Denis Chatelain

Glucocorticoids plus N-Acetylcysteine in Severe Alcoholic Hepatitis

BACKGROUND Mortality among patients with severe acute alcoholic hepatitis is high, even among those treated with glucocorticoids. We investigated whether combination therapy with glucocorticoids plus N-acetylcysteine would improve survival. METHODS We randomly assigned 174 patients to receive prednisolone plus N-acetylcysteine (85 patients) or only prednisolone (89 patients). All patients received 4 weeks of prednisolone. The prednisolone-N-acetylcysteine group received intravenous N-acetylcysteine on day 1 (at a dose of 150, 50, and 100 mg per kilogram of body weight in 250, 500, and 1000 ml of 5% glucose solution over a period of 30 minutes, 4 hours, and 16 hours, respectively) and on days 2 through 5 (100 mg per kilogram per day in 1000 ml of 5% glucose solution). The prednisolone-only group received an infusion in 1000 ml of 5% glucose solution per day on days 1 through 5. The primary outcome was 6-month survival. Secondary outcomes included survival at 1 and 3 months, hepatitis complications, adverse events related to N-acetylcysteine use, and changes in bilirubin levels on days 7 and 14. RESULTS Mortality was not significantly lower in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (27% vs. 38%, P = 0.07). Mortality was significantly lower at 1 month (8% vs. 24%, P = 0.006) but not at 3 months (22% vs. 34%, P = 0.06). Death due to the hepatorenal syndrome was less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (9% vs. 22%, P = 0.02). In a multivariate analysis, factors associated with 6-month survival were a younger age (P<0.001), a shorter prothrombin time (P<0.001), a lower level of bilirubin at baseline (P<0.001), and a decrease in bilirubin on day 14 (P<0.001). Infections were less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group (P = 0.001); other side effects were similar in the two groups. CONCLUSIONS Although combination therapy with prednisolone plus N-acetylcysteine increased 1-month survival among patients with severe acute alcoholic hepatitis, 6-month survival, the primary outcome, was not improved. (Funded by Programme Hospitalier de Recherche Clinique; AAH-NAC ClinicalTrials.gov number, NCT00863785 .).

Macrocystic form of serous pancreatic cystadenoma

OBJECTIVES:Macrocystic serous cystadenoma of the pancreas are benign lesions with sometimes difficult diagnostic issues. We aimed to describe clinicopathological and imaging features with cyst fluid analysis in a series of patients undergoing surgery for macrocystic serous cystadenoma.METHODS:Eight patients underwent pancreatic resection for a macrocystic lesion of the pancreas diagnosed on ultrasonography or CT. Endoscopic ultrasonography and preoperative fine-needle aspiration were performed in seven patients. Immunohistochemical analysis of the surgical specimen with antibodies to carcinoembryonic-antigen (CEA), carbohydrate antigen (CA) 19-9, estrogen receptor, and progesterone receptor antibodies was performed in all cases.RESULTS:Patients included seven women and one man, with a mean age of 48 yr. Lesions were incidentally discovered on ultrasonography in six patients and had a mean size of 3 cm (range, 1.5–5 cm). Endoscopic ultrasonography revealed millimetric cysts in three cases. In the seven aspirated cysts, cytological analysis was noncontributive, but biochemical analysis showed low content of CEA (<5 ng/ml) and CA72.4 (<40U/ml) in all but two. At histology, cysts were lined by clear cuboidal cells. They focally expressed CA19-9 but were negative for anti-CEA, anti-estrogen receptor, and anti-progesterone receptor antibodies. Microscopic cysts in the wall of the lesions were demonstrated in five cases.CONCLUSIONS:Macrocystic serous cystadenoma is a particular variant of pancreatic serous cystadenoma. Endoscopic ultrasonography may be useful in detecting peripherally located millimetric cysts in unilocular lesions, and measurement of enzymes and tumor markers in cyst fluid may also contribute to the diagnosis showing low concentrations.

The ciliated hepatic foregut cyst, an unusual bronchiolar foregut malformation: A histological, histochemical, and immunohistochemical study of 7 cases

