Spatial and Temporal Mapping of Breast Cancer Lung Metastases Identify TREM2 Macrophages as Regulators of the Metastatic Boundary.

Cancer mortality primarily stems from metastatic recurrence, emphasizing the urgent need for developing effective metastasis-targeted immunotherapies. To better understand the cellular and molecular events shaping metastatic niches, we used a spontaneous breast cancer lung metastasis model to create a single-cell atlas spanning different metastatic stages and regions. We found that premetastatic lungs are infiltrated by inflammatory neutrophils and monocytes, followed by the accumulation of suppressive macrophages with the emergence of metastases. Spatial profiling revealed that metastasis-associated immune cells were present in the metastasis core, with the exception of TREM2+ regulatory macrophages uniquely enriched at the metastatic invasive margin, consistent across both murine models and human patient samples. These regulatory macrophages (Mreg) contribute to the formation of an immune-suppressive niche, cloaking tumor cells from immune surveillance. Our study provides a compendium of immune cell dynamics across metastatic stages and niches, informing the development of metastasis-targeting immunotherapies. SIGNIFICANCE: Temporal and spatial single-cell analysis of metastasis stages revealed new players in modulating immune surveillance and suppression. Our study highlights distinct populations of TREM2 macrophages as modulators of the microenvironment in metastasis, and as the key immune determinant defining metastatic niches, pointing to myeloid checkpoints to improve therapeutic strategies. This article is featured in Selected Articles from This Issue, p. 2489.

The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response.

Despite their key regulatory role and therapeutic potency, the molecular signatures of interactions between T cells and antigen-presenting myeloid cells within the tumor microenvironment remain poorly characterized. Here, we systematically characterize these interactions using RNA sequencing of physically interacting cells (PIC-seq) and find that CD4+PD-1+CXCL13+ T cells are a major interacting hub with antigen-presenting cells in the tumor microenvironment of human non-small cell lung carcinoma. We define this clonally expanded, tumor-specific and conserved T-cell subset as T-helper tumor (Tht) cells. Reconstitution of Tht cells in vitro and in an ovalbumin-specific αß TCR CD4+ T-cell mouse model, shows that the Tht program is primed in tumor-draining lymph nodes by dendritic cells presenting tumor antigens, and that their function is important for harnessing the antitumor response of anti-PD-1 treatment. Our molecular and functional findings support the modulation of Tht-dendritic cell interaction checkpoints as a major interventional strategy in immunotherapy.

Relationship between religiosity, spirituality and physical and mental outcomes in fibromyalgia patients.

OBJECTIVES: The coping mechanisms utilised by patients with the fibromyalgia syndrome (FM) pose a crucial focus of treatment. Previous research points to the positive effects of religiosity and spirituality (R/S) as tools for coping with illness. The role of these factors in coping with chronic pain in FM has not previously been studied. The aim of this study was to evaluate the link between R/S and FM outcomes. METHODS: Fifty-five FM patients (ACR criteria) attending a tertiary rheumatology clinic completed a packet of questionnaires assessing demographic data, levels of religiosity and spirituality (SpREUK) and locus of control (LOC). These variables were then individually assessed for influence on FM outcome measures, using the Fibromyalgia Impact Questionnaire (FIQ), the SF-36, and the Beck Depression Index (BDI). RESULTS: A high score on SpREUK I (search for meaningful support) was negatively correlated with the Role-Physical (p=0.032) and Role-Emotional (p<0.005) scales on SF-36. Secular patients scored higher on SF-36 domains of "Role limitation due to emotional health" and "General health" (p<0.05). Employment demonstrated a positive correlation with the FIQ (p<0.01), the BDI (p<0.001), and the SF-36 (p<0.05). Physical activity correlated positively with BDI scores (p=0.012) and better scores on SF-36: energy/fatigue (p=0.024), social-functioning (p=0.014) and physical-functioning (p<0.01). No significant correlation was found between LOC (internal versus external) and FM outcomes. No significant correlation was found between SpREUK domains and the BDI. CONCLUSIONS: FM patients do not appear to benefit from high levels of R/S. Physicians should be aware of the impact of R/S on well-being in this population.

Anticoagulant and antiplatelet treatment in cancer patients with thrombocytopenia.

A B S T R A C T Antithrombotic therapy (anticoagulation or antiplatelet therapy) is frequently prescribed in cancer patients for prior or new indications such as venous thromboembolism, secondary prevention of arterial thrombosis or atrial fibrillation. Therefore, it is not uncommon for thrombocytopenic cancer patients to have an indication for antithrombotic therapy. Thrombocytopenia does not reduce the risk of recurrent thrombosis. The bleeding risk with anticoagulation appears to increase when platelets are <50×109/L, but individual platelet counts are poor predictors of bleeding. Management options when platelets are <50×109/L include no change, temporarily withholding antithrombotic therapy, reducing dose, changing the regimen, and increasing the platelet transfusion threshold. There are currently no data on use of direct oral anticoagulants when platelets are below 50×109/L, and there is reason in restricting their use. Little is known on antiplatelet therapy in this setting, although recent data suggest the prognostic importance and apparent safety of aspirin in acute myocardial infarction and thrombocytopenia. This paper will review the evidence, guidelines, current practice and ongoing studies on anticoagulation and antiplatelet therapy in thrombocytopenic patients with cancer.

