Recurrent glioblastoma treatment

Recurrent glioblastoma treatment

Less than 10% of recurrent gliomas recur away from the original tumor site 1).

Reoperation extends survival by an additional 36 weeks in patients with glioblastoma, and 88 weeks in anaplastic astrocytoma 2) 3) (duration of high quality survival was 10 weeks and 83 weeks, respectively, and was lower with pre-op Karnofsky score < 70). In addition to Karnofsky performance score, significant prognosticators for response to repeat surgery include: age and time from the first operation to reoperation (shorter times → worse prognosis) 4). Morbidity is higher with reoperation (5–18%); the infection rate is ≈ 3x that for first operation, wound dehiscence is more likely


The standard of care management for newly diagnosed GBM includes surgery, radiation, temozolomide (TMZ) chemotherapy, and tumor treating fields 5).

There is no consensus as to the standard of care as no therapeutic options have produced substantial survival benefit for recurrent glioblastomas (GBMs) 6) 7).

A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogression, pseudoresponse, or radionecrosis.

Based on parameters like localization and tumor volume, patient’s Karnofsky Performance Score, time from initial diagnosis, and availability of alternative salvage therapies, reoperation can be considered as a treatment option to extend the overall survival and quality of life of the patient.

The achieved extent of resection of the relapsed tumor—especially with the intention of having a safe, complete resection of the enhancing tumor—most likely plays a crucial role in the ultimate outcome and prognosis of the patient, regardless of other modes of treatment. Validated scores to predict the prognosis after reoperation of a patient with a recurrent glioblastoma can help to select suitable candidates for surgery. Safety issues and complication avoidance are pivotal to maximally preserve the patient’s quality of life. Besides a possible direct oncological effect, resampling of the recurrent tumor with detailed pathological and molecular analysis might have an impact on the development, testing, and validation of new salvage therapies 8).

Options

Options include repeat surgical resection, repeat fractionated radiation, radiosurgery.

Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy have been recommended to recurrent glioma.

Given the lack of consensus on optimal management of recurrent GBM, knowledge of care patterns used for these patients and the criteria used to determine therapeutic strategy is germane to clinicians who care for these patients.


In a study, Hundsberger et al investigated which treatments are currently being used for recurrent GBM within a single nation (Switzerland) and how clinicians are deciding to use them 9)

The authors surveyed Swiss hospitals with comprehensive multidisciplinary neuro-oncology practices (neurosurgery, radiation therapy, medical neuro-oncology, and a dedicated neuro-oncology tumor board) about treatment recommendations for recurrent GBM. They identified relevant clinical decision-making criteria, called diagnostic nodes or “dodes,” and compared treatment recommendations using a decision-tree format.

Eight hospitals participated. The most common treatment options for recurrent GBM were combination repeat surgical resection with temozolomide or bevacizumab, monotherapy temozolomide or bevacizumab, and best supportive care. Alternative therapies, including radiotherapy, were less common. Despite widespread disagreement between centers in clinical decision making, the decision-tree analysis found agreement (>63%) between most centers for only 4 specific clinical scenarios. Patients without an appropriate performance status were usually managed with best supportive care. Patients with rapid recurrence, nonresectable tumors, unmethylated O(6)-methylguanine DNA methyltransferase (MGMT) promoter, and high performance status were usually managed with bevacizumab. Patients with late recurrence, nonresectable tumors, overt clinical symptoms, methylated MGMT promoter, multifocal disease, and high performance status were usually managed with repeat temozolomide therapy. Patients with late recurrence, nonresectable tumors, no clinical symptoms, methylated MGMT promoter, tumor multifocality, and high performance status were usually managed with temozolomide.The findings of this study underscore the lack of effective first- and second-line treatments for GBM, and the interhospital variability in practice patterns is not surprising. It seems likely that similar heterogeneity would also be noted in a study of American neuro-oncology centers. It is interesting to note that despite the availability of an increasing number of molecular markers for GBM stratification, MGMT promoter methylation appears to be the only biological marker widely used across multiple centers in this study. It remains to be seen when and how broadly other markers such as the epidermal growth factor receptor variant III or isocitrate dehydrogenase mutations will be adopted for clinical decision making.The authors are to be congratulated for identifying core clinical decision-making criteria that may be useful in future studies of recurrent GBM. This decision tree is an excellent reference for clinical trial development, and several active clinical trials already target the dodes identified in this study. Subsequent studies may help to determine whether similar decision trees exist in American neuro-oncologic centers now or will exist in the future 10).

