Home Medicine Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature
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Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature

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Published/Copyright: April 9, 2021
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From the journal Open Medicine Volume 16 Issue 1

Abstract

Brain metastases (BMs) are the most common intracranial malignancy with poor prognosis. Patients with intracranial tumors are at greater risk for thrombotic complications and intracranial hemorrhage. Rivaroxaban is a potent oral anticoagulant with the high selectivity of direct factor Xa inhibition. The incidence and severity of rivaroxaban-triggered intratumoral hemorrhage (ITH) in patients with BMs remain unknown. A 57-year-old woman was diagnosed with multiple lung, bone, and BMs from unknown primary cancer origin, and refused any invasive procedures to confirm tumor pathology. However, this patient had a relatively favorable outcome after treating with cabozantinib, an inhibitor of multiple tyrosine kinases. The patient survived over 2 years and developed deep vein thrombosis of right lower limb. Oral rivaroxaban was prescribed, and the multifocal catastrophic ITH was encountered after 1 week. The last head computed tomography imaging revealed a rare but typical image of diffuse hemorrhagic metastases. Hemorrhagic-prone BMs, therapeutic rivaroxaban, and cabozantinib treatment increase risks to develop ITH. In this case rivaroxaban was the trigger to this terminal event. This case is a miserable lesson and keeps reminding us to stay vigilant in clinical practice even when there is a potential benefit for anticoagulation in such population.

Keywords: brain metastases; rivaroxaban; intratumoral hemorrhage; venous thromboembolism

1 Introduction

Metastatic brain tumor is the hallmark of disseminated end stage disease condition in patients with cancers. At this stage, patients are prone to venous thromboembolism (VTE) and intratumoral hemorrhage (ITH) [1,2,3]. The spontaneous hemorrhagic potential of brain metastases (BMs) contraindicates the routine use of anticoagulants for VTE treatment and prophylaxis. However, increasing evidence suggests no harm of therapeutic anticoagulants and guides the change in recommendation for patients with BMs [2,4,5,6,7,8]. In this study, we report that a patient with innumerable BMs from unknown primary site, previously treated with cabozantinib, developed concurrent multifocal intracerebral hemorrhage after acute treatment of deep vein thrombosis (DVT) by oral rivaroxaban. As far as our concern, the understanding of rivaroxaban-associated ITH is relatively limited in patients with BMs, and the unique clinical presentation of this case may contribute to further understanding of this situation. We provided the timeline for disease progression and reviewed literature for the possible risk factors (Figure 1a).

Figure 1 Timeline of major disease-related events and representative images of head imaging. (a) A schematic timeline displayed the major events during disease progression. (b) The initial head CT revealed extensive iso-dense and several hyperdense ill-defined masses. (c) CE-MRI identified diffuse T1 gadolinium-positive (T1 Gd+) lesions. Several high signals on T1 image indicated ITH, and typically hyperintense metastases were identified without significant mass effects. (d) There was negative finding on head CT imaging when the patient was diagnosed with DVT. (e) The last head CT showed diffuse open-ring or hollow circles of hyperintensities with sulci effacement, compatible with diffuse hemorrhagic metastases. The white arrow pointed to a same hemorrhagic metastasis.
Figure 1

Timeline of major disease-related events and representative images of head imaging. (a) A schematic timeline displayed the major events during disease progression. (b) The initial head CT revealed extensive iso-dense and several hyperdense ill-defined masses. (c) CE-MRI identified diffuse T1 gadolinium-positive (T1 Gd+) lesions. Several high signals on T1 image indicated ITH, and typically hyperintense metastases were identified without significant mass effects. (d) There was negative finding on head CT imaging when the patient was diagnosed with DVT. (e) The last head CT showed diffuse open-ring or hollow circles of hyperintensities with sulci effacement, compatible with diffuse hemorrhagic metastases. The white arrow pointed to a same hemorrhagic metastasis.