Anticoagulation in thrombocytopenic patients with hematological malignancy: A multinational clinical vignette-based experiment.

BACKGROUND: Thrombocytopenia in cancer patients with an indication for anticoagulation poses a unique clinical challenge. There are guidelines for the setting of venous thromboembolism but not atrial fibrillation (AF). Evidence is lacking and current practice is unclear. OBJECTIVE: To identify patient and physician characteristics associated with anticoagulation management in hematological malignancy and thrombocytopenia. METHODS: A clinical vignette-based experiment was designed. Eleven hematologists were interviewed, identifying 5 relevant variable categories with 2-5 options each. Thirty hypothetical vignettes were generated. Each physician received 5 vignettes and selected a management strategy (hold anticoagulation; no change; transfuse platelets; modify type/dose). The survey was distributed to hematologists and thrombosis specialists in 3 countries. Poisson regression models with cluster robust variance estimates were used to calculate relative risks for using one management option over the other, for each variable in comparison to a reference variable. RESULTS: 168 physicians answered 774 cases and reported continuing anticoagulation for venous thromboembolism or AF in 607 (78%) cases, usually with dose reduction or platelet transfusion support. Overall, management was affected by platelet count, anticoagulation indication, time since indication, type of hematological disease and treatment, and prior major bleeding, as well as physician demographics and practice setting. The CHA2DS2-VASc score and time since AF diagnosis affected anticoagulation management in AF. CONCLUSION: This study indicates what the widely accepted management strategies are. These strategies, and possibly others, should be assessed prospectively to ascertain effectiveness. The decision process is intricate and compatible with current venous thromboembolism guidelines.

Current treatment of lymphoma in pregnancy.

Introduction: Lymphoproliferative diseases occurring during pregnancy present the treating physician with unique diagnostic and therapeutic challenges, aiming to achieve maternal cure without impairing fetal health, growth, and survival. Due to the rarity of this complication, there is limited data to guide clinical decision-making, especially regarding the safety of novel emerging therapies. Areas covered: The presented review describes the current practice of treatment for Hodgkin's (HL) and non-Hodgkin's (NHL) lymphoma in the pregnant patient, according to disease stage and trimester of pregnancy. Novel agents for treatment of lymphoma in the setting of pregnancy are discussed. Therapeutic dilemmas and areas of uncertainty are illuminated. Expert opinion: HL and NHL are potentially curable diseases in the pregnant patient with generally good outcomes for the mother and the offspring, when tailoring the treatment according to the individual patient. The complexity of the situation merits shared decision-making with the patient and her family, explicitly outlining the risks and benefits. The pregnant patient is best managed by a multidisciplinary team, familiar with the intricacies of the gestational period, and providing the necessary support and sensitivity. Further studies are needed regarding the safety of novel agents in pregnancy.

Intravenous immunoglobulin-induced acute thrombocytopenia.

BACKGROUND: Intravenous immunoglobulin (IVIG) has known efficacy in various hematologic conditions, including immune thrombocytopenic purpura. STUDY DESIGN AND METHODS: We present the clinical course of a patient with splenic marginal zone lymphoma, who developed acute thrombocytopenia on three consecutive episodes, with nadir counts of 27 × 109 , 50 × 109 , and 9 × 109 /L, upon administration of Intratect IVIG for hypogammaglobulinemia. An immunofluorescence test applying flow cytometry and monoclonal antibody immobilization of platelet antigens (MAIPA) assay were used to evaluate the reaction between IgG present in the IVIG preparations and the patient's or healthy donors' platelets (PLTs). RESULTS: A strong direct binding reaction was observed between the patient's PLTs and Intratect IgG using both methods. A similar reaction failed to materialize with controls. Binding was not antigen specific according to MAIPA. CONCLUSIONS: This is the first reported case of thrombocytopenia as a possible adverse effect of IVIG.

Extended Small-Dose Platelet Transfusions in Multitransfused Hemato-Oncological Patients: A Single-Center Experience.

BACKGROUND: Refractoriness to platelet transfusion, prevalent among 15-20% of hemato-oncological patients, is associated with multitransfusions and inferior outcomes. We evaluated the effectiveness of extended slow-dose transfusion (ESDT) in increasing platelet increments in multitransfused patients. METHODS: Patients treated after the implementation of ESDT were compared with historical controls treated with standard single-donor platelet (SDP) transfusions. Cohorts of early and late recipients were assembled for comparison, i.e. the 8th or 9th and 11th platelet unit per patient, respectively. Patients in the ESDT group received transfusions equal to half an SDP unit, administered over 4 h. Effectiveness was defined as a higher corrected count increment (CCI) at 1, 12, and 24 h after transfusion. RESULTS: In the early-recipients cohort, 24-h-posttransfusion increments were available for 29 ESDT patients and 6 standard patients, and did not differ significantly between the groups (p = 0.078). The 24-h-posttransfusion increment was available for 20 ESDT patients and 7 standard patients in the late-recipients cohort. The CCI was significantly higher in the ESDT group (p = 0.042). ABO compatibility improved the CCI (p = 0.01). CONCLUSIONS: ESDT demonstrated slightly higher increments at 24 h after transfusion in late recipients, suggesting this could be a cost-effective approach for the treatment of thrombocytopenic multitransfused hemato-oncological patients.