Arterial Thromboembolism in Patients With AF and CHA2DS2-VASc Score 0-2 With and Without Cancer.

Background: It is unclear whether newly diagnosed cancer adds to the risk of arterial thromboembolism (ATE) in patients with atrial fibrillation/flutter (AF). This is especially relevant for AF patients with low to intermediate CHA2DS2-VASc scores in whom the risk-benefit ratios between ATE and bleeding are delicately balanced. Objectives: The objectives were to evaluate the ATE risk in AF patients with a CHA2DS2-VASc score of 0 to 2 with and without cancer. Methods: A population-based retrospective cohort study was performed. Patients with a CHA2DS2-VASc score of 0 to 2 not receiving anticoagulation at cancer diagnosis (or the matched index date) were included. Patients with embolic ATE or cancer before study index were excluded. AF patients were categorized into AF and cancer and AF and no cancer cohorts. Cohorts were matched for multinomial distribution of age, sex, index year, AF duration, CHA2DS2-VASc score, and low/high/undefined ATE risk cancer. Patients were followed from study index until the primary outcome or death. The primary outcome was acute ATE (ischemic stroke, transient ischemic attack, or systemic ATE) at 12 months using International Classification of Diseases-Ninth Revision codes from hospitalization. The Fine-Gray competing risk model was used to estimate the HR for ATE with death as a competing risk. Results: The 12-month cumulative incidence of ATE was 2.13% (95% CI: 1.47-2.99) in 1,411 AF patients with cancer and 0.8% (95% CI: 0.56-1.10) in 4,233 AF patients without cancer (HR: 2.70; 95% CI: 1.65-4.41). The risk was highest in men with CHA2DS2-VASc = 1 and women with CHA2DS2-VASc = 2 (HR: 6.07; 95% CI: 2.45-15.01). Conclusions: In AF patients with CHA2DS2-VASc scores of 0 to 2, newly diagnosed cancer is associated with an increased incidence of stroke, transient ischemic attack, or systemic ATE compared with matched controls without cancer.

Direct oral anticoagulants in patients with venous thromboembolism and hematological malignancies.

Data are needed on direct oral anticoagulants (DOACs) for the treatment of venous thromboembolism (VTE) in hematological malignancies (HM). Retrospective studies to date lacked a control group and did not focus on patients with VTE. Out aim was to assess the incidence of VTE recurrence and bleeding in HM patients treated with low molecular weight heparin (LMWH) or DOACs for acute VTE. This is a retrospective cohort study including patients with active HM and newly-diagnosed VTE, indexed on the first day of anticoagulation and followed for 12 months. The outcome was a composite of recurrent VTE, major bleeding or clinically relevant non-major bleeding. Cumulative incidence [95% confidence interval (CI)] was calculated for each anticoagulation group (LMWH, DOAC) and hazard ratios (HR) were calculated using cox-proportional hazards model, with death as a competing risk. 143 HM patients treated with LMWH (96) or DOACs (47) for acute VTE were included. The most common HM types were lymphoma in 83 (58%) and plasma cell dyscrasia in 32 (22.3%). The 12-month cumulative incidence of the composite outcome was 24.2% (95% CI 15.9-33.5%; n = 22) in the LMWH group and 18.5% (8.5-31.5%; n = 8) in the DOAC group (HR 1.51 [0.695-3.297]). Two recurrent VTE occurred (both in the DOAC group while off-treatment). Nine (9.4%) LMWH-treated patients had major bleeding compared to 1 (2.1%) DOAC-treated patient (HR 4.85 [0.64-36.56]). This study generates the hypothesis that DOACs may be a safe and effective alternative to LMWH for VTE in patients with HM types represented in the study.

Effect of aspirin on primary prevention of cardiovascular disease and mortality among patients with chronic kidney disease.