2 Case presentation

A 57-year-old woman was diagnosed with multiple lung, bone, and BMs from unknown primary cancer origin by a cancer center and refused any invasive procedures to confirm tumor pathology. No other medical history had been recorded. As a compromise, the patient agreed to receive a liquid biopsy, which confirmed a CCDC6-RET rearrangement in circulating tumor DNA. An oncologist recommended the regimen of whole brain radiotherapy (WBT) in combination with targeted therapy to control systemic disease progression. However, WBT was denied by the patient herself and family because of the concern of neurological complications in exposing to radiation, even though the probable survival benefit was repeatedly emphasized. Targeted therapy was the only acceptable therapeutic option, and the treatment began with cabozantinib, an oral inhibitor against the tyrosine kinase domain of CCDC6-RET fusion, at a dosage of 60 mg daily. The chief complaints of this patient were frequent fatigue, multiple bone pain, and occasional dizziness. No neurological deficits were found on the initial physical examination. After 17 months of medication, the patient visited our emergency room (ER) for the first time and presented with a 1-month history of gradual neurologic decline involving confusion, memory loss, and imbalance. A head computed tomography (CT) performed without the administration of contrast material revealed extensive iso-dense and several hyperdense ill-defined mass located supratentorially at the junction of gray and white matters. Only sporadic minor peritumoral edema and ITH or calcification were observed at the initial CT scan (Figure 1b). The patient was assigned to an observation room for subsequent contrast-enhanced magnetic resonance imaging (CE-MRI). After 3 days, a gadolinium-based CE-MRI was performed, and during this period, no further deterioration in clinical status was encountered. Contrasted MRI showed innumerable avid enhancements of the parenchymal metastases, which distribute across brain lobes, cerebrum, cerebellum, and brain stem. Sporadic hemorrhagic other than calcified metastases were confirmed on T1, which was indicated by intrinsic high signal (Figure 1c). Only mild peritumoral edema was identified on T2, and the use of mannitol or corticosteroids was suspended. As a concern of disease progression at the primary and metastatic sites, a tissue biopsy and WBT were recommended and again denied. The patient was then discharged in a week. After taking cabozantinib for 26 months, this patient was transferred to our ER in a coma with a Glasgow Coma Scale score of 3 (E1 V1 M1). This patient had a 7-day history of conscious decline and was found to be unresponsive for 2 h. Before 2 weeks, because of a swelling right lower limb for over 2 months, DVT was diagnosed at our department of vascular surgery by compression ultrasonography (CUS). The laboratory test revealed no coagulopathy, thrombocytopenia, or severe liver/renal dysfunction. The D-dimer level was 6,950 ng/mL (normal level: <500). A head CT was scheduled and no hemorrhagic BMs was identified (Figure 1d). Oral rivaroxaban was prescribed at an initial treatment dosing of 15 mg twice a day for 3 weeks. However, after anticoagulation with rivaroxaban for 7 days, this patient confronted with a declined consciousness and subsequent comatose, highly suspected to be the major bleeding complication of intracranial hemorrhage (ICH). Laboratory test revealed the D-dimer level was 3,620 ng/mL. The prothrombin time and international normalized ratio were slightly elevated, and platelet count was normal. The head CT scan confirmed the diagnosis and revealed the extensive but separate foci of intraparenchymal hemorrhage and general brain swelling (Figure 1e). Based on her previous history of extensive BMs, the open-ring or hollow circles of hyperintensities which occupied the majority of hemorrhagic sites were suspected to be hemorrhagic metastases. The patient developed dyspnea right after the CT scan. However, after discussions with the patient’s family, the goals of care were shifted toward comfort measures and no intubation was performed.

  1. Consent for publication: Written informed consent for publication of their clinical details and/or clinical images was obtained from the daughter of the patient. A copy of the consent form is available for review by the Editor of this journal.

  2. Ethics approval and consent to participate: The CARE guidelines were thoroughly followed to present this case.

3 Discussion

BMs are the most common intracranial tumors, and the incidence is estimated at least three times the number of newly diagnosed primary malignant brain tumors [9]. The most frequent primary sites for BMs are lung cancer, breast cancer, and melanoma, accounting for 67–80% of all cancers [10,11]. In patients with four or more BMs, incidence in patients was negatively correlated with the number of metastases, and only less than 5% of patients were diagnosed with 10 or more BMs [12]. With regard to this patient, countless number of BMs is a very rare performance and passive attitude to receive standard treatment could exacerbate the disease progression. CCDC6-RET rearrangement identified in circulating tumor DNA provided an acceptable option of cancer management, and the patient settled for targeted treatment. Cabozantinib inhibits tyrosine kinase activity of RET, MET, VEGFR1, etc. and is approved for the treatment of patients with progressive, metastatic medullary thyroid cancer, advanced renal cell carcinoma with/without history of anti-angiogenic therapy, and hepatocellular carcinoma [13,14]. Phase 3 clinical trials on cabozantinib have been conducted in various malignancies but not in primary or secondary brain tumor. Some sporadic reports showed the potential of cabozantinib in treating BMs. A brief report showed promising intracranial activity of cabozantinib in MET-positive lung cancer with BMs [15]. Another report indicated that cabozantinib was able to reach brain tumors and induce significant regression in two patients with radioresistant BMs from renal cell carcinoma [16]. Therefore, it is likely that this patient could benefit from cabozantinib treatment at the primary and metastatic tumors, though histopathology remains unknown.

Recent advances in chemotherapy and targeted therapies have significantly prolonged the life expectancy in patients with systemic malignancy, but in the meantime, the lifetime risks to develop BMs and cancer-associated comorbidities increase [17]. Patients with intracranial tumors are at greater risk for thrombotic complications and ICH, which accelerates the natural course to the end-of-life period. Significant ICH is reported to occur in 20–50% of patients with BMs [2]. Therefore BMs are considered to be a bleeding risk factor and excluded from most of the selected anticoagulant trials. Another leading cause of morbidity and mortality in this population is the thrombotic complications. Active cancer is a well-established risk factor for DVT and pulmonary embolism, collectively referred to as VTE. Thromboprophylaxis and remedy with anticoagulants may be offered by clinician to selected high-risk cancer patients who will inevitably suffer from a high rate of VTE recurrence and bleeding complications [4]. A meta-analysis focused on ICH in patients with brain tumors receiving therapeutic anticoagulation, and the conclusion is that no significantly increased risk of ICH in patients with BMs [7]. The safety of long-term anticoagulation in 125 patients with BMs has been reviewed by a retrospective study, and the result demonstrated that the incidence of ICH did not increase with the use of anticoagulant therapy [8]. A matched cohort study on ICH in patients with BMs treated with therapeutic enoxaparin concluded that therapeutic anticoagulation in such population did not increase the risk of ICH, but there was four-fold higher about the risk of ICH in patients with melanoma or renal cell carcinoma [2]. The American Society of Clinical Oncology recommends that intracranial malignancy or BMs should not be regarded as an absolute contraindication for therapeutic anticoagulation [6]. Rivaroxaban is a potent NOAC with the high selectivity of direct factor Xa inhibition, and it is recommended in cancer patients for prevention and treatment of VTE [18]. The EINSTEIN program demonstrated that a single drug, rivaroxaban, offered the benefit-to-risk profile of anticoagulation in the short-term and continued treatment of symptomatic venous thrombosis [19]. The CASSINI trial provided information regarding the non-superiority in lowering the incidence of VTE or death because of VTE in high-risk ambulatory patients with cancer. However, during the 180-day trial period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding [20]. As the aforementioned concern of anticoagulant-related intracranial bleeding, both trials exclude patients with BMs and whether these population with VTE could safely benefit from rivaroxaban treatment remains to be further investigated.

