Qualification of a multiplexed tissue imaging assay and detection of novel patterns of HER2 heterogeneity in breast cancer.

Emerging data suggests that HER2 intratumoral heterogeneity (ITH) is associated with therapy resistance, highlighting the need for new strategies to assess HER2 ITH. A promising approach is leveraging multiplexed tissue analysis techniques such as cyclic immunofluorescence (CyCIF), which enable visualization and quantification of 10-60 antigens at single-cell resolution from individual tissue sections. In this study, we qualified a breast cancer-specific antibody panel, including HER2, ER, and PR, for multiplexed tissue imaging. We then compared the performance of these antibodies against established clinical standards using pixel-, cell- and tissue-level analyses, utilizing 866 tissue cores (representing 294 patients). To ensure reliability, the CyCIF antibodies were qualified against HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) data from the same samples. Our findings demonstrate the successful qualification of a breast cancer antibody panel for CyCIF, showing high concordance with established clinical antibodies. Subsequently, we employed the qualified antibodies, along with antibodies for CD45, CD68, PD-L1, p53, Ki67, pRB, and AR, to characterize 567 HER2+ invasive breast cancer samples from 189 patients. Through single-cell analysis, we identified four distinct cell clusters within HER2+ breast cancer exhibiting heterogeneous HER2 expression. Furthermore, these clusters displayed variations in ER, PR, p53, AR, and PD-L1 expression. To quantify the extent of heterogeneity, we calculated heterogeneity scores based on the diversity among these clusters. Our analysis revealed expression patterns that are relevant to breast cancer biology, with correlations to HER2 ITH and potential relevance to clinical outcomes.

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia.

ABSTRACT: CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/-VEN in combination. The recommended phase 2 dose of TAG was 12 µg/kg/day for 3 days, with 7-day AZA +/- 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643.

A randomized phase II study of metronomic cyclophosphamide and methotrexate (CM) with or without bevacizumab in patients with advanced breast cancer.

PURPOSE: Metronomic chemotherapy has the potential to offer tumor control with reduced toxicity when compared to standard dose chemotherapy in patients with metastatic breast cancer. As metronomic chemotherapy may target the tumor microvasculature, it has the potential for synergistic effects with antiangiogenic agents such as the VEGF-A inhibitor bevacizumab. METHODS: In this randomized phase II study, patients with metastatic breast cancer were randomized to receive metronomic oral cyclophosphamide and methotrexate (CM) combined with bevacizumab (Arm A) or CM alone (Arm B). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: A total of 55 patients were enrolled, with 34 patients treated on Arm A and 21 patients treated on Arm B. The ORR was modestly higher in Arm A (26%) than in Arm B (10%); neither met the 40% cutoff for further clinical evaluation. The median time to progression (TTP) was 5.52 months (3.22-13.6) on Arm A and 1.82 months (1.54-6.70) on Arm B (log-rank p = 0.008). The median OS was 29.6 months (17.2-NA) on Arm A and 16.2 months (15.7-NA) on Arm B (log-rank p = 0.7). Common all-grade adverse events in both arms included nausea, fatigue, and elevated AST. CONCLUSION: The combination of metronomic CM with bevacizumab significantly improved PFS over CM alone, although there was no significant difference in OS. Oral metronomic chemotherapy alone has limited activity in advanced breast cancer. CLINICALTRIALS: gov Identifier: NCT00083031. Date of Registration: May 17, 2004.

Influence of thrombocytopenia on bleeding and vascular events in atrial fibrillation.

