Long-Term Treatment with the Calcitonin Gene-Related Peptide Receptor Antagonist Erenumab in CADASIL: Two Case Reports.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of cerebral small vessel disease, caused by a mutation in the NOTCH3 gene on chromosome 19. The main clinical features include migraine (often with aura), early onset, recurrent subcortical ischemic strokes, mood disturbances, and cognitive impairment, frequently leading to dementia and disability with a reduction in life expectancy. Cerebral chronic global hypoperfusion, due to impaired cerebrovascular reactivity, seems to play a primary role in CADASIL. Migraine is the most common early feature of the disease, and to date, there are no consensus guidelines for treatment. Given the vasomodulatory influence of many antimigraine drugs, there is concern about their use in this disease. In particular, the calcitonin gene-related peptide (CGRP) system serves as a vasodilatory protective mechanism during cerebral and cardiac ischemia. Blocking this system could exacerbate ischemic events. Herein, we describe two CADASIL patients who were treated with the calcitonin gene-related peptide (CGRP) receptor antagonist erenumab for chronic migraine, reporting a significant reduction in the frequency of attacks and intensity of pain, and an improvement in quality of life without adverse effects.

Transjugular intrahepatic Porto-systemic shunt positively influences the composition and metabolic functions of the gut microbiota in cirrhotic patients.

BACKGROUND & AIMS: Cirrhosis and its complications may affect gut microbiota (GM) composition. Transjugular intrahepatic portosystemic shunt (TIPS) represents the most effective treatment for portal hypertension (PH). We aimed to evaluate whether TIPS placement modifies GM composition and metabolic function. METHODS: A compositional and functional GM analysis was prospectively performed in 13 cirrhotic patients receiving TIPS. Patients receiving systemic or non-absorbable antibiotics for any indications were excluded. Fecal samples were collected before and three months after TIPS. GM was analyzed by 16S ribosomal RNA sequencing. Small- and medium-chain fatty acids (SCFAs and MCFAs, respectively) were measured by gas chromatography/mass spectrometry. RESULTS: TIPS placement resulted in a mean 48% reduction in portal-caval pressure gradient. No recurrence of PH related complications was observed. After TIPS, increased levels of Flavonifractor spp. (p = 0.049), and decreased levels of Clostridiaceae (p = 0.024), these latter linked to abdominal infections in cirrhotic patients, were observed. No differences were found in the SCFAs signature while analysis of MCFA profiles showed a decreased abundance of pro-inflammatory isohexanoic (p<0.01), 2-ethylhexanoic (p<0.01) and octanoic acids (p<0.01) after TIPS. CONCLUSION: Correction of PH following TIPS results in modifications of GM composition which could be potentially beneficial and reduces the levels of fecal pro-inflammatory MCFAs.

Mortality after transjugular intrahepatic portosystemic shunt in older adult patients with cirrhosis: A validated prediction model.

BACKGROUND AND AIMS: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) improves survival in patients with cirrhosis with refractory ascites and portal hypertensive bleeding. However, the indication for TIPS in older adult patients (greater than or equal to 70 years) is debated, and a specific prediction model developed in this particular setting is lacking. The aim of this study was to develop and validate a multivariable model for an accurate prediction of mortality in older adults. APPROACH AND RESULTS: We prospectively enrolled 411 consecutive patients observed at four referral centers with de novo TIPS implantation for refractory ascites or secondary prophylaxis of variceal bleeding (derivation cohort) and an external cohort of 415 patients with similar indications for TIPS (validation cohort). Older adult patients in the two cohorts were 99 and 76, respectively. A cause-specific Cox competing risks model was used to predict liver-related mortality, with orthotopic liver transplant and death for extrahepatic causes as competing events. Age, alcoholic etiology, creatinine levels, and international normalized ratio in the overall cohort, and creatinine and sodium levels in older adults were independent risk factors for liver-related death by multivariable analysis. CONCLUSIONS: After TIPS implantation, mortality is increased by aging, but TIPS placement should not be precluded in patients older than 70 years. In older adults, creatinine and sodium levels are useful predictors for decision making. Further efforts to update the prediction model with larger sample size are warranted.

Portosystemic shunt is an effective treatment for complications of portal hypertension in hepatic myeloid metaplasia and improves nutritional status.

In patients affected by myelofibrosis with hepatic myeloid metaplasia (HMM), portal hypertension (PHT) complications may develop. In this case series, we analysed the efficacy and safety of transjugular portosystemic shunt (TIPS) in the treatment of PHT-related complications and its effects on the nutritional status. Six patients were evaluated and the average follow-up period after TIPS was 33 (IQR 5) months. None of the patients developed hepatic failure, nor any recurrence of variceal bleeding was recorded. No additional paracentesis or endoscopic prophylactic treatment for PHT-related complications were required. In all subjects, the average dose of diuretics was almost halved three months after TIPS. Three patients died during the follow-up, but none for liver-related causes. All patients showed an improvement in the global nutritional status. In conclusion, TIPS represent an effective and safe treatment option for patients affected by complications of PHT secondary to HMM and drives to an improvement of the nutritional status.

Dynamics of endothelial progenitor cells in patients with advanced hepatocellular carcinoma.

BACKGROUND AND AIMS: Circulating endothelial progenitor cells (EPC) predict tumor vascularization and disease progression, but limited information is available on their dynamics in hepatocellular carcinoma (HCC) undergoing systemic treatment. METHODS: We prospectively analyzed different populations of EPC in 16 patients with advanced HCC receiving sorafenib. Patients were studied before therapy (T0, n = 16) and after two (T2, n = 12) and eight weeks (T8, n = 8), using high-performance flow-cytometry. The tumor response at T8 was categorized as progressive disease (PD) or clinical benefit (CB, all other responses). RESULTS: At T0, higher levels of CD34+CD133+KDR+ and CD34+KDR+ were observed in patients with alpha-fetoprotein ≥400 ng/ml or non-viral liver disease, whereas CD34+CD133+KDR+ cells were virtually absent in patients with vascular invasion. CD34+KDR+ and CD34+CD133+KDR+ were directly correlated with platelet count. Frequencies of all populations of EPC declined in patients receiving sorafenib. Levels of CD34+CD133+ were higher at T0 in patients with CB compared to patients with PD. In patients belonging to the CB group CD34+KDR+ cells at T0 were directly correlated to platelet count. CONCLUSION: In patients with advanced HCC, EPC are directly correlated with platelet count, suggesting a common activation of selected bone marrow pathways. Levels of a CD34+KDR+ are higher at baseline in patients responding to sorafenib.