In our case, the patient received unexpected clinical benefit from cabozantinib treatment. The patient survived over 2 years until the presence of catastrophic ITH or ICH. Prior minor bleeding of BMs, therapeutic anticoagulation, and cabozantinib treatment were possible causes responsible for the eventual multifocal ICH of this patient. Up to 50% of patients with BMs suffered from spontaneous ICH [2], and the initial head CT/MRI imaging of this patient had revealed several minor intratumoral bleedings, indicating the high-risk hemorrhagic potential (Figure 1b and c). Prior hemorrhagic BMs is a relative contraindication in therapeutic anticoagulation, while the active major bleeding is a situation in which anticoagulation should not be given. Therefore after confirmation of DVT by CUS and significantly elevated D-dimer level, the patient received the second head CT and no trace of hemorrhage diminished the concern of hemorrhagic complication of therapeutic rivaroxaban (Figure 1d). Anticoagulant therapy with NOACs is a simple regimen for treating acute DVT without the need for repeated subcutaneous injection and laboratory monitoring. Increasing evidence supports the safety of NOACs in patients with BMs, without significant increase in the risk of ICH, but the risk of spontaneous ICH can reach as high as 50% in this population [2,7,8]. The exact incidence of rivaroxaban-associated ICH in patients with BMs is still unknown, and further clinical studies are required to ascertain whether the risk of harm associated with hemorrhagic complications exceeds the potential benefit from rivaroxaban. Compared with warfarin-associated ICH, relatively smaller volume of hemorrhage, less chance of hematoma expansion, and more favorable outcomes were found in rivaroxaban-associated ICH [21]. The hemorrhagic features of this patient, small ICH and no expansion of hematoma, shared the similar features of rivaroxaban-associated ICH, but the major difference was the unfavorable outcome. We suspected that the onset of ICH occurred within the first week of rivaroxaban treatment, and no special attention was paid to the neurological decline of the patient until the sudden loss of consciousness, which had been 2 weeks after the possible initial symptomatic ICH. This patient was transferred to our ER at a severe condition and received comfort measures after rapid disease exacerbation. Apart from the two major risk factors of hemorrhage, complication of cabozantinib regimen should not be ignored. The safety of cabozantinib has been evaluated by various clinical trials. However, 3–5% of patients receiving cabozantinib treatment are at risk of hemorrhagic events [13,14]. A phase 1 trial of cabozantinib in the newly diagnosed patients with high-grade gliomas reported that 31% of patients experienced the grade 3/4 adverse event of thrombocytopenia. One of the 26 recruited patients encountered with an adverse event of ICH but do not require surgical intervention [22]. In addition, cabozantinib and rivaroxaban are both substrates of CYP3A4 and P-gp, two important factors in drug metabolism [13,14,23]. It is unclear whether the coexistence of both drugs posts any impact on a single drug exposure, increasing the possibility of hemorrhagic complications. It is believed that the oral rivaroxaban may trigger the diffuse hemorrhagic transformation of BMs in this patient, and, to some extent, diffuse hemorrhage-prone BMs and cabozantinib treatment may also contribute to this malignant transformation.

Emerging evidence supports the use of therapeutic anticoagulants in patients with BMs. Because of the miserable prognosis of anticoagulant-associated ICH, more studies with a greater sample size should be performed to address concerns and guide decisions in clinical practice. Besides, sporadic case reports will also provide novel insights for patient stratification. Clinical characteristics on those patients with severe adverse events will help to identify stratification factors for absolute contraindications for anticoagulation. Therefore, it is recommended that clinicians should still be vigilant to balance the desirable and undesirable effects in this setting.

Abbreviations list

BMs

brain metastases

CE-MRI

contrast-enhanced magnetic resonance imaging

CT

computed tomography

CUS

compression ultrasonography

DVT

deep vein thrombosis

ER

emergency room

ICH

intracranial hemorrhage

ITH

intratumoral hemorrhage

NOACs

non-vitamin K oral anticoagulants

VTE

venous thromboembolism

WBT

whole brain radiotherapy

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  1. Funding information: Language editing, data analysis, literature collection, and figure organization were funded by Training Program for The Young Talents of The Fujian Health System (grant number 2017-ZQN-90) and The Natural Science Foundation of Fujian Province (grant number 2018J01399).