Chronic kidney disease is associated with an increased risk for cardiovascular and bleeding events. Data regarding the effectiveness and risks of aspirin therapy for primary prevention in the high-risk group of patients with chronic kidney disease are scant and controversial. This retrospective study included patients with chronic kidney disease. Participants were divided according to aspirin use. Outcomes included non-fatal cardiovascular events, major bleeding events and all-cause mortality. Among 10,303 patients, 2169 met the inclusion criteria and 1818 were included after 1:1 propensity-score matching. Our final cohort included patients with mean age of 73.4 ± 11.6 years, estimated glomerular filtration rate of 31.5 ± 10.5 ml/min/1.73m2 with follow up of 4.9 ± 1.5 years. There were no significant differences in all-cause mortality and bleeding events (odds ratio = 1.03, confidence interval [0.62, 1.84], p = .58 and odds ratio = 1.09, confidence interval [0.65, 1.72], p = .87 respectively). The incidence of cardiovascular events was higher in aspirin users versus non-users on univariate analysis (p < 0.01) and was comparable after controlling for possible risk-factors (OR = 1.05, CI [0.61, 3.14], p = .85). Chronic aspirin use for primary prevention of cardiovascular disease was not associated with lower mortality, cardiovascular events or increased bleeding among patients with chronic kidney disease. Those results were unexpected and should prompt further research in this field.

Fighting SARS-CoV-2 with green seaweed Ulva sp. extract: extraction protocol predetermines crude ulvan extract anti-SARS-CoV-2 inhibition properties in in vitro Vero-E6 cells assay.

Due to the global COVID-19 pandemic, there is a need to screen for novel compounds with antiviral activity against SARS-COV-2. Here we compared chemical composition and the in vitro anti- SARS-COV-2 activity of two different Ulva sp. crude ulvan extracts: one obtained by an HCl-based and another one by ammonium oxalate-based (AOx) extraction protocols. The composition of the crude extracts was analyzed and their antiviral activity was assessed in a cytopathic effect reduction assay using Vero E6 cells. We show that the extraction protocols have a significant impact on the chemical composition, anti- SARS-COV-2 activity, and cytotoxicity of these ulvan extracts. The ulvan extract based on the AOx protocol had a higher average molecular weight, higher charge, and 11.3-fold higher antiviral activity than HCl-based extract. Our results strongly suggest that further bioassay-guided investigation into bioactivity of compounds found in Ulva sp. ulvan extracts could lead to the discovery of novel anti-SARS-CoV-2 antivirals.

Ribosomal proteins as distinct "passengers" of microvesicles: new semantics in myeloma and mesenchymal stem cells' communication.

Aberrant mesenchymal stem cells (MSCs) in multiple myeloma (MM) bone marrows (BM) promote disease progression and drug resistance. Here, we assayed the protein cargo transported from MM-MSCs to MM cells via microvesicles (MVs) with focus on ribosomal proteins (RPs) and assessment of their influence on translation initiation and design of MM phenotype. Proteomics analysis (mass spectrometry) demonstrated increased levels and repertoire of RPs in MM-MSCs MVs compared to normal donors (ND) counterparts (n = 3-8; P = 9.96E - 08). We limited the RPs load in MM-MSCs MVs (starvation, RSK and XPO1 inhibitions), reapplied the modified MVs to MM cell lines (U266, MM1S), and demonstrated that the RPs are essential to the proliferative effect of MM-MSCs MVs on MM cells (n = 3; P < 0.05). We also observed that inhibition with KPT-185 (XPO1 inhibitor) displayed the most extensive effect on RPs delivery into the MVs (↓80%; P = 3.12E - 05). Using flow cytometry we assessed the expression of select RPs (n = 10) in BM-MSCs cell populations (ND and MM; n ≥ 6 each). This demonstrated a heterogeneous expression of RPs in MM-MSCs with distinct subgroups, a phenomenon absent from ND-MSCs samples. These findings bring to light a new mechanism in which the tumor microenvironment participates in cancer promotion. MVs-mediated horizontal transfer of RPs between niche MSCs and myeloma cells is a systemic way to bestow pro-cancer advantages. This capacity also differentiates normal MSCs from the MM-modified MSCs and may mark their reprogramming. Future studies will be aimed at assessing the clinical and therapeutic potential of the increased RPs levels in MM-MSCs MVs.

Multiple myeloma BM-MSCs increase the tumorigenicity of MM cells via transfer of VLA4-enriched microvesicles.