Figure. A through F, clinical decision-making tree for recurrent glioblastoma multiforme (GBM) based on clinical scenarios that achieved a majority recommendation (ie, at least 5 of 8 Swiss hospitals). BEV, bevacizumab; BSC, best supportive care; rGBM, recurrent glioblastoma multiforme; TMZ, temozolomide. Modified with kind permission from Springer Science+Business Media: Journal of Neuro-Oncology, Patterns of care in recurrent glioblastoma in Switzerland: a multicenter national approach based on diagnostic nodes (published online ahead of print October 12. 2015), Hundsberger T, Hottinger AF, Roelcke U, et al [doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0 ].

Resection

Temozolomide

Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation 11).

Bevacizumab

Intraarterial chemotharapy

Intrarterial chemotherapy is a viable methodology in recurrent GBM patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications 12).

Low-dose fractionated radiotherapy LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted 13).

Second surgery plus carmustine wafers followed by intravenous fotemustine

Second surgery plus carmustine wafers followed by intravenous fotemustine in twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia.

This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions 14).

Immunotherapy

The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent GBM. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation 15).

Laser induced interstitial thermotherapy

see Laser interstitial thermotherapy.

Galldiks et al monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent GBM using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent GBM before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value 16).

Outcome

A more favorable prognosis following surgery for recurrence or progression is associated with younger age, smaller tumor volume (~50%), motor speech-middle cerebral artery scoring and preoperative Karnofsky performance score (KPS) >80% 17) 18).

Reviews

Optimal treatment for recurrent high grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients.

In a analysis, of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence 19).

Case series

2018

Twenty patients with recurrent glioma were treated with BEV (5-10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20).

Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2-10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline.

BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma 20).

References

2016

Quick-Weller et al. performed tumour resections in seven patients with rGBM, combining 5-ALA (20 mg/kg bodyweight) with iMRI (0.15 T). Radiologically complete resections were intended in all seven patients.

They assessed intraoperative fluorescence findings and compared these with intraoperative imaging. All patients had early postoperative MRI (3 T) to verify final iMRI scans and received adjuvant treatment according to interdisciplinary tumour board decision.

Median patient age was 63 years. Median KPS score was 90, and median tumour volume was 8.2 cm(3). In six of seven patients (85%), 5-ALA induced fluorescence of tumour-tissue was detected intraoperatively. All tumours were good to visualise with iMRI and contrast media. One patient received additional resection of residual contrast enhancing tissue on intraoperative imaging, which did not show fluorescence. Radiologically complete resections according to early postoperative MRI were achieved in all patients. Median survival since second surgery was 7.6 months and overall survival since diagnosis was 27.8 months.

5-ALA and iMRI are important surgical tools to maximise tumour resection also in rGBM. However, not all rGBMs exhibit fluorescence after 5-ALA administration. They propose the combined use of 5-ALA and iMRI in the surgery of rGBM 21).

1)

Choucair AK, Levin VA, Gutin PH, et al. Development of Multiple Lesions During Radiation Therapy and Chemotherapy. J Neurosurg. 1986; 65:654–658
2)

Harsh GR, Levin VA, Gutin PH, et al. Reoperation for Recurrent Glioblastoma and Anaplastic Astrocytoma. Neurosurgery. 1987; 21:615–621
3)

Ammirati M, Galicich JH, Arbit E, et al. Reoperation in the Treatment of Recurrent Intracranial Malignant Gliomas. Neurosurgery. 1987; 21:607–614
4)

Brem H, Piantadosi S, Burger PC, et al. Placebo- Controlled Trial of Safety and Efficacy of Intraoperative Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gliomas. Lancet. 1995; 345:1008–1012
5)

Stupp R, Taillibert S, Kanner A et al (2017) Effect of tumortreating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318:2306–2316
6)

Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma–are we there yet? Neuro Oncol. 2013 Jan;15(1):4-27. doi: 10.1093/neuonc/nos273. Epub 2012 Nov 7. Review. PubMed PMID: 23136223; PubMed Central PMCID: PMC3534423.
7)

Lukas RV, Mrugala MM (2017) Pivotal trials for infiltrating gliomas and how they affect clinical practice. Neuro Oncol Pract 4:209–219
8)

Dejaegher J, De Vleeschouwer S. Recurring Glioblastoma: A Case for Reoperation? In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 14. Available from http://www.ncbi.nlm.nih.gov/books/NBK469991/ PubMed PMID: 29251867.
9)

Hundsberger T, Hottinger AF, Roelcke U, et al.. Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes [published online ahead of print October 12, 2015]. J Neuro Oncol. doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0.
10)

Zussman BM, Engh JA. Patterns of Care and Clinical Decision Making for Recurrent Glioblastoma Multiforme. Neurosurgery. 2016 Feb;78(2):N12-4. doi: 10.1227/01.neu.0000479889.72124.20. PubMed PMID: 26779791.
11)