  2. Authors contribution: L. Y. C. and E. C. retrieved and analyzed patient data and imaging. L. Y. C. and Y. L. H. searched literatures and wrote the original draft. X. H. T. and L. Y. C. reviewed and edited the manuscript. Y. L. H. and X. H. T. made substantial contributions in data retrieval and data interpretation. All authors read and approved the final manuscript.

  3. Conflict of interest: The authors declare that the manuscript was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

  4. Availability of data and material: All data and images are available on demand to the corresponding author.

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Received: 2020-10-26
Revised: 2021-01-27
Accepted: 2021-03-01
Published Online: 2021-04-09

© 2021 Luyue Chen et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  102. Microvessel density as a prognostic indicator of prostate cancer: A systematic review and meta-analysis
  103. Characteristics of BCR–ABL gene variants in patients of chronic myeloid leukemia
  104. Knee alterations in rheumatoid arthritis: Comparison of US and MRI
  105. Long non-coding RNA TUG1 aggravates cerebral ischemia and reperfusion injury by sponging miR-493-3p/miR-410-3p
  106. lncRNA MALAT1 regulated ATAD2 to facilitate retinoblastoma progression via miR-655-3p
  107. Development and validation of a nomogram for predicting severity in patients with hemorrhagic fever with renal syndrome: A retrospective study
  108. Analysis of COVID-19 outbreak origin in China in 2019 using differentiation method for unusual epidemiological events
  109. Laparoscopic versus open major liver resection for hepatocellular carcinoma: A case-matched analysis of short- and long-term outcomes
  110. Travelers’ vaccines and their adverse events in Nara, Japan
  111. Association between Tfh and PGA in children with Henoch–Schönlein purpura
  112. Can exchange transfusion be replaced by double-LED phototherapy?
  113. circ_0005962 functions as an oncogene to aggravate NSCLC progression
  114. Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells
  115. Serum intact fibroblast growth factor 23 in healthy paediatric population
  116. Algorithm of rational approach to reconstruction in Fournier’s disease
  117. A meta-analysis of exosome in the treatment of spinal cord injury
  118. Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma
  119. Dexmedetomidine may decrease the bupivacaine toxicity to heart
  120. Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression
  121. Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p
  122. External fixation via the anterior inferior iliac spine for proximal femoral fractures in young patients
  123. miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12
  124. HAGLR promotes neuron differentiation through the miR-130a-3p-MeCP2 axis
  125. Phosphoglycerate mutase 2 is elevated in serum of patients with heart failure and correlates with the disease severity and patient’s prognosis
  126. Cell population data in identifying active tuberculosis and community-acquired pneumonia
  127. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression
  128. Mean platelet volume and red blood cell distribution width is associated with prognosis in premature neonates with sepsis
  129. 3D-printed porous scaffold promotes osteogenic differentiation of hADMSCs
  130. Association of gene polymorphisms with women urinary incontinence
  131. Influence of COVID-19 pandemic on stress levels of urologic patients
  132. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer
  133. miR-519d downregulates LEP expression to inhibit preeclampsia development
  134. Comparison of single- and triple-port VATS for lung cancer: A meta-analysis
  135. Fluorescent light energy modulates healing in skin grafted mouse model
  136. Silencing CDK6-AS1 inhibits LPS-induced inflammatory damage in HK-2 cells
  137. Predictive effect of DCE-MRI and DWI in brain metastases from NSCLC
  138. Severe postoperative hyperbilirubinemia in congenital heart disease
  139. Baicalin improves podocyte injury in rats with diabetic nephropathy by inhibiting PI3K/Akt/mTOR signaling pathway
  140. Clinical factors predicting ureteral stent failure in patients with external ureteral compression
  141. Novel H2S donor proglumide-ADT-OH protects HUVECs from ox-LDL-induced injury through NF-κB and JAK/SATA pathway
  142. Triple-Endobutton and clavicular hook: A propensity score matching analysis
  143. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis
  144. Serum exosomal miR-122-5p, GAS, and PGR in the non-invasive diagnosis of CAG
  145. miR-513b-5p inhibits the proliferation and promotes apoptosis of retinoblastoma cells by targeting TRIB1
  146. Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p
  147. The diagnostic and prognostic value of miR-92a in gastric cancer: A systematic review and meta-analysis
  148. Prognostic value of α2δ1 in hypopharyngeal carcinoma: A retrospective study
  149. No significant benefit of moderate-dose vitamin C on severe COVID-19 cases
  150. circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p
  151. Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions
  152. Educational program for orthopedic surgeons’ influences for osteoporosis
  153. Expression and function analysis of CRABP2 and FABP5, and their ratio in esophageal squamous cell carcinoma
  154. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells
  155. lncRNA-ZFAS1 promotes the progression of endometrial carcinoma by targeting miR-34b to regulate VEGFA expression
  156. Anticoagulation is the answer in treating noncritical COVID-19 patients
  157. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT
  158. Comparison of Dako HercepTest and Ventana PATHWAY anti-HER2 (4B5) tests and their correlation with silver in situ hybridization in lung adenocarcinoma
  159. VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway
  160. Comparison of vaginal birth outcomes in midwifery-led versus physician-led setting: A propensity score-matched analysis