Multiple myeloma (MM) cells accumulate in the bone marrow (BM) where their interactions impede disease therapy. We have shown that microvesicles (MVs) derived from BM mesenchymal stem cells (MSCs) of MM patients promote the malignant traits via modulation of translation initiation (TI), whereas MVs from normal donors (ND) do not. Here, we observed that this phenomenon is contingent on a MVs' protein constituent, and determined correlations between the MVs from the tumor microenvironment, for example, MM BM-MSCs and patients' clinical characteristics. BM-MSCs' MVs (ND/MM) proteomes were assayed (mass spectrometry) and compared. Elevated integrin CD49d (X80) and CD29 (X2) was determined in MM-MSCs' MVs and correlated with patients' staging and treatment response (free light chain, BM plasma cells count, stage, response to treatment). BM-MSCs' MVs uptake into MM cell lines was assayed (flow cytometry) with/without integrin inhibitors (RGD, natalizumab, and anti-CD29 monoclonal antibody) and recipient cells were analyzed for cell count, migration, MAPKs, TI, and drug response (doxorubicin, Velcade). Their inhibition, particularly together, attenuated the uptake of MM-MSCs MVs (but not ND-MSCs MVs) into MM cells and reduced MM cells' signaling, phenotype, and increased drug response. This study exposed a critical novel role for CD49d/CD29 on MM-MSCs MVs and presented a discriminate method to inhibit cancer promoting action of MM-MSCs MVs while retaining the anticancer function of ND-MSCs-MVs. Moreover, these findings demonstrate yet again the intricacy of the microenvironment involvement in the malignant process and highlight new therapeutic avenues to be explored.

Placental supernatants' enhancement of the metastatic potential of breast cancer cells: is estrogen receptor (ERα) essential for this phenomenon?

PURPOSE: Pregnancy-associated breast cancer (PABC) is usually diagnosed at an advanced stage in comparison to non-pregnant women. The placenta secretes hormones and cytokines, which affect breast cancer progression. Previously, we demonstrated that human placental secretome facilitates the survival and migration of ERα+ breast cancer cells (BCCL), but pregnant women have a relatively high frequency of ERα-negative tumors. In the current study, we analyzed the effect of placental secretome on ERα-negative BCCL. METHODS: BCCL [MCF-7(estrogen/progesterone receptor positive (ERα+/PR+), ERα reduced MCF-7 (siRNA, MCF-7 ERα-), HS-578 and BT-549 cells (both ER-/PR-)] were exposed to supernatants (collected from first trimester human placental explants and from control BCCL) or to E2 + P4 (estrogen + progesterone) in placental supernatant concentrations and then tested for cell proliferation (number, cell cycle, PCNA), cell-death, cell migration, STAT3 pathway activation and functionality. RESULTS: Silencing ERα in the MCF-7 cells negated the placental supernatant and E2 + P4 enhancement of cell migration (> 130%, p < 0.05), number (> 120%) and survival (~ 130%). However, it had no such effect on MCF-7-ER- migration, which was still elevated in the presence of placental secretome. ER-/PR- BCCL were unaffected by the hormones, but placental secretome significantly elevated their migration (115%), number (140-170%), STAT3 phosphorylation (~ 180%) and BT-549 STAT3 level. These effects were negated by the STAT3 inhibitor. CONCLUSIONS: Placental supernatant facilitates BCCL malignant characteristics by activating ERα in estrogen responsive cells and STAT3 in ERα- BCCL. This indicates a possible mechanism that may underlie PABC's advanced state and suggests STAT3 pathway as a therapeutic target for PABC.

The Muddied Waters of Ibrutinib Therapy.

A 37-year-old male was admitted with an atypical presentation of central nervous system (CNS) aspergillosis while on ibrutinib therapy for a CNS relapse of mantle cell lymphoma. This case highlights the importance of a high clinical suspicion of opportunistic infections in patients receiving small-molecule kinase inhibitors. This report includes a review of reported cases of Aspergillus infections in patients receiving ibrutinib and the shared features of these cases.

BM-MSCs-derived ECM modifies multiple myeloma phenotype and drug response in a source-dependent manner.

