died 4 h after surgery. These cases indicate that the TTP block is technically feasible in rabbits and can contribute to intraoperative analgesia during thoracic surgery. Further studies are needed to evaluate the optimal injectate volume and its distribution, as well as the safety and efficacy of the anesthetic dose.

Hepatic alveolar echinococcosis (HAE) is characterized by infiltrative growth and remodeling of perilesional host tissue, including microvascular changes. We investigated whether quantitative contrast-enhanced ultrasound (CEUS) could characterize perilesional perfusion and its animal-level association with CD34-positive cell density in a standardized rat model. Twenty female Sprague Dawley rats underwent ultrasound-guided intrahepatic HAE modeling and CEUS 10 weeks later. Peak enhancement (PE), rise time (RT), time to peak (TTP), wash-in rate (WiR), wash-in perfusion index (WiPI), and wash-in area under the curve (WiAUC) were measured in the perilesional zone and reference liver parenchyma. CD34-positive cell density was quantified by digital pathology. The perilesional zone showed higher PE, WiR, WiPI, and WiAUC and shorter RT and TTP than the reference liver parenchyma (all FDR-adjusted p < 0.001). CD34-positive cell density correlated positively with PE (ρ = 0.696, FDR-adjusted p = 0.004), WiR (ρ = 0.525, FDR-adjusted p = 0.026), WiPI (ρ = 0.614, FDR-adjusted p = 0.012), and WiAUC (ρ = 0.534, FDR-adjusted p = 0.026), but not with RT or TTP. Within this experimental model, these findings indicate increased and accelerated perilesional perfusion and support quantitative CEUS as a contrast-enhanced imaging-based approach for characterizing its relationship with local microvascularity.

Background/Objectives: Melanoma antigen recognized by T cells 1 (MART-1) is a tumor-associated antigen overexpressed in melanoma cells that serves as a target for different immunotherapeutic strategies. These approaches differ substantially in their efficacy and safety and are associated with various immunologic challenges, including the incidence of autoimmunity. Although multiple clinical trials evaluated anti-MART-1 immunotherapies, the available evidence is highly heterogeneous and requires systematic evaluation. The present study aimed to systematically summarize and descriptively compare the reported efficacy and safety of different MART-1-targeted immunotherapeutic strategies. Methods: Clinical trial registries and bibliographic databases were systematically searched to identify clinical trials investigating anti-MART-1 immunotherapies. Data on the objective response rate (ORR), median relapse-free survival (RFS), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and adverse effects were extracted and structured. Potential immunologic challenges underlying the observed outcomes were also discussed. Results: Fifty-four clinical trials comprising 1292 treated patients were included, of whom 517 entered their trial with measurable disease and were evaluable for an objective response by RECIST. Higher objective response rates were reported in the autologous cell transfer and TCR-T trials than in the peptide- and DNA-based vaccine trials, whereas the vaccine trials reported fewer immune-related adverse events. These are uncontrolled cross-trial observations. The cell-based regimens were administered after non-myeloablative lymphodepletion and usually with high-dose IL-2, whereas the vaccination protocols were not, so the differences between modalities cannot be attributed to MART-1 targeting alone. No meta-analysis and no formal comparative efficacy analysis were performed. Conclusions: Based on the available data, MART-1-targeted immunotherapeutic strategies showed distinct efficacy and safety profiles. Higher objective response rates were reported in some adoptive cell therapy trials, together with a higher frequency of immune-related adverse events; these are uncontrolled cross-trial observations, and the contribution of concomitant lymphodepletion and IL-2 cannot be separated from that of MART-1 targeting. Peptide- and DNA-based vaccine approaches were associated with fewer immune-related adverse events and may warrant further evaluation as components of combined regimens.

Background:KRAS mutations are common oncogenic drivers in metastatic lung cancer (mLC) and may have prognostic and therapeutic implications. Circulating tumor DNA (ctDNA) analysis offers a minimally invasive approach for detecting tumor-specific alterations and monitoring tumor dynamics. This pilot study investigated the concordance between tissue and plasma KRAS mutational status and evaluated its clinical significance. Methods: Forty patients with mLC (25 males, 15 females; mean age 70.8 years) were included. KRAS mutations were analyzed in formalin-fixed paraffin-embedded tumor tissue using next-generation sequencing and in baseline plasma ctDNA using the Biocartis Idylla™ system. Concordance was assessed using Cohen's kappa statistics. Associations with clinicopathological characteristics and survival outcomes (overall survival (OS), progression-free survival (PFS), and time to progression (TTP)) were examined. Longitudinal ctDNA monitoring was performed in a subset of patients. Results:KRAS mutations were detected in 14/36 (38.89%) of tumor tissues and 12/40 (30.00%) of plasma samples, predominantly involving codon 12, with G12C as the most frequent variant. Tissue-plasma concordance was assessed in the 36 patients with matched samples and was substantial (κ = 0.64), while mutation subtype showed almost perfect agreement among concordant cases (percentage of agreement: 88.9%, κ = 0.80, p = 0.002, 95% CI: 0.4400-1.0000). No significant associations were observed with clinicopathological variables. Longitudinal analysis revealed dynamic ctDNA changes, with molecular progression occasionally preceding clinical progression. Patients with KRAS-mutated ctDNA had shorter PFS and OS compared to those with wild-type ctDNA (median PFS: 134 vs. 146 days; median OS: 163 vs. 193 days). Conclusions: Plasma ctDNA detection of KRAS mutations identifies a poor-prognosis subgroup of mLC patients and provides dynamic insights into tumor evolution. Serial ctDNA monitoring may anticipate disease progression and support real-time assessment of treatment response, highlighting its potential role in translational research and precision oncology.