DNA lesions correlate with lymphocyte function after selective internal radiotherapy.

In patients with non-resectable hepatic malignancies selective internal radiotherapy (SIRT) with yttrium-90 is an effective therapy. However, previous data indicate that SIRT leads to impaired immune function. The aim of the current study was to determine the extent of DNA lesions in peripheral blood mononuclear cells of SIRT patients and to correlate these lesions with cellular immune responses. In ten patients γH2AX and 53BP1 foci were determined. These foci are markers of DNA double-strand breaks (DSBs) and occur consecutively. In parallel, lymphocyte proliferation was assessed after stimulation with the T cell mitogen phytohemagglutinin. Analyses of vital cells were performed prior to and 1 h and 1 week after SIRT. 1 h and 1 week after SIRT numbers of γH2AX and of 53BP1 foci were more than threefold larger than before (p < 0.01). Already at baseline, foci were more abundant than published in healthy controls. Lymphocyte proliferation at baseline was below the normal range and further decreased after SIRT. Prior to therapy, there was an inverse correlation between lymphocyte proliferation and the quotient 53BP1/γH2AX; which could be considered as a measure of the course of DNA DSB repair (r = - 0.94, p < 0.0001). Proliferative responses were inversely correlated with 53BP1 foci prior to therapy and γH2AX and 53BP1 foci 1 h after therapy (r < - 0.65, p < 0.05). In conclusion, DNA foci in SIRT patients were correlated with impaired in vitro immune function. Unrepaired DNA DSBs or cell cycle arrest due to repair may cause this impairment.

Impaired lymphocyte function in patients with hepatic malignancies after selective internal radiotherapy.

The purpose of our study was to assess the immune function of patients with inoperable hepatic malignancies after treatment with selective internal radiotherapy (SIRT) and to identify possible correlations with clinical parameters. In 25 patients receiving SIRT lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) after stimulation with mitogens and microbial antigens were tested prior to therapy, directly after therapy (day 1) and at day 2, 7 and 28 post therapy using the lymphocyte transformation test and enzyme-linked immunospot assays. Absolute counts and percentages of leukocyte and lymphocyte subsets were determined by flow cytometry. The most prominent finding was an immediate and significant (p < 0.05) decrease of lymphocyte proliferation and interferon-γ production directly after therapy which lasted until day 28 and was stronger upon stimulation with microbial antigens than with mitogens. Moreover, lymphopenia was revealed, affecting all lymphocyte subsets (CD3+, CD4+, CD8+ T cells, CD4+ CD8+ T cells, B cells and NK cells). SIRT led to a reduction in the percentage of activated HLA-DR+ monocytes and of CD45R0+ memory T cells. Higher radiation activity, the presence of liver cirrhosis, chronic kidney disease, diabetes mellitus and metastases were unfavorable factors for immunocompetence, while a better Eastern Cooperative Oncology Group performance status was associated with stronger immunological reactions. In conclusion, SIRT leads to severe impairment of cellular in vitro immune responses. Further studies are needed to assess a potential clinical impact.

Antimicrobial Regimens in Cement Spacers for Periprosthetic Joint Infections: A Critical Review.

Antibiotic-loaded cement spacers (ALCSs) are essential for treating periprosthetic joint infections (PJIs) by providing mechanical support and local antibiotic delivery. The purpose of this review is to comprehensively examine the various types of spacers utilised in the management of periprosthetic joint infections (PJIs), including both static and articulating variants and to analyse the fundamental principles underlying spacer use, their clinical benefits, the selection and administration of antimicrobial agents, appropriate dosages, and potential adverse effects. Articulating spacers, which allow joint mobility, often yield better outcomes than static ones. Spacer pharmacokinetics are vital for maintaining therapeutic antibiotic levels, influenced by cement porosity, mixing techniques, and the contact area. Antibiotic choice depends on heat stability, solubility, and impact on cement's mechanical properties. Mechanical properties are crucial, as spacers must withstand physical stresses, with antibiotics potentially affecting these properties. Complications, such as tissue damage and systemic toxicity, are discussed, along with mitigation strategies. Future advancements include surface modifications and novel carriers to enhance biofilm management and infection control.