Multiple myeloma (MM) malignant plasma cells accumulate in the bone marrow (BM) where their interaction with the microenvironment promotes disease progression and drug resistance. Previously, we have shown that MM cells cocultured with BM-mesenchymal stem cells (MSCs) comodulated cells' phenotype in a MAPKs/translation initiation (TI)-dependent manner. Dissection of the coculture model showed that BM-MSCs secretomes and microvesicles (MVs) participate in this crosstalk. Here, we addressed the role of the BM-MSCs extracellular matrix (ECM). MM cell lines cultured on decellularized ECM of normal donors' (ND) or MM patients' BM-MSCs were assayed for phenotype (viability, cell count, death, proliferation, migration, and invasion), microRNAs (MIR125a-3p, MIR199a-3p) and targets, MAPKs, TI epithelial-to-mesenchymal transition (EMT), CXCR4, and autophagy. Drug (doxorubicin, velcade) response of MM cells cultured on ND/MM-MSCs' ECM with/without adhered MVs was also evaluated. ECM evoked opposite responses according to its origin: MM cells cultured on ND-MSCs' ECM demonstrated a rapid and continued decrease in MAPK/TI activation (↓10%-25%, P < 0.05) (15-24 hours) followed by diminished viability, cell count, proliferation, migration, and invasion (16-72 hours) (↓10%-50%, P < 0.05). In contrast, MM cells cultured on MM-MSCs' ECM displayed activated MAPK/TI, proliferation, EMT, and CXCR4 (↑15%-250%, P < 0.05). Corresponding changes in microRNAs relevant to the MM cells' altered phenotype were also determined. The hierarchy and interdependence of MAPKs/TI/autophagy/phenotype cascade were demonstrated. Finally, we showed that the ECM cooperates with MVs to modulate MM cells drug response. These data demonstrate the contribution of BM-MSCs' ECM to MM niche design and underscore the clinical potential of identifying targetable signals.

Placenta-conditioned extracellular matrix (ECM) activates breast cancer cell survival mechanisms: A key for future distant metastases.

The extracellular matrix (ECM) affects cancer cell characteristics. Inability of normal epithelial cells to attach to the ECM induces apoptosis (anoikis). Cancer cells are often anoikis resistant, a prerequisite for their metastatic spread. Previously we demonstrated that the placenta manipulates its surrounding ECM in a way that prevents breast cancer cells (BCCL) attachment and induces their motility and aggregation. This fits with the fact that although breast cancer during pregnancy is often advanced, metastasis to the placenta is rarely observed. Placental intervillous space provides suitable conditions for cancer cell arrival. Yet, the outcome of the short communication between the placental ECM to the BCCL and its effect on BCCL malignant potential are unknown, and are the focus of our study. In the current study we analyzed the effect of placental ECM on BCCL survival pathways and drug resistance. Microarray analysis suggested activation of the NF-κB and stress response pathways. Indeed, the placenta-conditioned ECM induced autophagy in ERα + BCCL, inactivated the NF-κB inhibitor (IκB) and increased integrin α5 in the BCCL. The autophagy mediated MCF-7 and T47D migration and the placental ECM-BCCL interactions reduced the BCCL sensitivity to Taxol. We also demonstrated by using siRNA that integrin α5 was responsible for the MCF-7 autophagy and suggest this molecule as a suitable target for therapy.

Mean platelet volume and risk of thrombotic and bleeding complications in patients with Philadelphia chromosome negative myeloproliferative neoplasms.

: Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are associated with increased thrombosis and bleeding risk. Mean platelet volume (MPV) is associated with thrombosis in nonmalignant settings. This study evaluates the association between MPV and thrombosis and bleeding in MPN. Patients with MPN without prior thrombosis, nonhematologic malignancy or anticoagulant use were included in this retrospective analysis. The primary endpoint was arterial or venous thrombosis. The secondary endpoints were any bleeding and major bleeding. MPV was measured at diagnosis and during the index episode. A total of 135 MPN patients met the inclusion criteria. Over a median follow-up of 6.6 years, 23 patients (15.6%) experienced thrombosis. There was no difference in MPV at diagnosis (8.47 vs. 8.73 fl, P = 0.4) or during the index event between patients with or without thrombosis. Twelve patients (8.9%) had a bleeding event, whereas seven (5.2%) had major bleeding. MPV was significantly higher among patients with major bleeding, both at diagnosis (10.04 vs. 8.61, P = 0.005) and during the bleeding episode. There was no association after regression analysis of variables associated with MPV at diagnosis. MPV is not associated with thrombotic events in MPN. The study generates the hypothesis that MPV may be an indirect marker of bleeding in MPN.

Microvesicles derived from normal and multiple myeloma bone marrow mesenchymal stem cells differentially modulate myeloma cells' phenotype and translation initiation.

