Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

From Waldenström's macroglobulinemia to aggressive diffuse large B-cell lymphoma: a whole-exome analysis of abnormalities leading to transformation.

Transformation of Waldenström's macroglobulinemia (WM) to diffuse large B-cell lymphoma (DLBCL) occurs in up to 10% of patients and is associated with an adverse outcome. Here we performed the first whole-exome sequencing study of WM patients who evolved to DLBCL and report the genetic alterations that may drive this process. Our results demonstrate that transformation depends on the frequency and specificity of acquired variants, rather than on the duration of its evolution. We did not find a common pattern of mutations at diagnosis or transformation; however, there were certain abnormalities that were present in a high proportion of clonal tumor cells and conserved during this transition, suggesting that they have a key role as early drivers. In addition, recurrent mutations gained in some genes at transformation (for example, PIM1, FRYL and HNF1B) represent cooperating events in the selection of the clones responsible for disease progression. Detailed comparison reveals the gene abnormalities at diagnosis and transformation to be consistent with a branching model of evolution. Finally, the frequent mutation observed in the CD79B gene in this specific subset of patients implies that it is a potential biomarker predicting transformation in WM.

[Hypotonia and lethargy: initial manifestations of a new case of galactosemia]. / Hipotonía y letargia: manifestaciones iniciales de un nuevo caso de galactosemia.

INTRODUCTION: Galactosemia is a metabolic disease that is transmitted by autosomal recessive inheritance in which there is an enzymatic deficit that prevents the metabolism of galactose. Three enzymes could be involved, but the lack of galactose-1-phosphate uridyltransferase (GALT) is the most frequent. Incidence is two cases per 100,000 newborn infants. As a consequence of this enzymatic deficit, on ingesting milk the newborn infant will present a progressive neurological deterioration, cataracts and digestive tract and kidney disorders. An early diagnosis is essential so that galactose can be withdrawn from the diet as soon as possible, which in the newborn infant means discontinuing mother's milk and feeding with galactose-free milk. CASE REPORT: We report the case of a newborn female, the daughter of consanguineous parents (second cousins) from the gypsy ethnic group, who was diagnosed as suffering from galactosemia with a total GALT deficit. The patient was given normal milk for the first 10 days of her life and presented hypotonia, lethargy, jaundice, hepatomegaly, refusal to eat, low weight gain and a urinary infection caused by gram negative bacteria. Following diagnosis, galactose was withdrawn from the diet (she was given soy milk) and the physical exploration became progressively more normal. CONCLUSIONS: This is an extremely unusual pathology, but the patient's outcome is largely dependent on an early diagnosis and treatment.