The ciliated hepatic foregut cyst is an unusual solitary cystic lesion of the liver. In a series of 7 cases of hepatic ciliated cysts, we performed a histological, histochemical, and immunohistochemical study to better define the histogenesis of this rare entity. The patients were 4 women and 3 men, aged 39 to 75 years. Four patients presented with abdominal pain. In 3 cases the cyst was discovered incidentally on ultrasonography. The cysts measured from 1 to 4 cm in diameter. Microscopically, the lining of the columnar epithelium was composed of ciliated cells and mucin secreting goblet cells. The wall was composed of bands of smooth-muscle fibers surrounded by an outer fibrous capsule. The goblet cells stained with PAS, alcian blue, and high-iron diamine. The immunohistochemical study showed that endocrine cells were present within the cyst epithelium, positive for chromogranin, synaptophysin, bombesin, and calcitonin, and negative for serotonin, somatostatin, glucagon, insulin, gastrin, and pancreatic polypeptide. In all the cases, immunoreactivity of some cells for CC10 strongly suggested the presence of Clara cells. Our study shows that the epithelium lining ciliated hepatic foregut cysts has histological, histochemical, and immunohistochemical features similar to those observed in the bronchiolar epithelium. This lesion is a developmental ventral foregut abnormality that could arise from a bronchiolar bud of the tracheobronchial diverticulum.

Small-vessel vasculitis surrounding an uninflamed temporal artery: A new diagnostic criterion for polymyalgia rheumatica?

OBJECTIVE To assess the prevalence and clinical significance of small-vessel vasculitis (SVV) surrounding an uninflamed temporal artery (TA) in patients diagnosed as having giant cell (temporal) arteritis (GCA) and/or polymyalgia rheumatica (PMR). METHODS Patients with GCA and/or PMR (n = 490) were included in this multicenter prospective study. Slides of TA biopsy specimens were reviewed by 2 pathologists who were blinded with regard to clinical information. SVV was defined as aggregates of mononuclear inflammatory cells surrounding a capillary, distant from an uninflamed temporal artery. Clinical and biologic data of patients in the SVV group (n = 35) were compared with data of patients with biopsy-proven GCA (n = 280) and with negative TA biopsy findings (n = 175). RESULTS SVV was diagnosed in 18 women and 17 men (mean +/- SD age 74.5 +/- 9.4 years). The group of patients with SVV had a higher proportion of men than in the entire GCA series, had systemic symptoms, headache, jaw claudication, and an abnormal temporal artery less frequently at clinical examination, but had symptoms of PMR more often than patients in the biopsy-proven GCA group (P = 2.6 x 10(-7), odds ratio 9.17 [95% confidence interval 3.44-24.4]). Levels of inflammation markers were significantly lower in the SVV group. Patients in the SVV group had fever less frequently than patients in the group with negative TA biopsy findings, but otherwise shared the same clinical (including PMR symptoms) and biologic features. Eighteen of the 94 patients with pure PMR (19%) had SVV. CONCLUSION SVV is often neglected by pathologists, and appears to be strongly associated with PMR symptoms in patients with a clinical diagnosis of GCA and/or PMR. However, SVV as a new diagnostic criterion for PMR must be assessed in prospective studies.

The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells

Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour. The loss of function of the retinoblastoma (Rb) protein is an important event during liver carcinogenesis, but it is unclear whether the Rb status modulates the response of HCC cells to sorafenib. Here, we examined this question in HCC cells with reduced levels of Rb achieved through stable RNA interference. We show that HCC cells with reduced levels of Rb exhibit a two- to threefold increase in cell death induction upon exposure to sorafenib compared with controls. Sorafenib treatment of Balb/c nude mice that received tumour xenografts derived from HCC cells with reduced Rb levels resulted in complete tumour regression in 50% of the animals treated, compared with tumour stabilization in mice that received control cells. We show that, upon exposure to sorafenib, the Rb-negative status of HCC cells promotes the occurrence of ferroptosis, a form of oxidative necrosis. The findings highlight the role of Rb in the response of HCC cells to sorafenib and the regulation of ferroptosis.

BAD, a proapoptotic member of the BCL2 family, is a potential therapeutic target in hepatocellular carcinoma.

Proteins of the BCL2 family are key regulators of apoptosis. Their expression levels are frequently altered in cancers, enabling tumor cells to survive. To gain insight into the pathogenesis of hepatocellular carcinoma (HCC), we performed a comprehensive survey of the expression of the members of the BCL2 family in samples obtained from surgically resected HCCs. Here, we report the occurrence of a new molecular anomaly, consisting of a strong reduction in the expression of the proapoptotic protein BAD in HCC compared with surrounding nontumoral tissue. We investigate the function of BAD in a panel of HCC cell lines. Using gene overexpression and RNA interference, we show that BAD is involved in the cytotoxic effects of sorafenib, a multikinase blocker, which is currently the sole therapeutic drug effective for the treatment of HCC. Finally, we report that ABT-737, a compound that interacts with proteins of the BCL2 family and exhibits a BAD-like reactivity, sensitizes HCC cells toward sorafenib-induced apoptosis. Collectively, our findings indicate that BAD is a key regulator of apoptosis in HCC and an important determinant of HCC cell response to sorafenib. Mol Cancer Res; 8(8); 1116–25. ©2010 AACR.

