Anticoagulation Versus Antiplatelets in Spontaneous Cervical Artery Dissection: A Systematic Review and Meta-Analysis.

BACKGROUND: It is uncertain whether antiplatelets or anticoagulants are more effective in preventing early recurrent stroke in patients with cervical artery dissection. Following the publication of the observational Antithrombotic for STOP-CAD (Stroke Prevention in Cervical Artery Dissection) study, which has more than doubled available data, we performed an updated systematic review and meta-analysis comparing antiplatelets versus anticoagulation in cervical artery dissection. METHODS: The systematic review was registered in PROSPERO (CRD42023468063). We searched 5 databases using a combination of keywords that encompass different antiplatelets and anticoagulants, as well as cervical artery dissection. We included relevant randomized trials and included observational studies of dissection unrelated to major trauma. Where studies were sufficiently similar, we performed meta-analyses for efficacy (ischemic stroke) and safety (major hemorrhage, symptomatic intracranial hemorrhage, and death) outcomes using relative risks. RESULTS: We identified 11 studies (2 randomized trials and 9 observational studies) that met the inclusion criteria. These included 5039 patients (30% [1512] treated with anticoagulation and 70% [3527]) treated with antiplatelets]. In meta-analysis, anticoagulation was associated with a lower ischemic stroke risk (relative risk, 0.63 [95% CI, 0.43 to 0.94]; P=0.02; I2=0%) but higher major bleeding risk (relative risk, 2.25 [95% CI, 1.07 to 4.72]; P=0.03, I2=0%). The risks of death and symptomatic intracranial hemorrhage were similar between the 2 treatments. Effect sizes were larger in randomized trials. There are insufficient data on the efficacy and safety of dual antiplatelet therapy or direct oral anticoagulants. CONCLUSIONS: In this study of patients with cervical artery dissection, anticoagulation was superior to antiplatelet therapy in reducing ischemic stroke but carried a higher major bleeding risk. This argues for an individualized therapeutic approach incorporating the net clinical benefit of ischemic stroke reduction and bleeding risks. Large randomized clinical trials are required to clarify optimal antithrombotic strategies for management of cervical artery dissection.

Direct Oral Anticoagulants Versus Vitamin K Antagonists in Cerebral Venous Thrombosis: A Systematic Review and Meta-Analysis.

BACKGROUND: High level evidence for direct oral anticoagulants (DOACs) in patients with cerebral venous thrombosis is lacking. We performed a systematic review and meta-analysis to assess the efficacy and safety of DOACs versus vitamin K antagonists in patients with cerebral venous thrombosis. METHODS: This systematic review was registered in PROSPERO (CRD42021228800). We searched MEDLINE (via Ovid), EMBASE, CINAHL, and the Web of Science Core Collection between January 1, 2007 and Feb 22, 2022. Search terms included a combination of keywords and controlled vocabulary terms for cerebral venous thrombosis, vitamin K antagonists/warfarin, and DOACs. We included both randomized and nonrandomized studies that compared vitamin K antagonists and DOACs in 5 or more patients with cerebral venous thrombosis. Where studies were sufficiently similar, we performed meta-analyses for efficacy (recurrent venous thromboembolism and complete recanalization) and safety (major hemorrhage) outcomes, using relative risks (RRs). RESULTS: Out of 10 665 records identified, we screened 254 as potentially eligible. Nineteen studies (16 observational studies [n=1735] and 3 randomized controlled trials [n=215]) met the inclusion criteria. All 3 randomized controlled trials had some concerns, and all 16 observational studies had at least moderate risk of bias. When compared with vitamin K antagonist treatment, DOAC had comparable risks of recurrent venous thromboembolism (relative risk [RR], 0.85 [95% CI, 0.52-1.37], I2=0%), major hemorrhage (RR, 0.70 [95% CI, 0.40-1.21], I2=0%), intracranial hemorrhage (RR, 0.58 [95% CI, 0.30-1.12]; I2=0%), death (RR, 1.14 [95% CI, 0.54-2.43], I2=1%), and complete venous recanalization (RR, 0.98 [95% CI, 0.87-1.11]; I2=0%). CONCLUSIONS: This systematic review and meta-analysis suggest that in patients with cerebral venous thrombosis, DOACs, and warfarin may have comparable efficacy and safety. Given the limitations of the studies included (low number of randomized controlled trials, modest total sample size, rare outcome events), our findings should be interpreted with caution pending confirmation by ongoing randomized controlled trials and large, prospective, observational studies.

Cerebral Vein Thrombosis With Vaccine-Induced Immune Thrombotic Thrombocytopenia.