  161. Treatment of osteoporosis with teriparatide: The Slovenian experience
  162. New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB
  163. Superenhancer–transcription factor regulatory network in malignant tumors
  164. β-Cell function is associated with osteosarcopenia in middle-aged and older nonobese patients with type 2 diabetes: A cross-sectional study
  165. Clinical features of atypical tuberculosis mimicking bacterial pneumonia
  166. Proteoglycan-depleted regions of annular injury promote nerve ingrowth in a rabbit disc degeneration model
  167. Effect of electromagnetic field on abortion: A systematic review and meta-analysis
  168. miR-150-5p affects AS plaque with ASMC proliferation and migration by STAT1
  169. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p
  170. Effects of remifentanil and propofol on distant organ lung injury in an ischemia–reperfusion model
  171. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway
  172. Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer
  173. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy
  174. Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
  175. circATP2A2 promotes osteosarcoma progression by upregulating MYH9
  176. Prognostic role of oxytocin receptor in colon adenocarcinoma
  177. Review Articles
  178. The function of non-coding RNAs in idiopathic pulmonary fibrosis
  179. Efficacy and safety of therapeutic plasma exchange in stiff person syndrome
  180. Role of cesarean section in the development of neonatal gut microbiota: A systematic review
  181. Small cell lung cancer transformation during antitumor therapies: A systematic review
  182. Research progress of gut microbiota and frailty syndrome
  183. Recommendations for outpatient activity in COVID-19 pandemic
  184. Rapid Communication
  185. Disparity in clinical characteristics between 2019 novel coronavirus pneumonia and leptospirosis
  186. Use of microspheres in embolization for unruptured renal angiomyolipomas
  187. COVID-19 cases with delayed absorption of lung lesion
  188. A triple combination of treatments on moderate COVID-19
  189. Social networks and eating disorders during the Covid-19 pandemic
  190. Letter
  191. COVID-19, WHO guidelines, pedagogy, and respite
  192. Inflammatory factors in alveolar lavage fluid from severe COVID-19 pneumonia: PCT and IL-6 in epithelial lining fluid
  193. COVID-19: Lessons from Norway tragedy must be considered in vaccine rollout planning in least developed/developing countries
  194. What is the role of plasma cell in the lamina propria of terminal ileum in Good’s syndrome patient?
  195. Case Report
  196. Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature
  197. CTU findings of duplex kidney in kidney: A rare duplicated renal malformation
  198. Synchronous primary malignancy of colon cancer and mantle cell lymphoma: A case report
  199. Sonazoid-enhanced ultrasonography and pathologic characters of CD68 positive cell in primary hepatic perivascular epithelioid cell tumors: A case report and literature review
  200. Persistent SARS-CoV-2-positive over 4 months in a COVID-19 patient with CHB
  201. Pulmonary parenchymal involvement caused by Tropheryma whipplei
  202. Mediastinal mixed germ cell tumor: A case report and literature review
  203. Ovarian female adnexal tumor of probable Wolffian origin – Case report
  204. Rare paratesticular aggressive angiomyxoma mimicking an epididymal tumor in an 82-year-old man: Case report
  205. Perimenopausal giant hydatidiform mole complicated with preeclampsia and hyperthyroidism: A case report and literature review
  206. Primary orbital ganglioneuroblastoma: A case report
  207. Primary aortic intimal sarcoma masquerading as intramural hematoma
  208. Sustained false-positive results for hepatitis A virus immunoglobulin M: A case report and literature review
  209. Peritoneal loose body presenting as a hepatic mass: A case report and review of the literature
  210. Chondroblastoma of mandibular condyle: Case report and literature review
  211. Trauma-induced complete pacemaker lead fracture 8 months prior to hospitalization: A case report
  212. Primary intradural extramedullary extraosseous Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (PIEES/PNET) of the thoracolumbar spine: A case report and literature review
  213. Computer-assisted preoperative planning of reduction of and osteosynthesis of scapular fracture: A case report
  214. High quality of 58-month life in lung cancer patient with brain metastases sequentially treated with gefitinib and osimertinib
  215. Rapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report
  216. Retrieval of intrarenal coiled and ruptured guidewire by retrograde intrarenal surgery: A case report and literature review
  217. Usage of intermingled skin allografts and autografts in a senior patient with major burn injury
  218. Retraction
  219. Retraction on “Dihydromyricetin attenuates inflammation through TLR4/NF-kappa B pathway”
  220. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part I
  221. An artificial immune system with bootstrap sampling for the diagnosis of recurrent endometrial cancers
  222. Breast cancer recurrence prediction with ensemble methods and cost-sensitive learning
https://doi.org/10.1515/med-2021-0261
Keywords for this article
brain metastases; rivaroxaban; intratumoral hemorrhage; venous thromboembolism
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Identification of ZG16B as a prognostic biomarker in breast cancer
  3. Behçet’s disease with latent Mycobacterium tuberculosis infection
  4. Erratum
  5. Erratum to “Suffering from Cerebral Small Vessel Disease with and without Metabolic Syndrome”
  6. Research Articles
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  8. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  9. Additional baricitinib loading dose improves clinical outcome in COVID-19
  10. The co-treatment of rosuvastatin with dapagliflozin synergistically inhibited apoptosis via activating the PI3K/AKt/mTOR signaling pathway in myocardial ischemia/reperfusion injury rats