Biliary drainage, photodynamic therapy and chemotherapy for unresectable cholangiocarcinoma with jaundice

Background and Aim:  The combination of photodynamic therapy and biliary stenting seems to be beneficial in the palliative treatment of unresectable cholangiocarcinoma. We aimed to assess the accuracy of photodynamic therapy in a single centre.

Diagnostic accuracy of community pathologists in the interpretation of colorectal polyps

Background and aims Management of patients with endoscopically removed colorectal polyps is generally dependent on pathological evaluation. The aim of this study was to assess the accuracy and clinical impact of pathologic interpretation of colorectal polyps by community pathologists. Methods Two expert gastrointestinal pathologists reviewed the slides of 300 colorectal polyps initially examined by 14 general pathologists. Polyps had been detected by a fecal occult blood test colorectal cancer screening program in Haut-Rhin, a French administrative district. Results Villous histology was overread in 24.8% of cases and high-grade dysplasia in 22.0%. The diagnosis of serrated adenoma was confirmed in 15.7% of cases. The diagnosis of T1 carcinoma was overestimated in seven cases (17.9%) and missed in four. In the screening program, the proportion of correct diagnoses of community pathologists was estimated at 45.3% of polyps, of misclassification without clinical impact at 27.5%, and of misclassification with a theoretical impact on management at 27.2%, leading to over-surveillance in 20.3% of polyps and to unnecessary surgical resection in three individuals. Overall, 37.5% of the pathology reports of malignant polyps were complete, presenting all criteria necessary for therapeutic decision-making. Conclusion Community pathologists exhibited moderate accuracy for interpreting colorectal polyps, with an impact on patient management for around one out of five individuals. Our results confirm the intrinsic poor reliability of the pathologic interpretation of villous histology and high-grade dysplasia and suggest that these advanced pathologic features should be abandoned for clinical use. They illustrate the need for a clarification of the nomenclature of serrated polyps.

Unilocular acinar cell cystadenoma of the pancreas an unusual acinar cell tumor.

We report an unusual case of acinar cell cystadenoma of the pancreas in a 52-year-old man treated for pulmonary adenocarcinoma. The lesion, located in the body of the pancreas, was revealed incidentally by abdominal computed tomography during follow-up for a pulmonary neoplasm. A left pancreatectomy was performed. The unilocular cystic lesion measured 5 cm and was lined by a single layer of columnar acinar cells with eosinophilic granular cytoplasm, faintly stained by periodic acid-Schiff. Immunohistochemical analysis showed the lining cells were positive for cytokeratin and trypsin, and electronic microscopy showed that they contained zymogen granules. Acinar cell tumors of the pancreas are rare and include acinar cell carcinomas, acinar cell cystadenocarcinomas, and acinar cell adenomas. We report a case of cystic acinar cell tumor of the pancreas with benign gross and histologic features that could be added to the list of cystic neoplasms of the pancreas as acinar cell cystadenoma.

Nutriose, a prebiotic low-digestible carbohydrate, stimulates gut mucosal immunity and prevents TNBS-induced colitis in piglets.

Background:We investigated a prebiotic low‐digestible carbohydrate (LDC) as a possible food ingredient to stimulate bowel functions in the treatment of inflammatory bowel disease. The study aimed to assess a fermentable dextrin fiber (Nutriose) and its relationship to the immune management of the disease and the microbiota profile in colitis‐bearing piglets. Methods:In a randomized placebo‐controlled parallel blind preclinical study, 32 male piglets were fed LDC (4% Nutriose) or dextrose placebo for 44 days before being challenged with trinitrobenzene sulfonic acid (TNBS) to induce colitis. We followed the microbiota profile using real‐time polymerase chain reaction (PCR) targeted to 9 bacterial genera. Secretory IgA was evaluated by enzyme‐linked immunosorbent assay (ELISA). Inflammatory protein profiles were monitored in blood and colonic tissues. Both histological scoring of biopsy samples and live endoscopic scoring were used to measure colitis development. Results:Prior and continuing LDC supplementation alleviated the symptoms of colitis (body weight loss, bloody stools) induced by a TNBS challenge. This effect was associated with an improvement in endoscopic and histological scores. LDC was shown to selectively downregulate some of the proinflammatory factors and their concomitant pyretic events and to stimulate the Th2‐related immune pathway (IL‐10 and s‐IgA). Conclusions:At the dose tested, LDC is a well‐tolerated prebiotic agent able to not only stimulate butyrogenic bacteria strains and reduce intestinal transit disorders and energy intake, but also to prevent chronic inflammatory intestinal injuries. Inflamm Bowel Dis 2010