Final Results from the First European Real-World Experience on Lusutrombopag Treatment in Cirrhotic Patients with Severe Thrombocytopenia: Insights from the REAl-World Lusutrombopag Treatment in ITalY Study.

Background and aims: Management of severe thrombocytopenia poses significant challenges in patients with chronic liver disease. Here, we aimed to evaluate the first real-world European post-marketing cohort of cirrhotic patients treated with lusutrombopag, a thrombopoietin receptor agonist, verifying the efficacy and safety of the drug. Methods: In the REAl-world Lusutrombopag treatment in ITalY (REALITY) study, we collected data from consecutive cirrhotic patients treated with lusutrombopag in 19 Italian hepatology centers, mostly joined to the "Club Epatologi Ospedalieri" (CLEO). Primary and secondary efficacy endpoints were the ability of lusutrombopag to avoid platelet transfusions and to raise the platelet count to ≥50,000/µL, respectively. Treatment-associated adverse events were also collected. Results: A total of 66 patients and 73 cycles of treatment were included in the study, since 5 patients received multiple doses of lusutrombopag over time for different invasive procedures. Fourteen patients (19%) had a history of portal vein thrombosis (PVT). Lusutrombopag determined a significant increase in platelet count [from 37,000 (33,000-44,000/µL) to 58,000 (49,000-82,000), p < 0.001]. The primary endpoint was met in 84% of patients and the secondary endpoint in 74% of patients. Baseline platelet count was the only independent factor associated with response in multivariate logistic regression analysis (OR for any 1000 uL of 1.13, CI95% 1.04-1.26, p 0.01), with a good discrimination power (AUROC: 0.78). Notably, a baseline platelet count ≤ 29,000/µL was identified as the threshold for identifying patients unlikely to respond to the drug (sensitivity of 91%). Finally, de novo PVT was observed in four patients (5%), none of whom had undergone repeated treatment, and no other safety or hemorrhagic events were recorded in the entire population analyzed. Conclusions: In this first European real-world series, lusutrombopag demonstrated efficacy and safety consistent with the results of registrational studies. According to our results, patients with baseline platelet counts ≤29,000/µL are unlikely to respond to the drug.

Waldenstrom's Macroglobulinemia and Ascites: A Case Report.

Background: Waldenstrom's disease is characterized by the presence of pathological changes in the B lymphocytes that are in the last stages of maturation. One characteristic of WM is the production of an abnormal high amount of IgM and hyper viscosity syndrome. The MW gets worse, symptoms such as fatigue, weight loss, night sweats, fever, recurrent infections and swollen lymph nodes develop in patients who have a known history of MGUS. In this clinical case, our patient without history of MGUS, presents for the first time for medical observation only for ascites and the presence of an interportocaval lymph node package. An atypical presentation of the disease that makes us reflect on the difficulty of making a diagnosis in the elderly patient and on pathogenetic hypotheses of ascites not yet explored. Case Presentation: Seventy-three-year-old patient, hospitalized for the onset of ascites with sloping edema, diffuse left pulmonary opacification. At the ultrasound check, cava and portal vessels patent and of regular caliber, however with inversion of flow in correspondence with the right branch and of the door to the hilum, with a subdiaphragmatic retrocaval focus with a maximum diameter of about 3 cm, which cannot be better viewed. CT scan of the abdomen with confirmation of the presence of an interportocaval lymph node package. After evidence of the electrophoretic protein picture of a double component, probably monoclonal with positive urinary immunofixation for free K chains. IgM dosage equal to 2190 mg. Serum immunofixation practice that confirms the diagnosis of type B lymphoproliferative syndrome as per Waldenstrom's disease, confirmed by bone marrow aspiration with morphological and flow cytometric study. Immediately begin chemotherapy with Bendamustine 120 mg. After 4 weeks of therapy with the reduction of IgM values, the patient no longer presented ascites. Conclusion: This case has an unusual presentation of this disease and we could shed a new light on the possible pathogenesis of portal hypertension in Waldenstrom'disease.

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Status and Novel Perspectives.

Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes in this cancer. Promising data from phase I/II studies in advanced HCC, showing durable objective response rates (~20% in first- and second-line settings) and good safety profile, have led to phase III studies with ICIs as single agents or in combination therapy, both in first and second line setting. While the activity of immunotherapy agents as single agents seems to be limited to an "ill-defined" small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab revealed a benefit in the outcomes when compared to sorafenib in the first line. In addition, the activity and efficacy of the combinations between anti-PD-1/anti-PD-L1 antibody and other ICIs, tyrosine kinase inhibitors, or surgical and locoregional therapies, has also been investigated in clinical trials. In this review, we provide an overview of the role of ICIs in the management of HCC with a critical evaluation of the current status and future directions.

The enthesopathy of celiac patients: effects of gluten-free diet.

Celiac disease (CD) is a gluten-sensitive enthesopathy occurring in genetically predisposed individuals that is caused by a permanent intolerance to gluten. The major environmental factor associated with the risk of developing celiac-related complications is persistent exposure to dietary gluten. The aim of this study was to determine the prevalence of lower limb enthesopathy in CD patients at first diagnosis compared with CD patients on a gluten-free diet (GFD). Fifty-five untreated CD patients (group A) and 55 CD patients on a GFD from at least 1 year (group B), matched for age and sex, attending gastroenterology outpatient clinic of the University Federico II of Naples, were enrolled in this study. All patients underwent clinical and ultrasonography examination. Among group A, 27 (49.8 %) patients presented at least one entheseal alteration as compared with 15 patients (27.2 %) of group B (prevalence rate ratio 1.83, I.C. 95 % = 0.48-7.01; p < 0.001). The Glasgow ultrasound enthesitis scoring system (GUESS) was significantly higher in patients of group A than in patients of group B. In conclusion, our study shows that enthesopathy is more frequent in untreated CD subjects with positive anti-tissue transglutaminase antibodies title, as compared to those on GFD and absence of serum anti-tissue transglutaminase antibodies title.

The occurrence of lower limb enthesopathy in coeliac disease patients without clinical signs of articular involvement.

OBJECTIVE: Coeliac disease (CD) is a systemic autoimmune condition induced by gluten consumption in genetically predisposed people, affecting ∼1% of the general population. In the literature, there are many studies that report the association between CD and different kinds of arthritis. The aim of this study was to investigate the presence of entheseal abnormalities by US in patients with CD without clinical signs of articular involvement as compared with healthy control subjects. METHODS: Sixty patients with CD attending the gastroenterology outpatient clinic of the University Federico II of Naples and 60 healthy control subjects matched for age and sex were enrolled in this study. Coeliac patients and healthy controls underwent clinical and US examination. RESULTS: Among 60 CD patients, 24 (40%) presented at least one entheseal alteration as compared with 6 (10%) control subjects (P < 0.01). In CD patients, the entheseal site more frequently involved was patellar (distal and proximal), while in the healthy controls the enthesopathies were all localized at the Achilles tendon. CONCLUSION: In conclusion, the results of this study underline the ability of US to detect signs of subclinical enthesopathy and indicate the presence of a higher prevalence of subclinical enthesopathies in asymptomatic CD patients.

Lower prevalence of diverticulosis in patients with ulcerative colitis.

PURPOSE: Colonic diverticulosis is characterized by abnormal thickening of the bowel wall, associated with luminal overpressure and increase of sigmoid contractility. However, patients with ulcerative colitis show chronic inflammatory alterations determining a reduction of both bowel wall muscle tone and contractility. Thus, we could presume ulcerative colitis and colonic diverticulosis as two pathophysiologically and mutually excluding diseases. This study was designed to evaluate the prevalence of colonic diverticulosis in patients with ulcerative colitis compared with a control endoscopic population. METHODS: We prospectively analyzed the prevalence of colonic diverticulosis in 85 patients, older than aged 45 years, with known ulcerative colitis compared with that in 85 age/gender-matched patients without colitis. All patients underwent pancolonoscopy with ulcerative colitis and colonic diverticulosis diagnosis made by endoscopy and histopathology. The patients with ulcerative colitis also were divided in three subgroups according to the age at diagnosis (<30 years, 30-45 years, >45 years) and extension of disease (sigmoiditis, left colitis, extensive colitis). RESULTS: Colonic diverticulosis was present in 7 of 85 patients with and in 24 patients without ulcerative colitis (8.2 vs. 28.2 percent; P < 0.001; relative risk, 3.4; 95 percent confidence interval, 1.56-7.52). All seven patients with both diseases were diagnosed with ulcerative colitis when older than age 45 years. No differences were found between the two groups in terms of extension of diverticula. CONCLUSIONS: Patients with ulcerative colitis show a significantly lower prevalence of colonic diverticulosis, with this finding probably reflecting the motor alterations caused by chronic bowel wall inflammation. In the patients affected by ulcerative colitis with late onset of the disease, the reduced prevalence of colonic diverticulosis is not evident.

Noninvasive diagnosis of small bowel Crohn's disease: combined use of bowel sonography and Tc-99m-HMPAO leukocyte scintigraphy.

BACKGROUND: Crohn's disease (CD) is frequently localized in the small bowel, with the diagnosis of disease and the assessment of its extension made by ileo-colonoscopy (IC) and small bowel enteroclysis (SBE). Transabdominal bowel sonography (BS) and Tc-99m-HMPAO leukocyte scintigraphy (LS) are increasingly used for the diagnosis of CD because of their minimal invasiveness, reproducibility, and acceptable costs. METHODS: From March 2000 to July 2003, we performed IC, SBE, BS, and LS in 84 patients with either suspected or known small bowel CD. RESULTS: Small bowel CD was present in 50 patients, whereas the other 34 patients received a different diagnosis. Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were, respectively, 98%, 97%, 98%, 97%, and 0.97 for SBE; 92%, 97%, 98%, 88%, and 0.94 for BS; and 90%, 93%, 96%, 85%, and 0.92 for LS. In addition, the combined use of BS and LS led to overall sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of 100%, 93%, 96%, 100%, and 0.97, respectively. BS showed a fair concordance with SBE in terms of location (k = 0.71) and a correlation with the extension of the disease (r = 0.67, P < 0.001). LS showed a concordance with SBE with regard to location in about one-half the population (k = 0.54), whereas it was less effective than SBE in defining disease extension. CONCLUSIONS: BS and LS are 2 accurate techniques for the diagnosis of small bowel CD, and their combined use can be recommended as an early diagnostic approach to patients in which the disease is suspected. SBE remains the best procedure for the definition of the location and extension of the disease.

Bowel wall thickness at abdominal ultrasound and the one-year-risk of surgery in patients with Crohn's disease.

OBJECTIVES: Abdominal ultrasound can assess the extent and localization of Crohn's disease, and an increased bowel wall thickness is the most common finding. Our aim was to correlate bowel wall thickness at ultrasound, with the risk of short-term surgical outcome in patients with Crohn's disease. MATERIALS AND METHODS: From 1997 to 2000 we performed ultrasound in 174 consecutive patients with Crohn's disease. Surgical operations were recorded over a 1-yr follow-up. Logistic regression analysis was performed to identify clinical and ultrasound risk factors for surgery. RESULTS: Fifty-two patients underwent surgery within 1 yr. Indication for surgery was strictures in most of the cases. Median bowel wall thickness was higher in patients with surgery (8 mm) than those without surgery (6 mm) (p < 0.0001). A receiver operating characteristic (ROC) curve was constructed taking into account bowel wall thickness for selecting patients with a high risk of surgery. The optimized cut-off for equally important sensitivity and specificity was calculated at 7.008 mm. The binary regression analysis showed that CDAI > 150, absence of previous surgery, stricturing-penetrating pattern, the presence of intestinal complications, and intestinal wall thickness >7 mm were associated with an increased risk of surgery. Patients with intestinal wall thickness >7 mm at ultrasound had the highest risk (OR: 19.521, 95% CI: 5.362-71.065). CONCLUSIONS: Data suggest that bowel wall thickness >7 mm at ultrasound is a risk factor for intestinal resection over a short period of time. Routine use of abdominal ultrasound during evaluation of patients with Crohn's disease may identify a subgroup that is at high risk for surgery. (Am J Gastroenterol 2004;99:1-7)