Whether thrombocytopenia substantively increases the risk of hemorrhage associated with anticoagulation in patients with atrial fibrillation (AF) is not established. The purpose of this study was to compare rates of bleeding in patients with AF and thrombocytopenia (platelet count < 100 000/µL) to patients with AF and normal platelet counts (>150 000/µL). We performed a propensity score-matched, retrospective cohort study of adults (n = 1070) with a new diagnosis of AF who received a prescription for an oral anticoagulant between 2015 and 2020. The thrombocytopenia cohort was defined as having at least 2 platelet counts <100 000/µL on separate days in the period spanning the 12 weeks preceding the initiation of anticoagulation to 6 weeks after the initiation of anticoagulation. The primary end point was the 1-year cumulative incidence of major bleeding; secondary end points included clinically relevant bleeding, arterial and venous thrombotic events, and all-cause mortality. Patients with AF and thrombocytopenia experienced a higher 1-year cumulative incidence of major bleeding (13.3% vs 5.7%; P < .0001) and clinically relevant bleeding (24.5% vs 16.7%; P = .005) than the controls. Thrombocytopenia was identified as an independent risk factor for major bleeding (hazard ratio, 2.20; confidence interval, 1.36-3.58; P = .001), with increasing risk based on the severity of thrombocytopenia. The cumulative incidence of arterial thrombosis at 1 year was 3.6% in the group with thrombocytopenia and 1.5% in controls (Gray test, P = .08). These findings suggest that baseline platelet counts are an important biomarker for hemorrhagic outcomes in AF and that the degree of thrombocytopenia is an important factor in determining the level of risk.

Atmospheric deposition of microplastics in a rural region of North China Plain.

Microplastics (MPs) pollution is becoming one of the most pressing environmental issues globally. MPs in the marine, freshwater and terrestrial environments have been fairly well investigated. However, knowledge of the atmospheric-mediated deposition of MPs within rural environments is limited. Here, we present the results of bulk (dry and wet) atmospheric MPs deposition in a rural region of Quzhou County in the North China Plain (NCP). Samples of MPs in the atmospheric bulk deposition were collected for individual rainfall events over a 12-month period from August 2020 to August 2021. The number and size of MPs from 35 rainfall samples were measured by fluorescence microscopy, while the chemical composition of MPs was identified using micro-Fourier transform infrared spectroscopy (µ-FTIR). The results showed that the atmospheric MPs deposition rate in summer (892-75,421 particles/m2/day) was highest compared to 735-9428, 280-4244 and 86-1347 particles/m2/day in spring, autumn, and winter, respectively. Furthermore, the MPs deposition rates in our study were 1-2 orders of magnitude higher than those in other regions, indicating a higher rate of MPs deposition in the rural region of the NCP. MPs with a diameter of 3-50 µm accounted for 75.6 %, 78.4 %, 73.4 % and 66.1 % of total MPs deposition in spring, summer, autumn, and winter, respectively, showing that the majority of MPs in the current study were small in size. Rayon fibers accounted for the largest proportion (32 %) of all MPs, followed by polyethylene terephthalate (12 %) and polyethylene (8 %). This study also found that a significant positive correlation between rainfall volume and MPs deposition rate. In addition, HYSPLIT back-trajectory modelling showed that the farthest source of deposition MPs may have come from Russia.

Antiplatelet medications and intracranial hemorrhage in patients with primary brain tumors.

BACKGROUND: Spontaneous intracranial hemorrhage (ICH) is a frequent and severe consequence of primary brain tumors. The safety of antiplatelet medications in this patient population is undefined. OBJECTIVE: The primary objective was to determine whether antiplatelet medications are associated with an increased risk of ICH in patients with primary brain tumors. PATIENTS/METHODS: We performed a matched, retrospective cohort study of patients with the diagnosis of primary brain tumor treated at our institution between 2010 and 2021. Radiographic images of all potential ICH events underwent blinded review. The primary end point of the study was the cumulative incidence of ICH at 1 year after tumor diagnosis. RESULTS AND CONCLUSIONS: A total of 387 patients with primary brain tumors were included in the study population (130 exposed to antiplatelet agents, 257 not exposed). The most common malignancy was glioblastoma (n = 256, 66.1%). Among the intervention cohort, 119 patients received aspirin monotherapy. The cumulative incidence of any ICH at 1 year was 11.0% (95% CI, 5.3-16.6) in those receiving antiplatelet medications and 13.0% (95% CI, 8.5-17.6) in those not receiving antiplatelet medications (Gray test, p = 0.6). The cumulative incidence of major ICH was similar between the cohorts (3.3% in antiplatelet cohort vs 2.9% in control cohort, p = 1.0). This study did not identify an increased incidence of ICH in patients with primary brain tumors exposed to antiplatelet medications.