  11. SLC12A8 plays a key role in bladder cancer progression and EMT
  12. LncRNA ATXN8OS enhances tamoxifen resistance in breast cancer
  13. Case Report
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  16. Research Articles
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  18. CircRNA circ_0004370 promotes cell proliferation, migration, and invasion and inhibits cell apoptosis of esophageal cancer via miR-1301-3p/COL1A1 axis
  19. LncRNA XIST regulates atherosclerosis progression in ox-LDL-induced HUVECs
  20. Potential role of IFN-γ and IL-5 in sepsis prediction of preterm neonates
  21. Rapid Communication
  22. COVID-19 vaccine: Call for employees in international transportation industries and international travelers as the first priority in global distribution
  23. Case Report
  24. Rare squamous cell carcinoma of the kidney with concurrent xanthogranulomatous pyelonephritis: A case report and review of the literature
  25. An infertile female delivered a baby after removal of primary renal carcinoid tumor
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  27. Hypertension, BMI, and cardiovascular and cerebrovascular diseases
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  33. Hepatoid adenocarcinoma of the lung: An analysis of the Surveillance, Epidemiology, and End Results (SEER) database
  34. Research Articles
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  38. The influence of smoking in minimally invasive spinal fusion surgery
  39. Impact of body mass index on left atrial dimension in HOCM patients
  40. Expression and clinical significance of CMTM1 in hepatocellular carcinoma
  41. miR-142-5p promotes cervical cancer progression by targeting LMX1A through Wnt/β-catenin pathway
  42. Comparison of multiple flatfoot indicators in 5–8-year-old children
  43. Early MRI imaging and follow-up study in cerebral amyloid angiopathy
  44. Intestinal fatty acid-binding protein as a biomarker for the diagnosis of strangulated intestinal obstruction: A meta-analysis
  45. miR-128-3p inhibits apoptosis and inflammation in LPS-induced sepsis by targeting TGFBR2
  46. Dynamic perfusion CT – A promising tool to diagnose pancreatic ductal adenocarcinoma
  47. Biomechanical evaluation of self-cinching stitch techniques in rotator cuff repair: The single-loop and double-loop knot stitches
  48. Review Articles
  49. The ambiguous role of mannose-binding lectin (MBL) in human immunity
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  51. Membranous nephropathy with pulmonary cryptococcosis with improved 1-year follow-up results: A case report
  52. Fertility problems in males carrying an inversion of chromosome 10
  53. Acute myeloid leukemia with leukemic pleural effusion and high levels of pleural adenosine deaminase: A case report and review of literature
  54. Metastatic renal Ewing’s sarcoma in adult woman: Case report and review of the literature
  55. Burkitt-like lymphoma with 11q aberration in a patient with AIDS and a patient without AIDS: Two cases reports and literature review
  56. Skull hemophilia pseudotumor: A case report
  57. Judicious use of low-dosage corticosteroids for non-severe COVID-19: A case report
  58. Adult-onset citrullinaemia type II with liver cirrhosis: A rare cause of hyperammonaemia
  59. Clinicopathologic features of Good’s syndrome: Two cases and literature review
  60. Fatal immune-related hepatitis with intrahepatic cholestasis and pneumonia associated with camrelizumab: A case report and literature review
  61. Research Articles
  62. Effects of hydroxyethyl starch and gelatin on the risk of acute kidney injury following orthotopic liver transplantation: A multicenter retrospective comparative clinical study
  63. Significance of nucleic acid positive anal swab in COVID-19 patients
  64. circAPLP2 promotes colorectal cancer progression by upregulating HELLS by targeting miR-335-5p
  65. Ratios between circulating myeloid cells and lymphocytes are associated with mortality in severe COVID-19 patients
  66. Risk factors of left atrial appendage thrombus in patients with non-valvular atrial fibrillation
  67. Clinical features of hypertensive patients with COVID-19 compared with a normotensive group: Single-center experience in China
  68. Surgical myocardial revascularization outcomes in Kawasaki disease: systematic review and meta-analysis
  69. Decreased chromobox homologue 7 expression is associated with epithelial–mesenchymal transition and poor prognosis in cervical cancer
  70. FGF16 regulated by miR-520b enhances the cell proliferation of lung cancer
  71. Platelet-rich fibrin: Basics of biological actions and protocol modifications
  72. Accurate diagnosis of prostate cancer using logistic regression
  73. miR-377 inhibition enhances the survival of trophoblast cells via upregulation of FNDC5 in gestational diabetes mellitus
  74. Prognostic significance of TRIM28 expression in patients with breast carcinoma
  75. Integrative bioinformatics analysis of KPNA2 in six major human cancers
  76. Exosomal-mediated transfer of OIP5-AS1 enhanced cell chemoresistance to trastuzumab in breast cancer via up-regulating HMGB3 by sponging miR-381-3p
  77. A four-lncRNA signature for predicting prognosis of recurrence patients with gastric cancer
  78. Knockdown of circ_0003204 alleviates oxidative low-density lipoprotein-induced human umbilical vein endothelial cells injury: Circulating RNAs could explain atherosclerosis disease progression
  79. Propofol postpones colorectal cancer development through circ_0026344/miR-645/Akt/mTOR signal pathway
  80. Knockdown of lncRNA TapSAKI alleviates LPS-induced injury in HK-2 cells through the miR-205/IRF3 pathway
  81. COVID-19 severity in relation to sociodemographics and vitamin D use
  82. Clinical analysis of 11 cases of nocardiosis
  83. Cis-regulatory elements in conserved non-coding sequences of nuclear receptor genes indicate for crosstalk between endocrine systems