In the spring of 2021, reports of rare and unusual venous thrombosis in association with the ChAdOx1 and Ad26.COV2.S adenovirus-based coronavirus vaccines led to a brief suspension of their use by several countries. Thromboses in the cerebral and splanchnic veins among patients vaccinated in the preceding 4 weeks were described in 17 patients out of 7.98 million recipients of the Ad26.COV2.S vaccine (with 3 fatalities related to cerebral vein thrombosis) and 169 cases of cerebral vein thrombosis among 35 million ChAdOx1 recipients. Events were associated with thrombocytopenia and anti-PF4 (antibodies directed against platelet factor 4), leading to the designation vaccine-induced immune thrombotic thrombocytopenia. Unlike the related heparin-induced thrombotic thrombocytopenia, with an estimated incidence of <1:1000 patients treated with heparin, and a mortality rate of 25%, vaccine-induced immune thrombotic thrombocytopenia has been reported in 1:150 000 ChAdOx1 recipients and 1:470 000 Ad26.COV.2 recipients, with a reported mortality rate of 20% to 30%. Early recognition of this complication should prompt testing for anti-PF4 antibodies and acute treatment targeting the autoimmune and prothrombotic processes. Intravenous immunoglobulin (1 g/kg for 2 days), consideration of plasma exchange, and nonheparin anticoagulation (argatroban, fondaparinux) are recommended. In cases of cerebral vein thrombosis, one should monitor for and treat the known complications of venous congestion as they would in patients without vaccine-induced immune thrombotic thrombocytopenia. Now that the Ad26.COV2.S has been reapproved for use in several countries, it remains a critical component of our pharmacological armamentarium in stopping the spread of the human coronavirus and should be strongly recommended to patients. At this time, the patient and community-level benefits of these two adenoviral vaccines vastly outweigh the rare but serious risks of vaccination. Due to the relatively low risk of severe coronavirus disease 2019 (COVID-19) in young women (<50 years), it is reasonable to recommend an alternative vaccine if one is available. Ongoing postmarketing observational studies are important for tracking new vaccine-induced immune thrombotic thrombocytopenia cases and other rare side effects of these emergent interventions.

Emerging protein kinase inhibitors for non-small cell lung cancer.

INTRODUCTION: In the current paradigm of precision medicine in non-small cell lung cancer (NSCLC), the therapeutic strategy is determined by the molecular characteristics. The best examples of this approach are the kinase inhibitors that selectively target tumors bearing an epidermal growth factor receptor (EGFR) mutation or an anaplastic lymphoma kinase (ALK) rearrangement. Emerging protein kinase inhibitors may enhance our ability to effectively treat these and other genomic subtypes of NSCLC. AREAS COVERED: This article reviews the next-generation kinase inhibitors targeting EGFR and ALK-positive NSCLC. In addition, targeted kinase inhibitors in clinical development for other specific molecular subtypes of NSCLC are covered, including ROS1, BRAF, RET, HER2, KRAS (upstream of the MEK kinase), MET, PIK3CA, FGFR1, DDR2, VEGFR and AAK. EXPERT OPINION: In EGFR-mutant NSCLC, there are several kinase inhibitors with promising activity, most notably dacomitinib and CO-1686 in tumors with acquired resistance to EGFR-targeted therapy. Next-generation ALK inhibitors appear to have greater potency than crizotinib and several ongoing trials may shed light on their role in both ALK- and ROS1-positive NSCLC. While there is optimism regarding the role of kinase inhibitors in other molecular subtypes, the available evidence is too immature to make recommendations and results from prospective trials are needed.

Non-umbilical cutaneous metastasis of a pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is one of the deadliest human malignancies with the majority of cases diagnosed late in the course of the disease. Cutaneous metastases originating from pancreatic cancer are rare. The most common site reported is the umbilicus. Non-umbilical cutaneous metastases are far less common with only a few cases reported in the literature. Our case involved a 43-year-old man with pancreatic carcinoma who was offered resection and a Whipple procedure was planned. Intraoperatively, the patient was found to have a widely metastatic disease not seen on preoperative imaging. Postoperatively, cutaneous metastasis in the scalp was discovered. Although rare, the recognition of non-umbilical cutaneous metastases of pancreatic adenocarcinoma can be of value because they can not only detect an underlying tumour but also guide management.

Loss of transforming growth factor ß adaptor protein ß-2 spectrin leads to delayed liver regeneration in mice.