Persistence of Unequal Access to Classical Hematology Telemedicine Visits by Race and Other Demographics During the COVID-19 Pandemic.

Background: Unequal access to telemedicine services exacerbates health inequities and was evident at the start of the COVID-19 pandemic. We sought to explore whether unequal access persisted within a classical hematology division beyond the peak of COVID-19. Methods: Patient demographics by virtual visit type (telephone only [TO] or video only [VO]) between March 2020 and December 2021 were analyzed using adjusted odds ratio (aOR). Results: Of 8,207 patients, 18.4% had TO and 28.4% had VO visits. Fewer Black (21.8%; aOR 0.5 [0.4-0.62]), Hispanic or Latino (18.8%; 0.45 [0.34-0.59]), Spanish-speaking (7.6%; 0.32 [0.19-0.54]), high school (21.2%; 0.64 [0.52-0.78]), and older (24.2%) patients used VO compared with White (30.6%), English-speaking (29.5%), college (31%), postgraduate (34.9%), and younger (35.4%) patients. Conclusions: Groups that historically experience health inequities had fewer VO visits during and beyond the pandemic peak. Thus, there is a need to continue digital inclusion efforts to promote video access equity.

Absolute neutrophil count by Duffy status among healthy Black and African American adults.

Many people of African ancestry have lower absolute neutrophil counts (ANCs) without increased risk for infection. This is associated with the Duffy-null phenotype (nonexpression of the Duffy antigen on red blood cells), which is commonly found in those of African descent. Currently, there are no studies that compare the ANC of individuals with Duffy-null phenotype to those with Duffy non-null phenotypes within a self-identified Black population. The aim of this study was to assess the impact of Duffy status on ANCs based on complete blood counts with differential and Duffy testing in a healthy population of self-identified Black individuals at a single primary care center. This study found that 66.7% (80 of 120) of Black individuals have the Duffy-null phenotype and that there is a significant difference in ANCs between Duffy-null and Duffy non-null individuals (median, 2820 cells per µL vs 5005 cells per µL; P < .001). Additionally, 19 of 80 (23.8%) Duffy-null individuals had an ANC of <2000 cells per µL compared with no (0) Duffy non-null individuals. The Duffy-null phenotype is clinically insignificant; however, inappropriate reference ranges can propagate systemic racism. Therefore, we advocate for the development of Duffy-null-specific ANC reference ranges as well as replacing the term benign ethnic neutropenia with Duffy-nullassociated neutrophil count.

Pulmonary hypertension is associated with poor cardiovascular and hematologic outcomes in patients with myeloproliferative neoplasms and cardiovascular disease.

Cardiovascular events and hematologic progression to myelofibrosis or leukemia are leading causes of morbidity and mortality among patients with myeloproliferative neoplasms (MPN). Pulmonary hypertension (PH) is also associated with MPN and cardiovascular disease (CVD), though its prognostic significance in MPN is not well characterized. Our primary objective was to investigate the effect of PH, defined as right-ventricular systolic pressure (RVSP) ≥ 50 mmHg on echocardiogram or mean pulmonary artery pressure (mPAP) ≥ 20 on right heart catheterization, on cardiovascular and all-cause mortality and hematologic progression in patients with MPN and CVD (atrial fibrillation, heart failure hospitalization, and myocardial infarction after MPN diagnosis). Of the 197 patients included (86 ET, 80 PV, 31 PMF), 92 (47%) had PH and 98 (50%) were male. All-cause mortality (58 vs 37%, p = 0.004), cardiovascular death (35 vs 9%, p < 0.0001), and hematologic progression (23 vs 11%, p = 0.037) occurred more frequently in patients with PH. Multivariable competing-risk and proportional hazards regression showed that PH was associated with increased risk of all-cause death (adjusted hazard ratio [HR], 1.80, 95% CI 1.10-2.93), CV death (adjusted subdistribution HR 3.71, 95% CI 1.58-8.73), and hematologic progression (adjusted subdistribution HR 1.99, 95% CI 1.21-3.27).

