Safety, tolerability and pharmacokinetics of eteplirsen in young boys aged 6-48 months with Duchenne muscular dystrophy amenable to exon 51 skipping.

Eteplirsen is FDA-approved for the treatment of Duchenne muscular dystrophy (DMD) in exon 51 skip-amenable patients. Previous studies in boys > 4 years of age indicate eteplirsen is well tolerated and attenuates pulmonary and ambulatory decline compared with matched natural history cohorts. Here the safety, tolerability and pharmacokinetics of eteplirsen in boys aged 6-48 months is evaluated. In this open-label, multicenter, dose-escalation study (NCT03218995), boys with a confirmed mutation of the DMD gene amenable to exon 51 skipping (Cohort 1: aged 24-48 months, n = 9; Cohort 2: aged 6 to < 24 months, n = 6) received ascending doses (2, 4, 10, 20, 30 mg/kg) of once-weekly eteplirsen intravenously over 10 weeks, continuing at 30 mg/kg up to 96 weeks. Endpoints included safety (primary) and pharmacokinetics (secondary). All 15 participants completed the study. Eteplirsen was well tolerated with no treatment-related discontinuations, deaths or evidence of kidney toxicity. Most treatment-emergent adverse events were mild; most common were pyrexia, cough, nasopharyngitis, vomiting, and diarrhea. Eteplirsen pharmacokinetics were consistent between both cohorts and with previous clinical experience in boys with DMD > 4 years of age. These data support the safety and tolerability of eteplirsen at the approved 30-mg/kg dose in boys as young as 6 months old.

[Ileum and brain, unusual metastatic sites for a thymoma]. / Iléon et encéphale, des sites métastatiques inhabituels pour un thymome.

INTRODUCTION: Thymomas are epithelial neoplasms of thymic origin, preferentially localized in the anterior mediastinum. Recurrences after surgery are uncommon and usually occur in the intrathoracic area. The occurrence of extra-thoracic metastases is an unusual phenomenon. CASE REPORT: Here we report the case of a 61-year-old man with no special medical history. He smoked about 40 pack years but stopped in 1999. Initially he presented with a mediastinal thymoma and underwent surgical resection. One year later the development of abdominal pain and bowel disorders lead to the discovery of an ileal ulcero-necrotic tumour. After surgical resection, histological examination revealed secondary thymoma. A few months later he underwent cerebral MRI because of neurological symptoms. This revealed a second metastasis located in the brain. Stereotactic radiotherapy led to an improvement. After more than one year of follow-up the patient developed a papillary thyroid carcinoma but there were no signs of recurrence of the thymoma. CONCLUSIONS: Extra-thoracic metastases of thymoma are exceptional but their existence should not be overlooked. Their management is not standardised because of lack of data in the literature. Though surgical excision in oligo-metastatic subjects is a frequently reported therapeutic option, a radiotherapeutic approach, particularly in cerebral situations, could be a credible alternative.

Klippel-Trenaunay syndrome as a rare cause of chronic thromboemboembolic pulmonary hypertension.

Klippel-Trenaunay syndrome (KTS) is a congenital disorder characterized by cutaneous capillary malformations, soft tissue and bone hypertrophy, and multiple capillary, venous or lymphatic malformations. KTS is associated with recurrent thromboembolic events. We reported herein five cases of chronic thromboembolic pulmonary hypertension (CTEPH) associated with KTS (age minimum-maximum 26-50 years old, 3 males/2 females). Hemodynamics showed severe pulmonary hypertension (PH) with pulmonary vascular resistance ranging from 5.6 to 18.3 Wood units (WU), associated with marked clinical impairment (NYHA functional class III or IV in 4 patients). Computed tomography (CT) of the chest and pulmonary angiography confirmed proximal CTEPH accessible to surgical intervention in one patient and distal forms of CTEPH in 4 patients. Evolution after pulmonary endarterectomy showed hemodynamic normalization, while the patients with distal CTEPH had severe outcomes with 2 early deaths after PH diagnosis (44 and 35 months respectively). One patient with distal CTEPH was still alive 16 years after diagnosis on specific PH therapy and one was transplanted after 15 years because of right heart failure (death after 12 months). Histological analysis of the lung explants showed typical chronic thromboembolic material specific for CTEPH. In conclusion, KTS may be complicated by severe CTEPH requiring careful anticoagulation and multidisciplinary follow-up in expert centers to screen for disease potentially accessible to endarterectomy. In the modern management era of CTEPH, balloon pulmonary angioplasty will certainly be an interesting option in patients with inoperable disease.