Weller M, Tabatabai G, Kästner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bähr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Hüsing J, Reifenberger G, Wick W; DIRECTOR Study Group. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial. Clin Cancer Res. 2015 May 1;21(9):2057-64. doi: 10.1158/1078-0432.CCR-14-2737. Epub 2015 Feb 5. PubMed PMID: 25655102.
12)

Theodotou C, Shah AH, Hayes S, Bregy A, Johnson JN, Aziz-Sultan MA, Komotar RJ. The role of intra-arterial chemotherapy as an adjuvant treatment for glioblastoma. Br J Neurosurg. 2014 Jan 16. [Epub ahead of print] PubMed PMID: 24432794.
13)

Balducci M, Diletto B, Chiesa S, D’Agostino GR, Gambacorta MA, Ferro M, Colosimo C, Maira G, Anile C, Valentini V. Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma : Final report of a pilot study. Strahlenther Onkol. 2014 Jan 17. [Epub ahead of print] PubMed PMID: 24429479.
14)

Lombardi G, Della Puppa A, Zustovich F, Pambuku A, Farina P, Fiduccia P, Roma A, Zagonel V. The combination of carmustine wafers and fotemustine in recurrent glioblastoma patients: a monoinstitutional experience. Biomed Res Int. 2014;2014:678191. doi: 10.1155/2014/678191. Epub 2014 Apr 9. PubMed PMID: 24812626.
15)

Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, Butowski NA, Chang SM, Clarke JL, McDermott MW, Prados MD, Sloan AE, Bruce JN, Parsa AT. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 2013 Dec 12. [Epub ahead of print] PubMed PMID: 24335700.
16)

Galldiks N, von Tempelhoff W, Kahraman D, Kracht LW, Vollmar S, Fink GR, Schroeter M, Goldbrunner R, Schmidt M, Maarouf M. 11C-methionine positron emission tomographic imaging of biologic activity of a recurrent glioblastoma treated with stereotaxy-guided laser-induced interstitial thermotherapy. Mol Imaging. 2012 Jul-Aug;11(4):265-71. PubMed PMID: 22954142.
17)

Barbagallo GM, Jenkinson MD, Brodbelt AR. ‘Recurrent’ glioblastoma multiforme, when should we reoperate? Br J Neurosurg. 2008 Jun;22(3):452-5. doi: 10.1080/02688690802182256. Review. PubMed PMID: 18568742.
18)

Park JK, Hodges T, Arko L, Shen M, Dello Iacono D, McNabb A, Olsen Bailey N, Kreisl TN, Iwamoto FM, Sul J, Auh S, Park GE, Fine HA, Black PM. Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol. 2010 Aug 20;28(24):3838-43. doi: 10.1200/JCO.2010.30.0582. Epub 2010 Jul 19. PubMed PMID: 20644085; PubMed Central PMCID: PMC2940401.
19)

Hervey-Jumper SL, Berger MS. Reoperation for recurrent high-grade glioma: a current perspective of the literature. Neurosurgery. 2014 Nov;75(5):491-9; discussion 498-9. doi: 10.1227/NEU.0000000000000486. PubMed PMID: 24991712.
20)

Liu Y, Feng F, Ji P, Liu B, Ge S, Yang C, Lou M, Liu J, Li B, Gao G, Qu Y, Wang L. Improvement of health related quality of life in patients with recurrent glioma treated with bevacizumab plus daily temozolomide as the salvage therapy. Clin Neurol Neurosurg. 2018 Mar 27;169:64-70. doi: 10.1016/j.clineuro.2018.03.026. [Epub ahead of print] PubMed PMID: 29631109.
21)

Quick-Weller J, Lescher S, Forster MT, Konczalla J, Seifert V, Senft C. Combination of 5-ALA and iMRI in re-resection of recurrent glioblastoma. Br J Neurosurg. 2016 Jun;30(3):313-7. doi: 10.3109/02688697.2015.1119242. Epub 2016 Jan 8. PubMed PMID: 26743016.

Radiation necrosis treatment

Radiation necrosis treatment

Radiation necrosis (RN) will be increasingly encountered due to the widespread use of SRS. Symptomatic RN can cause significant morbidity and should be managed pro-actively. There is no single modality which can reliably distinguish RN from recurrent tumor, and a multi-modal approach is often required. For patients with symptomatic RN, oral corticosteroid therapy and bevacizumab are both effective. A minority of patients, with an unclear diagnosis, or refractory symptoms, will require surgical resection. As RN proves to be a challenging condition to diagnose and manage, risk factor mitigation becomes important in clinical decision making 1).