  84. Four long noncoding RNAs act as biomarkers in lung adenocarcinoma
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  86. Relation between IL-8 level and obstructive sleep apnea syndrome
  87. circAGFG1 sponges miR-28-5p to promote non-small-cell lung cancer progression through modulating HIF-1α level
  88. Nomogram prediction model for renal anaemia in IgA nephropathy patients
  89. Effect of antibiotic use on the efficacy of nivolumab in the treatment of advanced/metastatic non-small cell lung cancer: A meta-analysis
  90. NDRG2 inhibition facilitates angiogenesis of hepatocellular carcinoma
  91. A nomogram for predicting metabolic steatohepatitis: The combination of NAMPT, RALGDS, GADD45B, FOSL2, RTP3, and RASD1
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  93. The value of miR-510 in the prognosis and development of colon cancer
  94. Functional implications of PABPC1 in the development of ovarian cancer
  95. Prognostic value of preoperative inflammation-based predictors in patients with bladder carcinoma after radical cystectomy
  96. Sublingual immunotherapy increases Treg/Th17 ratio in allergic rhinitis
  97. Prediction of improvement after anterior cruciate ligament reconstruction
  98. Effluent Osteopontin levels reflect the peritoneal solute transport rate
  99. circ_0038467 promotes PM2.5-induced bronchial epithelial cell dysfunction
  100. Significance of miR-141 and miR-340 in cervical squamous cell carcinoma
  101. Association between hair cortisol concentration and metabolic syndrome
  102. Microvessel density as a prognostic indicator of prostate cancer: A systematic review and meta-analysis
  103. Characteristics of BCR–ABL gene variants in patients of chronic myeloid leukemia
  104. Knee alterations in rheumatoid arthritis: Comparison of US and MRI
  105. Long non-coding RNA TUG1 aggravates cerebral ischemia and reperfusion injury by sponging miR-493-3p/miR-410-3p
  106. lncRNA MALAT1 regulated ATAD2 to facilitate retinoblastoma progression via miR-655-3p
  107. Development and validation of a nomogram for predicting severity in patients with hemorrhagic fever with renal syndrome: A retrospective study
  108. Analysis of COVID-19 outbreak origin in China in 2019 using differentiation method for unusual epidemiological events
  109. Laparoscopic versus open major liver resection for hepatocellular carcinoma: A case-matched analysis of short- and long-term outcomes
  110. Travelers’ vaccines and their adverse events in Nara, Japan
  111. Association between Tfh and PGA in children with Henoch–Schönlein purpura
  112. Can exchange transfusion be replaced by double-LED phototherapy?
  113. circ_0005962 functions as an oncogene to aggravate NSCLC progression
  114. Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells
  115. Serum intact fibroblast growth factor 23 in healthy paediatric population
  116. Algorithm of rational approach to reconstruction in Fournier’s disease
  117. A meta-analysis of exosome in the treatment of spinal cord injury
  118. Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma
  119. Dexmedetomidine may decrease the bupivacaine toxicity to heart
  120. Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression
  121. Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p
  122. External fixation via the anterior inferior iliac spine for proximal femoral fractures in young patients
  123. miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12
  124. HAGLR promotes neuron differentiation through the miR-130a-3p-MeCP2 axis
  125. Phosphoglycerate mutase 2 is elevated in serum of patients with heart failure and correlates with the disease severity and patient’s prognosis
  126. Cell population data in identifying active tuberculosis and community-acquired pneumonia
  127. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression
  128. Mean platelet volume and red blood cell distribution width is associated with prognosis in premature neonates with sepsis
  129. 3D-printed porous scaffold promotes osteogenic differentiation of hADMSCs
  130. Association of gene polymorphisms with women urinary incontinence
  131. Influence of COVID-19 pandemic on stress levels of urologic patients
  132. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer
  133. miR-519d downregulates LEP expression to inhibit preeclampsia development
  134. Comparison of single- and triple-port VATS for lung cancer: A meta-analysis
  135. Fluorescent light energy modulates healing in skin grafted mouse model
  136. Silencing CDK6-AS1 inhibits LPS-induced inflammatory damage in HK-2 cells
  137. Predictive effect of DCE-MRI and DWI in brain metastases from NSCLC
  138. Severe postoperative hyperbilirubinemia in congenital heart disease
  139. Baicalin improves podocyte injury in rats with diabetic nephropathy by inhibiting PI3K/Akt/mTOR signaling pathway
  140. Clinical factors predicting ureteral stent failure in patients with external ureteral compression
  141. Novel H2S donor proglumide-ADT-OH protects HUVECs from ox-LDL-induced injury through NF-κB and JAK/SATA pathway
  142. Triple-Endobutton and clavicular hook: A propensity score matching analysis
  143. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis
  144. Serum exosomal miR-122-5p, GAS, and PGR in the non-invasive diagnosis of CAG
  145. miR-513b-5p inhibits the proliferation and promotes apoptosis of retinoblastoma cells by targeting TRIB1
  146. Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p
  147. The diagnostic and prognostic value of miR-92a in gastric cancer: A systematic review and meta-analysis
  148. Prognostic value of α2δ1 in hypopharyngeal carcinoma: A retrospective study
  149. No significant benefit of moderate-dose vitamin C on severe COVID-19 cases
  150. circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p
  151. Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions
  152. Educational program for orthopedic surgeons’ influences for osteoporosis
  153. Expression and function analysis of CRABP2 and FABP5, and their ratio in esophageal squamous cell carcinoma