Pulmonary complications of type 1 neurofibromatosis.

INTRODUCTION: Type 1 neurofibromatosis is one of the most common genetic diseases, with an incidence of 1/3500 live births. Its diagnosis primarily relies on the clinical features of the condition. CURRENT KNOWLEDGE: The life expectancy of these patients is reduced by 10 years, on average, compared to the general population. Type 1 neurofibromatosis has been shown to increase the risk of various types of neoplasia, primarily those affecting the neural crest. In addition, interstitial lung disease, lung cancer, and pulmonary hypertension have been observed during the third or the fourth decade of an adult's life. PERSPECTIVES: There are only few case reports available that address the pulmonary complications of neurofibromatosis type 1. It is thus crucial to fully understand this rare disease and its potential complications in order to allow for early diagnosis so we are able to improve the quality of life and survival of those suffering from the condition. CONCLUSIONS: The pulmonary complications of type 1 neurofibromatosis can be severe and life-threatening. Patients with this condition should thus undergo regular clinical visits and examinations to allow pulmonary complications to be detected and treatment to be initiated as early as possible.

Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension.

OBJECTIVE: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by obstruction of small pulmonary veins. Pulmonary venous involvement has been reported in pathologic assessment of patients with systemic sclerosis (SSc) presenting with precapillary PH. High-resolution computed tomography (HRCT) of the chest is a noninvasive diagnostic tool used to screen for PVOD. No HRCT data are available on SSc patients with precapillary PH. We undertook this study to evaluate the frequency and effect on prognosis of HRCT signs of PVOD in SSc patients with precapillary PH. METHODS: We reviewed chest HRCT data from 26 SSc patients with precapillary PH and 28 SSc patients without pulmonary arterial hypertension (PAH) or interstitial lung disease (ILD). RESULTS: The radiographic triad of HRCT signs of PVOD (lymph node enlargement [57.7% versus 3.6%], centrilobular ground-glass opacities [46.2% versus 10.7%], and septal lines [88.5% versus 7.1%]) was significantly more frequent in SSc patients with precapillary PH than in SSc patients without PAH or ILD (all P < 0.005). Indeed, 61.5% of SSc patients with precapillary PH had ≥ 2 of these signs. Cardiomegaly (P < 0.0001), pulmonary artery enlargement (P < 0.0001), and pericardial effusion (P < 0.0005) were also significantly more frequent in SSc patients with precapillary PH. Pulmonary venous involvement was histologically confirmed in 2 patients with radiographic signs of PVOD. The presence of ≥ 2 radiographic signs of PVOD was associated with the occurrence of pulmonary edema after initiation of PAH-specific therapy (in 8 of 16 patients) and with more rapid progression from diagnosis of PH to death. CONCLUSION: HRCT signs of PVOD are frequently observed in SSc patients with precapillary PH, correlated with histologic assessment, and were associated with a high risk of pulmonary edema.

Current management approaches to portopulmonary hypertension.

Portopulmonary hypertension (PoPH) is a rare but life-threatening complication of portal hypertension that is characterised by proliferative changes in the pulmonary microvasculature indistinguishable from other forms of pulmonary arterial hypertension (PAH). Although PoPH is most commonly observed in the setting of cirrhosis, patients with non-cirrhotic portal hypertension are also at risk of developing the disorder. A definitive diagnosis requires invasive haemodynamic confirmation by right heart catheterisation and screening for PoPH should be routinely performed in all patients being considered for liver transplantation. Although severe PoPH is considered a contraindication to liver transplantation, there is now compelling data supporting the use of PAH-specific therapies with the aim of improving pulmonary haemodynamics to allow transplantation to be successfully performed. This review explores possible relevant aetiological factors and summarises current diagnostic and therapeutic approaches for PoPH patients.