Multiple myeloma (MM) cells' interaction with the bone marrow (BM) microenvironment critically hinders disease therapy. Previously, we showed that MM co-culture with BM-mesenchymal stem cells (MSCs) caused co-modulation of translation initiation (TI) and cell phenotype and implicated secreted components, specifically microvesicles (MVs). Here, we studied the role of the BM-MSCs [normal donors (ND) and MM] secreted MVs in design of MM cells' phenotype, TI and signaling. BM-MSCs' MVs collected from BM-MSCs (MM/ND) cultures were applied to MM cell lines. After MVs uptake confirmation, the MM cells were assayed for viability, cell count and death, proliferation, migration, invasion, autophagy, TI status (factors, regulators, targets) and MAPKs activation. The interdependence of MAPKs, TI and autophagy was determined (inhibitors). ND-MSCs MVs' treated MM cells demonstrated a rapid (5 min) activation of MAPKs followed by a persistent decrease (1-24 h), while MM-MSCs MVs' treated cells demonstrated a rapid and continued (5 min-24 h) activation of MAPKs and TI (↑25-200%, P < 0.05). Within 24 h, BM-MSCs MVs were internalized by MM cells evoking opposite responses according to MVs origin. ND-MSCs' MVs decreased viability, proliferation, migration and TI (↓15-80%; P < 0.05), whereas MM-MSCs' MVs increased them (↑10-250%, P < 0.05). Inhibition of MAPKs in MM-MSCs MVs treated MM cells decreased TI and inhibition of autophagy elevated cell death. These data demonstrate that BM-MSCs MVs have a fundamental effect on MM cells phenotype in accordance with normal or pathological source implemented via TI modulation. Future studies will aim to elucidate the involvement of MVs-MM receptor ligand interactions and cargo transfer in our model.

The management of hodgkin lymphomas in pregnancies.

Hodgkin lymphoma is the most common hematological malignancy in pregnancy. Its management presents several unique challenges, as decisions have to take both maternal and fetal risks into consideration. Using three hypothetical cases, we review current evidence and guidelines and suggest our recommendations for managing pregnant Hodgkin lymphoma patients. The opportunity for a prompt and accurate diagnosis should not be missed; this may be achieved by vigilance to suggestive symptoms, performance of biopsy which is not contraindicated during pregnancy and use of MRI for staging. Most patients should receive treatment with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) after completion of the first trimester. Bridging therapy with corticosteroids or vinblastine should be considered during the first trimester. In most cases of early disease, the addition of chemotherapy cycles to the treatment plan seems preferable to radiation therapy. Diagnosis at relapse raises unique dilemmas regarding second-line chemotherapeutic regimens and timing of consolidation with high-dose therapy and autologous stem cell transplantation, an approach which is contraindicated during pregnancy. Considering the excellent outcomes of Hodgkin lymphoma outside pregnancy, every effort should be made to strive toward a curative treatment plan while balancing the multiple issues and dilemmas which arise when treating this malignancy in a pregnant patient.

Clinical, diagnostic, and therapeutic features of patients admitted to acute care hospitals with trunk compared to lower limb cellulitis.

The objective of this study is to report the clinical course and risk factors of trunk cellulitis, to identify diagnostic and therapeutic approaches, and compare them to patients with lower limb cellulitis. Medical records of adult patients with trunk cellulitis were reviewed and compared to an equal number of randomly selected patients with lower limb cellulitis. Demographic, clinical, and laboratory data were collected and analyzed using binary univariate and multivariate logistic regression analyses. Primary outcome was surgical drainage. Secondary outcomes were use of imaging studies, length of stay, readmission within 30 days, and 30-day mortality. During the study period, 74 patients were diagnosed with trunk cellulitis. Compared to patients with lower limb cellulitis, there are more women (57 vs. 39%, p = 0.032) and they are younger (mean age 59.7 vs. 68.4 years, p = 0.005). The only co-morbidity found as a significant risk factor for trunk cellulitis is malignancy (p = 0.017). These variables remain independent risk factors for trunk cellulitis after multivariate regression analysis. There is a trend toward more surgical interventions in the study group [6 (8%) patients vs. 1 (1%) with leg cellulitis, p = 0.116], and a longer hospital stay (5.8 days in the study group vs. 4.3 days in the control group, p = 0.025). Laboratory data are similar in both groups. There are risk factors for trunk cellulitis compared to lower limb cellulitis. However, diagnostic and therapeutic approaches are similar, except for a trend for more surgical interventions.