Posttraumatic stress disorder and posttraumatic stress symptoms among adults with hemophilia A and B.

Background: Persons with hemophilia may encounter various traumatic experiences related to their bleeding disorder throughout their lifetime. Little is known about the clinical impact of disease-related trauma on this population. Objectives: To explore the prevalence of posttraumatic stress disorder (PTSD) and posttraumatic stress symptoms in adults with hemophilia A and B and characterize the traumatic experiences they report. Methods: An online survey tool collecting data on participant characteristics and a validated questionnaire containing the PTSD checklist for Diagnostic and Statistical Manual of Mental Disorders 5 were distributed via Research Electronic Data Capture to adults with hemophilia A and B during their annual visit to their hemophilia treatment center. Participants were asked about traumatic experiences specific to their hemophilia prior to self-administering the PTSD checklist for Diagnostic and Statistical Manual of Mental Disorders 5 questionnaire. Results: Survey responses from 178 individuals across 3 hemophilia treatment centers were included in the analysis, representing a 70% response rate. One hundred one (56.7%) participants identified a hemophilia-related traumatic event, and 21 (11.8%) participants met criteria for a provisional diagnosis of PTSD. Multivariable analysis showed higher odds of a positive PTSD screen in participants with noninfectious (odds ratio [OR], 13.89; 95% CI, 2.23-86.62) and infectious comorbidities (OR, 11.18; 95% CI, 1.34-93.45) and in participants with >1 mental health comorbidity (OR, 10.07; 95% CI, 2.39-42.52). On the contrary, age >46 years (OR, 0.6; 95% CI, 0.01-0.62) and higher education (OR, 0.25; 95% CI, 0.07-0.88) reduced odds of PTSD. Conclusion: Persons with hemophilia are at risk of developing PTSD and posttraumatic stress symptoms. These data support the need for trauma screening, psychosocial services in the bleeding disorders community, and provision of trauma-informed care by providers.

A nonrandomized phase I and biomarker trial of regorafenib in advanced myeloid malignancies.

We conducted a single-center, open-label, dose escalation, and expansion phase I trial of the antiangiogenic multikinase inhibitor regorafenib in patients with advanced myeloid neoplasms. We enrolled 16 patients with relapsed/refractory acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), or myelodysplastic syndrome (MDS). A 3 + 3 dose escalation design was used with two planned dose levels (120 or 160 mg daily) and one de-escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. The recommended phase two dose of regorafenib was 160 mg daily, with no dose-limiting toxicities. The best overall disease response by International Working Group criteria included one partial and stable disease in 11 patients. Tissue studies indicated no change in Ras/mitogen-activated protein kinase (MAPK) pathway activation in responders. Pharmacodynamic changes in plasma VEGF, PlGF, and sVEGFR2 were detected during treatment. Baseline proinflammatory and angiogenic cytokine levels were not associated with clinical response. Single-agent regorafenib demonstrated an acceptable safety profile in relapsed/refractory myeloid malignancy patients. Most patients achieved stable disease, with modest improvements in cell counts in some MDS patients. Biomarker studies were consistent with on-target effects of regorafenib on angiogenesis. Future studies should investigate the role of regorafenib in combination therapy approaches.

Effects of plastic residues and microplastics on soil ecosystems: A global meta-analysis.