UNLABELLED: Liver regeneration, following partial hepatectomy (PHx), occurs through precisely controlled and synchronized cell proliferation, in which quiescent hepatocytes undergo one to two rounds of replication, with restoration of liver mass and function. We previously demonstrated that loss of the Smad3/4 adaptor protein ß-2 spectrin (ß2SP) is associated with faster entry into S phase, and hepatocellular cancer formation. These observations led us to further pursue the role of ß2SP in cell cycle progression in vivo. Liver regeneration studies with PHx in ß2SP(+/-) mice reveal a surprising and significant decrease in liver/body weight ratio at 48 hours after PHx in ß2SP(+/-) mice in comparison to wildtype mice. At 48 hours after PHx we also observe decreased levels of cyclin E (2.4-fold, P < 0.05), Cdk1 (7.2-fold, P < 0.05), cyclin A, pRb (Ser249/Thr252), proliferative cell nuclear antigen (PCNA), cyclin D1 with elevated levels of pCdk1 (Thr14) (3.6-fold, P < 0.05). Strikingly, at 24 hours elevated levels of p53 (4-fold, P < 0.05), phospho-p53 (ser15 and ser20), and p21 (200-fold, P < 0.05) persisting to 48 hours after PHx further correlated with raised expression of the DNA damage markers pChk2 (Thr68) and γH2AX (S139). However, compromised cell cycle progression with loss of ß2SP is not rescued by inhibiting p53 function, and that G(2) /M phase arrest observed is independent and upstream of p53. CONCLUSION: ß2SP deficiency results in dysfunctional hepatocyte cell cycle progression and delayed liver regeneration at 48 hours after PHx, which is p53-independent. ß2SP loss may increase susceptibility to DNA damage, impair cell cycle progression, and ultimately lead to hepatocellular cancer.

Human tissue-resident stem cells combined with hyaluronic acid gel provide fibrovascular-integrated soft-tissue augmentation in a murine photoaged skin model.

BACKGROUND: Transplantation of adipose tissue-resident mesenchymal stem cells has been found to contribute to the establishment of a supportive fibrovascular network. The authors sought to evaluate the potential of human adipose tissue-derived stem cells to integrate with nonanimal stabilized hyaluronic acid as a novel injectable soft-tissue filler. METHODS: Cell proliferation was measured by bromodeoxyuridine incorporation. Interactions of adipose tissue-derived stem cells with hyaluronic acid were documented by scanning electron microscopy. The effect of this combination on procollagen mRNA was assessed by real-time polymerase chain reaction. The potential therapeutic effects were evaluated in an athymic murine photoaged skin model by histology and by high-resolution magnetic resonance imaging. Angiogenesis was assessed by microvessel density analysis. RESULTS: Under in vitro culture conditions, the authors found an equal proliferation capacity of adipose tissue-derived stem cells grown on hyaluronic acid versus controls. Scanning electron microscopy showed enhanced establishment of complex microvillous networks in adipose tissue-derived stem cells adherent to hyaluronic acid compared with controls. Adipose tissue-derived stem cells and hyaluronic acid induced a significant increase in procollagen 1-alpha-2 mRNA expression compared with controls. In an athymic murine photoaged skin model, injection of this combination ablated photoinduced skin wrinkles. Magnetic resonance imaging revealed a consistent and stable volume fill by adipose tissue-derived stem cells and nonanimal stabilized hyaluronic acid at 3 weeks. Adipose tissue-derived stem cells actively incorporated into the hyaluronic acid fill and showed an organized fibrovascular network at 3 weeks. CONCLUSION: The combination of adipose tissue-derived stem cells and nonanimal stabilized hyaluronic acid holds promise as a tool with which to achieve lasting volume fill in reconstructive surgical soft-tissue augmentation.

Colon cancer stem cells.

Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Aggressive research in the last decade has led to a wealth of information about this disease; for example, we now know that more than 80% of sporadic colon tumors contain mutations in the Wnt and TGFß signaling pathways. The latest avenue of research is revealing the existence of and role for the cancer stem cell (CSC) model, which promotes the idea that malignancies originate from a small fraction of cancer cells that show self-renewal and multi- or pluripotency. The model also endorses that CSCs are capable of initiating and sustaining tumor growth. The body of evidence in favor of the CSC model is rapidly growing and includes analyses from flow cytometry of numerous CSC biomarkers, abnormal signaling pathways, symmetric division, dietary augmentation, and analysis of the behavior of these cells in spheroid culture formation. Although the incidence of death from CRC remains high, fervent research, both basic and translational, is beginning to improve patient outcomes. This paper focuses on stem cell biology in the context of CRC to help understand the mechanisms leading to tumor development and therapy resistance, with possible therapeutic indications.