Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors.

Heterozygous activin receptor-like kinase 1 (ALK1) mutations are associated with two vascular diseases: hereditary hemorrhagic telangiectasia (HHT) and more rarely pulmonary arterial hypertension (PAH). Here, we aimed to understand the impact of ALK1 mutations on BMP9 and BMP10 transcriptomic responses in endothelial cells. Endothelial colony-forming cells (ECFCs) and microvascular endothelial cells (HMVECs) carrying loss of function ALK1 mutations were isolated from newborn HHT and adult PAH donors, respectively. RNA-sequencing was performed on each type of cells compared to controls following an 18 h stimulation with BMP9 or BMP10. In control ECFCs, BMP9 and BMP10 stimulations induced similar transcriptomic responses with around 800 differentially expressed genes (DEGs). ALK1-mutated ECFCs unexpectedly revealed highly similar transcriptomic profiles to controls, both at the baseline and upon stimulation, and normal activation of Smad1/5 that could not be explained by a compensation in cell-surface ALK1 level. Conversely, PAH HMVECs revealed strong transcriptional dysregulations compared to controls with > 1200 DEGs at the baseline. Consequently, because our study involved two variables, ALK1 genotype and BMP stimulation, we performed two-factor differential expression analysis and identified 44 BMP9-dysregulated genes in mutated HMVECs, but none in ECFCs. Yet, the impaired regulation of at least one hit, namely lunatic fringe (LFNG), was validated by RT-qPCR in three different ALK1-mutated endothelial models. In conclusion, ALK1 heterozygosity only modified the BMP9/BMP10 regulation of few genes, including LFNG involved in NOTCH signaling. Future studies will uncover whether dysregulations in such hits are enough to promote HHT/PAH pathogenesis, making them potential therapeutic targets, or if second hits are necessary.

[Reversible posterior encephalopathy syndrome and cardiomyopathy after bevacizumab therapy]. / Syndrome d'encéphalopathie postérieure et atteinte cardiaque réversibles sous bévacizumab.

INTRODUCTION: Bevacizumab is an antibody directed against VEGF-A. It is approved for the treatment of many cancer diseases. Its side effects are currently not well known by physicians. CASE REPORT: A 70-year-old female with metastatic colonic adenocarcinoma was admitted in the intensive care unit because of a coma, four days after having received a combined monthly chemotherapy containing bevacizumab, oxaliplatine, 5 fluorouracil, and folinic acid for the fourth time. On clinical examination, she presented with lower limbs spasticity and hypertension. Etiologic investigations, including cerebral tomodensitometry, cerebrospinal fluid examination, psychotropic drugs urinary testing, and electroencephalogram, were negative. Consciousness improved without any other treatment than nicardipine and urapidil, but the patient was initially confused. Cerebral magnetic resonance imaging showed changes suggestive of posterior reversible encephalopathy syndrome, but also involving frontal lobes. There were additional biological and echocardiographic changes suggestive of cardiac involvement. The patient recovered completely of both cardiac and neurologic manifestations 10 days later. CONCLUSION: Physicians should be aware of cardiovascular adverse effects of bevacizumab. High blood pressure must be treated to avoid more severe complications. When a posterior reversible encephalopathy syndrome occurs, cardiac involvement should be investigated.

Long-term outcome in idiopathic granulomatous mastitis: a western multicentre study.

AIM: To investigate the presentation, disease course and long-term outcome of a western cohort of idiopathic granulomatous mastitis (IGM) and to analyse the impact of different therapeutic strategies. METHODS: Multicentre retrospective study of 23 women followed over an extended period. Patients were recruited in nine French internal medicine departments. RESULTS: The median follow-up was 6 years. IGM presented commonly as a single inflammatory unilateral extra-areolar lump of varying size. Clinical course was heterogeneous and frequently remitting/relapsing. Most patients had at least one recurrence (18/23, 78%). The mean number of recurrences was 1.3 ± 1.5. Seven women had a bilateral evolution. Twelve women received steroids (corticosteroids). Only two of these did not respond to corticosteroids, whereas six relapsed when dose was tapered off. Nine patients received colchicine and/or hydroxychloroquine. First-line treatment consisted of excisional surgery in eight cases. At the date of last interview, 91% of the patients declared to be healed, 15 being free of treatment. However, 12/21 (57%) reported significant sequelae (unsightly scars: eight and/or lasting pain: six). Unsightly scars were not more prevalent in patients who had received steroids whereas they tended to be more frequent after breast excisional surgery. In addition, we found that excisional surgery did not prevent recurrences more successfully than a conservative approach. CONCLUSIONS: Despite its retrospective nature, this Caucasian series provides novel information regarding long-term outcomes in IGM and argues in favour of conservative approaches. The value of immunomodulatory drugs such as colchicine or hydroxychloroquine deserves further investigation.

[Pulmonary hypertension due to tumor embolism]. / Hypertension artérielle pulmonaire par embolisation de cellules tumorales.

We report a 46-year-old woman with a metastatic breast cancer who developed a subacute pulmonary hypertension. The final diagnosis was microscopic pulmonary neoplastic emboli. She presented with the typical clinical picture of a pulmonary hypertension with a normal pulmonary angiographic computer tomography and multiple sub-segmental perfusion defects on radionuclide imaging. This serious condition must be known by physicians, because of an opportunity to obtain the diagnosis by the cytologic analysis of sampled microvascular blood obtained with a pulmonary artery catheterization. The prognosis is poor and there is no efficient therapy.