Plastic pollution is one of the global pressing environmental problems, threatening the health of aquatic and terrestrial ecosystems. However, the influence of plastic residues and microplastics (MPs) in soil ecosystems remains unclear. We conducted a global meta-analysis to quantify the effect of plastic residues and MPs on indicators of global soil ecosystem functioning (i.e. soil physicochemical properties, plant and soil animal health, abundance and diversity of soil microorganisms). Concentrations of plastic residues and MPs were 1-2700 kg ha-1 and 0.01-600,000 mg kg-1, respectively, based on 6223 observations. Results show that plastic residues and MPs can decrease soil wetting front vertical and horizontal movement, dissolved organic carbon, and total nitrogen content of soil by 14%, 10%, 9%, and 7%, respectively. Plant height and root biomass were decreased by 13% and 14% in the presence of plastic residues and MPs, while the body mass and reproduction rate of soil animals decreased by 5% and 11%, respectively. However, soil enzyme activity increased by 7%441% in the presence of plastic residues and MPs. For soil microorganisms, plastic residues and MPs can change the abundance of several bacteria phyla and families, but the effects vary between different bacteria.

Outcomes after treatment of breast cancer during pregnancy including taxanes and/or granulocyte colony-stimulating factor use: findings from a multi-institutional retrospective analysis.

BACKGROUND: Guidelines support comparable treatment for women diagnosed with breast cancer during pregnancy (PrBC) and nonpregnant women with limited case-specific modifications to ensure maternal-fetal safety. Experience during pregnancy with modern agents, such as taxanes or granulocyte colony-stimulating factors (GCSF), is limited. PATIENTS AND METHODS: We retrospectively identified a multi-institutional cohort of PrBC between 1996 and 2020. Propensity score analyses with multiple imputation for missing variables were applied to determine the associations between chemotherapy exposures during pregnancy, with or without taxanes or GCSF, and a compound maternal-fetal outcome including spontaneous preterm birth, preterm premature rupture of membranes, chorioamnionitis, small for gestational age newborns, congenital malformation, or 5-min Apgar score < 7. RESULTS: Among 139 PrBC pregnancies, 82 (59.0%) were exposed to chemotherapy, including 26 (31.7%) to taxane and 18 (22.0%) to GCSF. Chemotherapy use, in general, and inclusion of taxane and/or GCSF, specifically, increased over time. Pregnancies resulting in live singleton births (n = 123) and exposed to chemotherapy were as likely to reach term as those that were not (59.5% vs. 63.6%, respectively, punadjusted = 0.85). Among women treated with chemotherapy, propensity score-matched odds ratios (OR) for the composite maternal-fetal outcome were not significantly increased with taxane (OR 1.24, 95% CI 0.27-5.72) or GCSF (OR 2.11, 95% confidence interval (CI) 0.48-9.22) with similar effects in multiple imputation and sensitivity models. CONCLUSION: The judicious increased use of taxane chemotherapy and/or growth factor support during pregnancy was not associated with unfavorable short-term maternal-fetal outcomes. While these findings are reassuring, case numbers remain limited and continued surveillance of these patients and progeny is warranted.

Antiplatelet medications and risk of intracranial hemorrhage in patients with metastatic brain tumors.

Although intracranial hemorrhage (ICH) is frequent in the setting of brain metastases, there are limited data on the influence of antiplatelet agents on the development of brain tumor-associated ICH. To evaluate whether the administration of antiplatelet agents increases the risk of ICH, we performed a matched cohort analysis of patients with metastatic brain tumors with blinded radiology review. The study population included 392 patients with metastatic brain tumors (134 received antiplatelet agents and 258 acted as controls). Non-small cell lung cancer was the most common malignancy in the cohort (74.0%), followed by small cell lung cancer (9.9%), melanoma (4.6%), and renal cell cancer (4.3%). Among those who received an antiplatelet agent, 86.6% received aspirin alone and 23.1% received therapeutic anticoagulation during the study period. The cumulative incidence of any ICH at 1 year was 19.3% (95% CI, 14.1-24.4) in patients not receiving antiplatelet agents compared with 22.5% (95% CI, 15.2-29.8; P = .22, Gray test) in those receiving antiplatelet agents. The cumulative incidence of major ICH was 5.4% (95% CI, 2.6-8.3) among controls compared with 5.5% (95% CI, 1.5-9.5; P = .80) in those exposed to antiplatelet agents. The combination of anticoagulation plus antiplatelet agents did not increase the risk of major ICH. The use of antiplatelet agents was not associated with an increase in the incidence, size, or severity of ICH in the setting of brain metastases.

Feasibility of an Online Patient Community to Support Older Women With Newly Diagnosed Breast Cancer.

BACKGROUND: We conducted a feasibility study of integrating a free, online patient health community, PatientsLikeMe (PLM), into the neo/adjuvant care of older patients recently diagnosed with breast cancer. We assessed whether PLM was an appealing social forum to improve women's treatment experience during this stressful and often isolating time. PATIENTS AND METHODS: We enrolled women ages ≥60 years with recently diagnosed nonmetastatic invasive breast cancer at a single center. Our primary endpoint was feasibility of patient engagement with PLM, with successful engagement defined as using PLM for ≥50% of the total weeks of one's chemotherapy course or 4 months (if receiving hormonal and/or radiation therapy). Participants were surveyed about their health, social support, and experiences. RESULTS: During February 8, 2016 to June 25, 2018, 47 women enrolled; 14.9% were ages 71 to 75 years and 8.5% were ages ≥76 years; 63.8% received chemotherapy. Two women withdrew after consent; 45 were included in analyses. Overall, 1 (2.2%) patient met the feasibility endpoint, although 8 (17.8%) met engagement criteria for ≥25% of weeks on study. Over time, women submitted a total of >1200 posts to the "InstantMe" feature (rates how they feel) and >130 "MyFeed" stories. Evaluation of satisfaction with PLM was limited by the small number of end-of-study surveys. CONCLUSION: Although our online social support intervention did not meet the prespecified criteria for feasibility (required sustained PLM utilization), many engaged with PLM. Future interventions should explore ways we can optimally support older patients, who have an increasing access to technology while facing threats of social isolation.

Practice patterns and outcomes of direct oral anticoagulant use in myeloproliferative neoplasm patients.

Myeloproliferative neoplasms (MPNs) are characterized by an increased risk of thrombosis and bleeding. Vitamin K antagonists (VKAs) are the historic anticoagulant recommended for use in MPNs. Direct oral anticoagulants (DOACs) are being increasingly used in general and cancer populations. However, DOAC safety and efficacy in MPN patients remains unclear. We characterized real-world practice patterns of DOAC use in MPN patients and evaluated thrombosis and bleeding risk. We conducted a retrospective cohort study of 133 MPN patients prescribed DOACs for venous thromboembolism (VTE), atrial fibrillation, or arterial thromboembolism (ATE). Practice patterns including duration of anticoagulation, dosing, and concomitant use of antiplatelet/cytoreductive agents, were heterogeneous among MPN patients. The 1-year cumulative incidence of thrombosis and bleeding on DOAC was 5.5% (1.5-9.5%) and 12.3% (6.4-18.2%) respectively. In comparison, reported bleeding rates in MPN patients on DOAC and VKAs are 1-3%. On multivariable analysis, prior history of thrombosis, use of dabigatran or edoxaban, and younger age were significantly associated with a higher risk of recurrent thrombosis, while leukocytosis was associated with a higher risk of bleeding on DOAC. The higher-than-expected bleeding rate found in our study indicates the continued need for rigorous evaluation of DOACs in this population.

Anticoagulation in cancer-associated thromboembolism with thrombocytopenia: a prospective, multicenter cohort study.