Using the internal database for pharmaceutical products, all patients who received BEV in the University of Munich were identified. Only patients who received BEV as symptomatic treatment for radiation necrosis were included. Patient characteristics, symptoms before, during, and after treatment, and the use of dexamethasone were evaluated using medical reports and systematic internal documentation. The symptoms were graded using CTCAE version 5.0 for general neurological symptoms. Symptoms were graded directly before each cycle and after the treatment (approximately 6 weeks). Additionally, the daily steroid dose was collected at these timepoints. Patients who either improved in symptoms, received less dexamethasone after treatment, or both were considered to have a benefit from the treatment.

Twenty-one patients who received BEV due to radiation necrosis were identified. For 10 patients (47.6%) symptoms improved and 11 patients (52.4%) remained clinically stable during the treatment. In 14 patients (66.7%) the dexamethasone dose could be reduced during therapy, 5 patients (23.8%) received the same dose of dexamethasone before and after the treatment, and 2 patients (9.5%) received a higher dose at the end of the treatment. According to this analysis, overall, 19 patients (90.5%) benefited from the treatment with BEV. No severe adverse effects were reported.

BEV might be an effective and safe therapeutic option for patients with radiation necrosis as a complication after cranial radiation therapy. Patients seem to benefit from this treatment by improving symptomatically or through reduction of dexamethasone 2).


Perez-Torres et al. validated the VEGF specificity by comparing the therapeutic efficacy of anti-VEGF with non-specific isotype control antibody. Additionally, they found that VEGF over-expression and radionecrosis developed simultaneously, which precludes preventative anti-VEGF treatment 3).

References

1)

Vellayappan B, Tan CL, Yong C, Khor LK, Koh WY, Yeo TT, Detsky J, Lo S, Sahgal A. Diagnosis and Management of Radiation Necrosis in Patients With Brain Metastases. Front Oncol. 2018 Sep 28;8:395. doi: 10.3389/fonc.2018.00395. eCollection 2018. Review. PubMed PMID: 30324090; PubMed Central PMCID: PMC6172328.
2)

Bodensohn R, Hadi I, Fleischmann DF, Corradini S, Thon N, Rauch J, Belka C, Niyazi M. Bevacizumab as a treatment option for radiation necrosis after cranial radiation therapy: a retrospective monocentric analysis. Strahlenther Onkol. 2019 Oct 4. doi: 10.1007/s00066-019-01521-x. [Epub ahead of print] PubMed PMID: 31586230.
3)

Perez-Torres CJ, Yuan L, Schmidt RE, Rich KM, Drzymala RE, Hallahan DE, Ackerman JJ, Garbow JR. Specificity of vascular endothelial growth factor treatment for radiation necrosis. Radiother Oncol. 2015 Sep 12. pii: S0167-8140(15)00462-4. doi: 10.1016/j.radonc.2015.09.004. [Epub ahead of print] PubMed PMID: 26376163.

Osler-Weber-Rendu syndrome treatment

Osler-Weber-Rendu syndrome treatment

Osler-Weber-Rendu syndrome treatment focuses on reducing bleeding from blood vessel lesions, and sometimes surgery or other targeted interventions to remove arteriovenous malformations in organs. Chronic bleeding often requires iron supplements and sometimes blood transfusions.

Surgery is indicated mainly for the evacuation of hematoma or diagnosis, especially when favorably located. Also, consider surgery for recurrent hemorrhages (rupture has been reported even after normal angiography) or medically intractable seizures. Stereotactic radiosurgery has not had a satisfactorily high enough benefit to risk ratio to justify its use 1).


The risk of treatment of brain AVMs in patients with Osler-Weber-Rendu syndrome is quite low for appropriately selected patients with treatment individualized to radiosurgerymicrosurgery, or a combination of embolization and microsurgery 2).


Currently, conventional heparin and warfarin remain first choice anticoagulants. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban 3).

References

1)

Lindquist C, Guo W-Y, Kerlsson B, Steiner L. Radiosurgery for Venous Angiomas. J Neurosurg. 1993; 78:531–536
2)

Woodall MN, Nakaji P, Spetzler RF. Benefits of Treating Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: A Retrospective Analysis of 14 Patients. World Neurosurg X. 2019 Mar 9;3:100029. doi: 10.1016/j.wnsx.2019.100029. eCollection 2019 Jul. PubMed PMID: 31225521; PubMed Central PMCID: PMC6584483.
3)

Shovlin CL, Millar CM, Droege F, Kjeldsen A, Manfredi G, Suppressa P, Ugolini S, Coote N, Fialla AD, Geisthoff U, Lenato GM, Mager HJ, Pagella F, Post MC, Sabbà C, Sure U, Torring PM, Dupuis-Girod S, Buscarini E; VASCERN-HHT. Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2019 Aug 28;14(1):210. doi: 10.1186/s13023-019-1179-1. PubMed PMID: 31462308; PubMed Central PMCID: PMC6714298.
WhatsApp WhatsApp us
%d bloggers like this: