Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C.

BACKGROUND AND AIMS: The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting. METHODS: All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment. RESULTS: A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m2, and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x103/mm3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes. CONCLUSIONS: In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks. LAY SUMMARY: A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles.

Non-malignant breast papillary lesions - b3 diagnosed on ultrasound--guided 14-gauge needle core biopsy: analysis of 114 cases from a single institution and review of the literature.

One-hundred-fourteen consecutive cases of breast ultrasound-guided 14-gauge needle core biopsy (14G NCB) performed from January 2001 to June 2013 and diagnosed as non-malignant papillary lesion (PL)-B3, were reviewed and compared with definitive histological diagnosis on surgical excision (SE) to evaluate the diagnostic accuracy of ultrasound-guided 14G NCB. PL with epithelial atypia on 14G NCB were associated to malignancy on definitive histological diagnosis on SE in 22 (7 DCIS and 15 invasive carcinomas) of 46 cases with an underestimation rate of 47.8 %, while 9 (4 DCIS and 5 invasive carcinomas) cases out of 68 cases of PL without epithelial atypia were upgraded to carcinoma with an underestimation rate of 13.2 %. In cases of PL with epithelial atypia on ultrasound-guided 14G NCB, SE appears mandatory due to the high risk of associated malignancy. The diagnosis of PL without epithelial atypia on ultrasound-guided 14G NCB does not exclude malignancy at subsequent SE, consequently further assessment (by surgical or vacuum-assisted excision) is recommended to avoid the risk of delaying a diagnosis of malignancy, although this tends to be lower (1 in 8 patients).

Sclerosing paraganglioma of the carotid body: a potential pitfall of malignancy.

Paragangliomas (PGs) of the head and neck region are typically benign, slow-growing neuroendocrine tumours. At times, they may exhibit unusual histological features, such as prominent stromal sclerosis (sclerosing PG), which may raise concerns of malignancy. We describe a case of sclerosing PG of the carotid body, emphasizing the value of immunohistochemical stains for differential diagnosis. A 43-year-old woman presented with a painless lump on the neck. A magnetic resonance imaging scan demonstrated a hypervascular lesion of the carotid body, which was surgically excised. Grossly, the lesion measured 1.8 cm at maximum diameter. On microscopic examination, irregular nests and tiny bundles of neoplastic cells were found between thick bands of fibrous tissue. Focal nuclear cytomegaly and marked pleomorphism were noted. Neoplastic cells proved to be immunoreactive for chromogranin, synaptophysin and neuron specific enolase, but negative for cytokeratins, smooth muscle actin and CD34. Ultrastructurally, numerous mitochondria, rough endoplasmic reticulum structures and endocrine granules were seen in the cytoplasm of the tumour cells. On consideration of the above-mentioned clinico-pathological and ultrastructural findings a diagnosis of sclerosing PG was established. Sclerosing PG is a rare entity which may mimic a malignant neoplasm. The recognition of this unusual morphological variant of PG, together with appropriate immunostains, leads to the correct diagnosis.

Topoisomerase II alpha and TLE3 as predictive markers of response to anthracycline and taxane-containing regimens for neoadjuvant chemotherapy in breast cancer.

PURPOSE: Anthracyclines and taxanes are considered the standard for neoadjuvant chemotherapy of breast cancer, although they are often associated with serious side effects and wide variability of individual response. In this study, we analyzed the value of topoisomerase II alpha (TOP2A) and transducin-like enhancer of split 3 (TLE3) as predictive markers of response to therapy with anthracyclines and taxanes. MATERIALS AND METHODS: TOP2A and TLE3 protein expressions were evaluated using immunohistochemistry on 28 samples, obtained by core needle biopsy in patients with locally advanced breast carcinoma, subsequently subjected to epirubicin- and paclitaxel-based neoadjuvant chemotherapy. The immunohistochemical staining was correlated with the clinical response measured by the tumor size reduction evaluated by breast magnetic resonance imaging, prior and after chemotherapy, and by pathologic evaluation of the surgical specimen. RESULTS: Neoadjuvant chemotherapy achieved a size reduction in 26/28 tumors (92.9%), with an average percentage decrease of 45.6%. A downstaging was achieved in 71.4% of the cases of locally advanced carcinoma. TOP2A positivity was correlated with a greater reduction in tumor diameter (P=0.06); negative staining for TLE3 was predictive of a better response to neoadjuvant chemotherapy (P=0.07). A higher reduction in tumor diameter (P=0.03) was also found for tumors that were concurrently TLE3-negative and TOP2A-positive. CONCLUSION: TOP2A and TLE3 showed a correlation with response to neoadjuvant chemotherapy. While TOP2A is a well-known marker of response to anthracyclines-based chemotherapy, TLE3 is a new putative predictor of response to taxanes. Data from the current study suggest that TOP2A and TLE3 warrant further investigation in a larger series as predictors of response to neoadjuvant chemotherapy for locally advanced breast carcinoma.

The Italian Registry of Therapeutic Apheresis: granulocyte-monocyte apheresis in the treatment of inflammatory bowel disease. A multicentric study.

Leukocytes are thought to play an important role in the pathogenesis of inflammatory bowel diseases; granulocyte-monocyte adsorptive (GMA) apheresis, an extracorporeal technique aimed at removing activated circulating leukocytes from the blood, may represent a safe and effective therapeutic tool in these patients. The Italian Registry of Therapeutic Apheresis performed an observational, multicentric study involving 24 Gastroenterology Units. In this study, laboratory data and clinical outcomes of 230 patients (148 males, mean age 43.5 years) affected with ulcerative colitis (UC, n = 194) or Crohn's disease (CD, n = 36) who underwent one or more cycles of GMA were analyzed. Each cycle consisted of five GMA treatments. The patients were followed up for a mean of 8.7 (min. 3 to max. 12) months. At 3 months, positive outcome was achieved in 77.7% of UC patients (72.0% remission, 5.7% clinical response) and 61.3% of CD patients (54.8% remission, 6.5% clinical response). The cumulative proportion of positive outcome at 12 months was 87.1% for UC patients (83.7% remission, 3.4% clinical response) and 77.4% for CD patients (74.2% remission, 3.2% clinical response). No single clinical or laboratory parameter among those analyzed (age, sex, disease characteristics, history of smoking, medication history, baseline values of clinical activity index (CAI)/Crohn's disease activity index (CDAI), hemoglobin, white blood cells count, and erythrocyte sedimentation rate) was independently associated with clinical outcome. The procedure was well tolerated with no significant adverse effects registered.

Increased thrombin generation in inflammatory bowel diseases.

BACKGROUND: Inflammatory bowel diseases (IBD) are characterized by an increased thrombotic risk of uncertain etiology. Endogenous thrombin potential (ETP), a parameter of the thrombin generation curve, represents a new tool in the evaluation of thrombotic and bleeding disorders. AIMS: To study ETP in IBD patients and to correlate the results with clinical and biochemical features. METHODS: Seventy-four IBD patients (37 ulcerative colitis and 37 Crohn's disease) and 74 sex- and age-matched healthy individuals. ETP was measured upon activation of coagulation with small amounts of tissue factor and phospholipids in the presence or absence of thrombomodulin; results were expressed as nM thrombin.minutes. RESULTS: Mean+/-SD ETP values were significantly higher in patients (1,499+/-454) than controls (1,261+/-385) (p<0.001) only when the test was performed in the presence of thrombomodulin. ETP evaluated as ratio (with/without thrombomodulin), taken as an index of hypercoagulability, was significantly higher in patients (0.69+/-0.14) than controls (0.62+/-0.18) (p<0.006). Patients with increased C-reactive protein (CRP) had significantly higher mean ETP (1,721+/-458) than those with normal CRP (1,357+/-394) or controls (1,261+/-385) (p<0.001). Patients who at the time of blood sampling were classified as having a clinically active disease had ETP higher than those who were quiescent (1,655+/-451 versus 1,388+/-427, p<0.001) or controls (1,261+/-385, p<0.001). CONCLUSIONS: ETP measured in the presence of thrombomodulin or as ratio (with/without thrombomodulin) is increased in IBD patients, mainly in those with increased CRP or active disease. It may be considered as a candidate test for prospective studies aimed at assessing the risk of thrombosis in IBD patients.

Prevalence of celiac disease in inflammatory bowel diseases: An IG-IBD multicentre study.

BACKGROUND: An association has been described in case reports between celiac disease and inflammatory bowel diseases. The aim of the present study is to assess the prevalence of celiac disease in a large series of Italian patients with inflammatory bowel disease. METHODS: The Italian Group for Inflammatory Bowel Disease conducted a multicentre study between January 2002 and December 2004, in which 22 gastroenterology centres in Italy enrolled 1711 consecutive outpatients with inflammatory bowel disease. 860 (50.2%) had Crohn's disease (415 females, mean age 40, range 18-75), 791 (46.2%) had ulcerative colitis (371 females, mean age 40, range 18-80), and 60 (3.5%) had indeterminate colitis (27 females, mean age 40, range 18-78). All patients underwent serological testing for anti-endomysial antibodies and anti-tissue transglutaminase antibodies; if positive upper GI endoscopy with duodenal biopsy was performed. RESULTS: Nine of the 1711 patients (0.5%) had serological and histological findings compatible with the diagnosis of celiac disease; six of them had ulcerative colitis and three had Crohn's disease. CONCLUSIONS: Overall we found a lower risk of celiac disease in our cohort of inflammatory bowel disease patients than in the general population; prevalence of celiac disease was higher in patients with ulcerative colitis than in those with Crohn's disease.

Enteroscopy in the diagnosis and management of celiac disease.

Esophagogastroduodenoscopy (EGD) with 3 to 6 biopsies in the descending duodenum is the gold standard for the diagnosis of celiac disease. At the time of the first diagnosis of celiac disease, an extensive evaluation of the small bowel is not recommended. However, video capsule endoscopy, because of its good sensitivity and specificity in recognizing the Endoscopic features of celiac disease, can be considered a valid alternative to EGD in patients unable or unwilling to undergo EGD with biopsies. Capsule endoscopy is also a possible option in selected cases with strong suspicion of celiac disease but negative first-line tests. In evaluating patients with refractory or complicated celiac disease, in whom a complete evaluation of the small bowel is mandatory (at least in refractory celiac disease type II patients) because of the possible presence of complications beyond the reach of conventional endoscopes, both capsule endoscopy and balloon-assisted enteroscopy have been found to be helpful. In these patients, capsule endoscopy offers several advantages: it is well tolerated, it allows inspection of the entire small bowel, and it is able to recognize subtle mucosal changes. However, in this setting, capsule endoscopy should ideally be coupled with imaging techniques that provide important information about the thickness of the wall of the intestine and about extraluminal abnormalities. Although deep enteroscopy (such as balloon enteroscopy) is expensive, time-consuming, and potentially risky in these frail patients, they may have a key role, because they make it possible to take tissue samples from deep in the small intestine.

Gluten intolerance: gender- and age-related differences in symptoms.

OBJECTIVE: Gluten intolerance is a common, immunologically mediated disorder with a widely variable clinical presentation that affects genetically predisposed subjects. Women seem to be more frequently affected although data on sex differences are poor. In this study the prevalence of different clinical pictures according to sex and age is analysed in a large series of patients. MATERIAL AND METHODS: A total of 1436 patients with gluten intolerance were retrospectively considered, diagnosed from January 1975 to August 2001 based on compatible small-bowel biopsy and response to a gluten-free diet, plus immunofluorescent detection of granular IgA in papillary derma for dermatitis herpetiformis. The clinical picture at onset (classic, non-classic, silent) and age at diagnosis (< or = 2 years, > 2 and < or = 14 years, > 14 years) was recorded; 362 parents of coeliac probands undergoing a familial screening were also studied. The relations among sex, age class and symptoms were analysed using the chi2 test with Yates's correction. RESULTS: The overall female/male ratio was 2.3:1 but the inter-sex difference was significant only when the diagnosis was made in adulthood where a significant association between iron-deficiency anaemia as manifestation at onset in adult women (34% versus 7%) was found. Low weight, dyspepsia and hypertransaminasaemia were more common in adult men than women (20%, 14% and 7% versus 13%, 3% and 2%, respectively). Dermatitis herpetiformis was present more frequently in men (16% versus 9%). The prevalence of silent cases was 6% in men and 3% in women. Familial screening showed the same prevalence (9.3%) of current coeliac disease in fathers and mothers. CONCLUSIONS: Diagnosis of coeliac disease is more frequent in women but physicians' awareness of sex- and age-related differences in clinical presentation could improve diagnostic performances in men.