Intracranial hemorrhage with direct oral anticoagulants in patients with brain tumors.

Essentials Intracranial hemorrhage (ICH) is common in patients with brain tumors. We compared rates of ICH with DOACs and low molecular weight heparin. DOACs were associated with a lower incidence of ICH in primary brain tumors. DOACs appear safe to administer to patients with brain tumors. SUMMARY: Background Direct oral anticoagulants (DOACs) are efficacious in the treatment of cancer-associated thrombosis but are associated with an increased risk of hemorrhage compared with low-molecular-weight heparin in certain malignancies. Whether the DOACs increase the incidence of intracranial hemorrhage (ICH) in patients with brain tumors is not established. Objectives To determine the cumulative incidence of ICH in DOACs compared with Low-molecular-weight heparin (LMWH) in patients with brain tumors and venous thromboembolism. Patients and methods A retrospective comparative cohort study was performed. Radiographic images for all ICH events were reviewed and the primary endpoint was cumulative incidence of ICH at 12 months following initiation of anticoagulation. Results and conclusions A total of 172 patients with brain tumors were evaluated (42 DOAC and 131 LMWH). In the primary brain tumor cohort (n = 67), the cumulative incidence of any ICH was 0% in patients receiving DOACs vs. 36.8% (95% confidence interval [CI], 22.3-51.3%) in those treated with LMWH, with a major ICH incidence of 18.2% (95% CI, 8.4-31.0). In the brain metastases cohort (n = 105), DOACs did not increase the risk of any ICH relative to enoxaparin, with an incidence of 27.8% (95% CI, 5.5-56.7%) compared with 52.9% (95% CI, 37.4-66.2%). Similarly, DOAC did not increase the incidence of major ICH in brain metastases, with a cumulative incidence 11.1% (95% CI, 0.5-40.6%) vs. 17.8% (95% CI, 10.2-27.2%). We conclude that DOACs are not associated with an increased incidence of ICH relative to LMWH in patients with brain metastases or primary brain tumors.

Prestorage universal WBC reduction of RBC units does not affect the incidence of transfusion reactions.

BACKGROUND: Febrile nonhemolytic transfusion reaction (FNHTR) has been identified as a pivotal reason for prestorage universal WBC reduction. A regional blood center implemented universal prestorage WBC reduction for RBCs on January 1, 2000. Whether prestorage universal WBC reduction of RBC units will affect FNHTR is not known. STUDY DESIGN AND METHODS: All reports of RBC transfusion reactions at Barnes-Jewish Hospital submitted for evaluation to the blood bank, before and after the implementation of WBC reduction of RBCs, were retrospectively evaluated. RESULTS: For the 36,303 allogeneic RBC transfusions administered in 1999, 85 reactions (0.23%) were reported. These reactions were classified as FNHTR in 43 cases, allergic in 13, delayed hemolytic in 19, and miscellaneous in 10. For the 31,543 non-WBC-reduced RBC transfusions performed in 1999, 78 reactions (0.25%) were reported. These reactions were classified as FNHTR in 39 cases, allergic in 13, delayed hemolytic in 19, and miscellaneous in 7. In the first half of 2000, 32 reactions (0.20%) were reported for 16,093 prestorage WBC-reduced RBC transfusions (p = 0.41). There were 13 FNHTRs and 10 allergic, 7 delayed hemolytic, and 2 miscellaneous reactions. The use of prestorage WBC-reduced RBCs did not significantly affect the rate of reactions classified as allergic (0.04% in 1999; 0.06% in 2000; p = 0.43) or as FNHTR (0.12% in 1999; 0.08% in 2000; p = 0.33). For all patients, universal WBC reduction in 2000 did not reduce the rate of FNHTR from the rate seen with selective bedside WBC reduction, the practice used in 1999 (0.12% in 1999; 0.08% in 2000; p = 0.36). CONCLUSION: No significant difference was found in the incidence of transfusion reactions in patients receiving prestorage WBC-reduced RBCs and non-WBC-reduced RBCs. In addition, no difference was found in transfusion reaction rates when periods of prestorage universal WBC reduction were compared to those of selective WBC reduction.

Tumor suppressor gene regulation of cell growth: recent insights into neurofibromatosis 1 and 2 gene function.

The development of cancer involves a myriad of genetic changes that impact on multiple processes important for the orderly regulation of cell growth and differentiation. Genes whose protein products are disrupted during neoplastic transformation are termed "tumor suppressor genes" (TSGs). Many of these TSGs are associated with familial cancer predisposition syndromes, in which affected individuals have an increased risk of certain malignancies. Studies on the mechanism of action for known TSGs have revealed three intracellular loci of critical importance: environmental sensing and signal initiation, signal propagation and transduction, and cell cycle control. The neurofibromatosis 1 and neurofibromatosis 2 genes are discussed as illustrative examples of tumor suppressors that function at the levels of signal transduction and environmental sensing, respectively.

A potent cell death activity associated with transient high level expression of BCL-2.

The BCL-2 proto-oncogene contains unusually long untranslated 5' and 3' sequences. Deletion of the sequences flanking the BCL-2 open reading frame dramatically increases the level of protein expression. Transient high level BCL-2 protein expression mediated by plasmid transfection or by infection with recombinant adenovirus results in potent apoptosis of several cell lines. Detailed mutational (deletion and add-back) analysis reveals that both 5'- and 3'-flanking sequences contribute to the negative modulation of protein expression from the BCL-2 open reading frame. It appears that these sequences exert the negative regulatory effect in an orientation-dependent manner. Analysis of BCL-2 RNA levels indicate that elevated levels of mRNA may be the primary cause of elevated levels of protein expression. Apoptosis induced by adenovirus vectors expressing elevated levels of BCL-2 can be readily inhibited by the caspase inhibitor z-VAD-fmk, suggesting that high levels of BCL-2 expression induce apoptosis via the caspase cascade. Mutational analysis of BCL-2 indicates that its pro-apoptotic activity is separable from its anti-apoptosis activity. Our results raise the possibility that oncogenic conversion of BCL-2 may require somatic mutations in the pro-apoptotic activity, in addition to other activating mutations that result in enhanced expression. Consistent with this hypothesis, a somatic mutation of BCL-2 observed in multiple human tumors results in reduced apoptosis activity.

Deletion of a nonconserved region of Bcl-2 confers a novel gain of function: suppression of apoptosis with concomitant cell proliferation.

The Bcl-2 protein coded by the proto-oncogene bcl-2 is expressed in a variety of embryonic and postnatal tissues and is overproduced in several types of tumours. Bcl-2 expression suppresses apoptosis induced by a multitude of stimuli in diverse cell types without exerting significant effects on cell proliferation, and is believed to contribute to oncogenesis by extending cell survival. In certain B-cell lymphomas, chromosomal translocations result in a gain of function of Bcl-2 by overexpression. Here, we report that a deletion of a nonconserved region of human Bcl-2 (residues 51-85) confers a novel gain of function that not only suppresses apoptosis induced by the tumor suppressor protein p53 and the Myc oncoprotein but also permits continued cell proliferation. Our result raises the possibility that mutations within the bcl-2 gene may contribute to oncogenesis by both suppressing apoptosis and facilitating cell proliferation.