  154. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells
  155. lncRNA-ZFAS1 promotes the progression of endometrial carcinoma by targeting miR-34b to regulate VEGFA expression
  156. Anticoagulation is the answer in treating noncritical COVID-19 patients
  157. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT
  158. Comparison of Dako HercepTest and Ventana PATHWAY anti-HER2 (4B5) tests and their correlation with silver in situ hybridization in lung adenocarcinoma
  159. VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway
  160. Comparison of vaginal birth outcomes in midwifery-led versus physician-led setting: A propensity score-matched analysis
  161. Treatment of osteoporosis with teriparatide: The Slovenian experience
  162. New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB
  163. Superenhancer–transcription factor regulatory network in malignant tumors
  164. β-Cell function is associated with osteosarcopenia in middle-aged and older nonobese patients with type 2 diabetes: A cross-sectional study
  165. Clinical features of atypical tuberculosis mimicking bacterial pneumonia
  166. Proteoglycan-depleted regions of annular injury promote nerve ingrowth in a rabbit disc degeneration model
  167. Effect of electromagnetic field on abortion: A systematic review and meta-analysis
  168. miR-150-5p affects AS plaque with ASMC proliferation and migration by STAT1
  169. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p
  170. Effects of remifentanil and propofol on distant organ lung injury in an ischemia–reperfusion model
  171. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway
  172. Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer
  173. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy
  174. Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
  175. circATP2A2 promotes osteosarcoma progression by upregulating MYH9
  176. Prognostic role of oxytocin receptor in colon adenocarcinoma
  177. Review Articles
  178. The function of non-coding RNAs in idiopathic pulmonary fibrosis
  179. Efficacy and safety of therapeutic plasma exchange in stiff person syndrome
  180. Role of cesarean section in the development of neonatal gut microbiota: A systematic review
  181. Small cell lung cancer transformation during antitumor therapies: A systematic review
  182. Research progress of gut microbiota and frailty syndrome
  183. Recommendations for outpatient activity in COVID-19 pandemic
  184. Rapid Communication
  185. Disparity in clinical characteristics between 2019 novel coronavirus pneumonia and leptospirosis
  186. Use of microspheres in embolization for unruptured renal angiomyolipomas
  187. COVID-19 cases with delayed absorption of lung lesion
  188. A triple combination of treatments on moderate COVID-19
  189. Social networks and eating disorders during the Covid-19 pandemic
  190. Letter
  191. COVID-19, WHO guidelines, pedagogy, and respite
  192. Inflammatory factors in alveolar lavage fluid from severe COVID-19 pneumonia: PCT and IL-6 in epithelial lining fluid
  193. COVID-19: Lessons from Norway tragedy must be considered in vaccine rollout planning in least developed/developing countries
  194. What is the role of plasma cell in the lamina propria of terminal ileum in Good’s syndrome patient?
  195. Case Report
  196. Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature
  197. CTU findings of duplex kidney in kidney: A rare duplicated renal malformation
  198. Synchronous primary malignancy of colon cancer and mantle cell lymphoma: A case report
  199. Sonazoid-enhanced ultrasonography and pathologic characters of CD68 positive cell in primary hepatic perivascular epithelioid cell tumors: A case report and literature review
  200. Persistent SARS-CoV-2-positive over 4 months in a COVID-19 patient with CHB
  201. Pulmonary parenchymal involvement caused by Tropheryma whipplei
  202. Mediastinal mixed germ cell tumor: A case report and literature review
  203. Ovarian female adnexal tumor of probable Wolffian origin – Case report
  204. Rare paratesticular aggressive angiomyxoma mimicking an epididymal tumor in an 82-year-old man: Case report
  205. Perimenopausal giant hydatidiform mole complicated with preeclampsia and hyperthyroidism: A case report and literature review
  206. Primary orbital ganglioneuroblastoma: A case report
  207. Primary aortic intimal sarcoma masquerading as intramural hematoma
  208. Sustained false-positive results for hepatitis A virus immunoglobulin M: A case report and literature review
  209. Peritoneal loose body presenting as a hepatic mass: A case report and review of the literature
  210. Chondroblastoma of mandibular condyle: Case report and literature review
  211. Trauma-induced complete pacemaker lead fracture 8 months prior to hospitalization: A case report
  212. Primary intradural extramedullary extraosseous Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (PIEES/PNET) of the thoracolumbar spine: A case report and literature review
  213. Computer-assisted preoperative planning of reduction of and osteosynthesis of scapular fracture: A case report
  214. High quality of 58-month life in lung cancer patient with brain metastases sequentially treated with gefitinib and osimertinib
  215. Rapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report
  216. Retrieval of intrarenal coiled and ruptured guidewire by retrograde intrarenal surgery: A case report and literature review
  217. Usage of intermingled skin allografts and autografts in a senior patient with major burn injury
  218. Retraction
  219. Retraction on “Dihydromyricetin attenuates inflammation through TLR4/NF-kappa B pathway”
  220. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part I
  221. An artificial immune system with bootstrap sampling for the diagnosis of recurrent endometrial cancers
  222. Breast cancer recurrence prediction with ensemble methods and cost-sensitive learning
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