Diagnostic Accuracy of Rotational Thromboelastometry for Low-Virulence Periprosthetic Joint Infections: A Pilot Study.

BACKGROUND: Periprosthetic joint infections (PJIs) are associated with altered coagulation dynamics; therefore, coagulation laboratory studies could be valuable for diagnosing PJI. This study aimed to evaluate the diagnostic role of Rotational Thromboelastometry (ROTEM) in detecting PJIs caused by low-virulence pathogens. METHODS: A retrospective study was conducted, enrolling 78 patients who underwent exchange arthroplasty due to PJI due to high-virulence pathogens (Group A, n = 16), low-virulence pathogens (Group B, n = 20), or due to aseptic loosening (Group C, n = 20). Preoperative laboratory findings were compared among the three groups. RESULTS: Several ROTEM parameters differed in patients with PJIs caused by low-virulence pathogens, indicating a link between these infections and hypercoagulability. The development of low-virulence PJIs was associated with a higher maximum clot firmness (MCF) (Odds Ratio, 1.12; 95% Confidence Interval, 1.04-1.21; p = 0.001). Additionally, EXTEM MCF was found to have the highest diagnostic accuracy for these infections (Area Under the Curve, 0.841; sensitivity 90.0%; specificity 90.4%), surpassing that of C-reactive protein and the Erythrocyte Sedimentation Rate (p = 0.006 and p = 0.019, respectively). CONCLUSIONS: Our findings suggest that ROTEM analysis is a promising method for detecting the altered hemostatic dynamics associated with PJI caused by low-virulence pathogens.

Cancer-Associated Thrombosis: Pathophysiology, Laboratory Assessment, and Current Guidelines.

Dysregulated hemostasis in cancer patients is associated with various clinical conditions, from thromboembolic complications to disseminated intravascular coagulation. Despite the well-established association between cancer and thromboembolic complications, the mechanisms involved are not completely elucidated. There are several predisposing factors in cancer for increased thrombus generation, such as immobilization and chemotherapy. The term cancer-associated thrombosis (CAT) has been introduced to describe the close bidirectional relationship between cancer and thromboembolic events. Conventional coagulation tests (PT/aPTT) are more accurate in detecting a hypocoagulable rather than a hypercoagulable state; thus, their contribution to CAT management is limited. Traditionally, D-dimer levels have been the most common laboratory study for the evaluation of thrombotic risk. However, D-dimer levels only display a snapshot of the coagulation cascade, and they cannot provide a dynamic evaluation of evolving clot formation. Non-conventional assays, such as viscoelastic methods and microparticle formation are promising tools for the identification of patients at risk for developing CAT. Recent guidelines from the American Society of Clinical Oncology counsel against the estimation of thrombotic risk through a single test and recommend the use of scoring systems that take into account several risk factors. The present review outlines the current insights into the pathophysiological mechanisms of CAT and provides a comprehensive review of the latest advances in the laboratory assessment of CAT and the recent guidelines for the management of patients at risk for developing thromboembolic complications.

In Patients Treated by Selective Internal Radiotherapy, Cellular In Vitro Immune Function Is Predictive of Survival.

In patients with liver malignancies, the cellular immune function was impaired in vitro after selective internal radiotherapy (SIRT). Because immunosuppression varied substantially, in the current study, we investigated in 25 SIRT patients followed up for ten years whether the lymphocyte function was correlated with survival. Peripheral blood mononuclear cells were stimulated with four microbial antigens (tuberculin, tetanus toxoid, Candida albicans and CMV) before therapy and at four time points thereafter, and lymphocyte proliferation was determined by H3-thymidine uptake. The median sum of the responses to these four antigens decreased from 39,464 counts per minute (CPM) increment (range 1080-204,512) before therapy to a minimum of 700 CPM increment on day 7 after therapy (0-93,187, p < 0.0001). At all five time points, the median survival in patients with weaker responses was 2- to 3.5-fold shorter (p < 0.05). On day 7, the median survival in patients with responses below and above the cutoff of a 2 CPM increment was 185 and 523 days, respectively (χ2 = 9.4, p = 0.002). In conclusion, lymphocyte function could be a new predictor of treatment outcome after SIRT.