Venous thromboembolism (VTE) with concurrent thrombocytopenia is frequently encountered in patients with cancer. Therapeutic anticoagulation in the setting of thrombocytopenia is associated with a high risk of hemorrhage. Retrospective analyses suggest the utility of modified-dose anticoagulation in this population. To assess the incidence of hemorrhage or thrombosis according to anticoagulation strategy, we performed a prospective, multicenter, observational study. Patients with active malignancy, acute VTE, and concurrent thrombocytopenia (platelet count <100 000/µL) were enrolled. The cumulative incidences of hemorrhage or recurrent VTE were determined considering death as a competing risk. Primary outcomes were centrally adjudicated and comparisons made according to initial treatment with full-dose or modified-dose anticoagulation. A total of 121 patients were enrolled at 6 hospitals. Seventy-five patients were initially treated with full-dose anticoagulation (62%) and 33 (27%) with modified-dose anticoagulation; 13 (11%) patients received no anticoagulation. Most patients who received modified-dose anticoagulation had a hematologic malignancy (31 of 33 [94%]) and an acute deep vein thrombosis (28 of 33 [85%]). In patients who initially received full-dose anticoagulation, the cumulative incidence of major hemorrhage at 60 days was 12.8% (95% confidence interval [CI], 4.9-20.8) and 6.6% (95% CI, 2.4-15.7) in those who received modified-dose anticoagulation (Fine-Gray hazard ratio, 2.18; 95% CI, 1.21-3.93). The cumulative incidence of recurrent VTE at 60 days in patients who initially received full-dose anticoagulation was 5.6% (95% CI, 0.2-11) and 0% in patients who received modified-dose anticoagulation. In conclusion, modified-dose anticoagulation appears to be a safe alternative to therapeutic anticoagulation in patients with cancer who develop deep vein thrombosis in the setting of thrombocytopenia.

AC016405.3, a novel long noncoding RNA, acts as a tumor suppressor through modulation of TET2 by microRNA-19a-5p sponging in glioblastoma.

Long non-coding RNAs (lncRNAs) are crucial regulators in various malignancies including glioblastoma multiforme (GBM). In the present study, we screened out a new lncRNA, AC016405.3, through a previous genome-wide lncRNA microarray analysis in GBM. It showed that AC016405.3 was downregulated in GBM tissue specimens and cell lines, and it also illustrated that the downregulated AC016405.3 was closely correlated with several aggressive features of patients with GBM. Functionally, we found that overexpression of AC016405.3 suppressed GBM cells' proliferation and metastasis using a gain of function experiment. We further showed that microRNA (miR)-19a-5p, a carcinogenic miRNA, was a downstream miRNA of AC016405.3. AC016405.3 was revealed as a target of miR-19a-5p, and overexpression of miR-19a-5p reversed the inhibitive effect of AC016405.3 on GBM cell proliferation and metastasis. Furthermore, a novel downstream gene of miR-19a-5p, TET2, was identified through a constructed microarray analysis. We showed that TET2 was downregulated in GBM and was involved in miR-19a-5p-mediated proliferation and metastasis by directly being targeted. Finally, through a western blot assay and a series of functional CCK-8 and metastatic assays, we showed that AC016405.3 suppressed proliferation and metastasis through modulation of TET2 by sponging of miR-19a-5p in GBM cells. In summary, the findings of the current study identified a novel lncRNA and illustrated that AC016405.3, acting as an anti-oncogene, suppressed GBM cell proliferation and metastasis by regulating TET through miR-19a-5p sponging. Our present study might provide a new axis in the molecular treatment of GBM.

Trefoil factor 3 contributes to the malignancy of glioma via regulating HIF-1α.

Trefoil factor 3 (TFF3) plays significant roles in several solid tumors. However, the expression pattern and function of TFF3 in glioblastoma (GBM) have not been reported. Here, we report that expression level of TFF3 significantly elevated in glioma and correlated with the prognosis of glioma patients. Then we found TFF3 promotes proliferation, invasion, and migration and inhibits apoptosis of glioma cells in vitro, and delayed tumor progression in subcutaneous xenograft nude mice, and prolonged the median survival time in orthotopic xenograft mice. Moreover, knockdown of TFF3 reduced the expression of HIF-1α through a hypoxia-independent manner. These findings suggest that targeting TFF3 may offer a novel strategy for therapeutic intervention of malignant gliomas.