Safety and on-treatment efficacy of telaprevir: the early access programme for patients with advanced hepatitis C.

BACKGROUND AND AIM: Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1). METHODS: 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type. RESULTS: 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1-4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis). CONCLUSIONS: In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.

PACAP mediates the neural proliferative pathway of Mastomys enterochromaffin-like cell transformation.

BACKGROUND AND AIM: Pituitary adenylate-cyclase activating peptide (PACAP) is a more potent proliferative agent than gastrin for rat enterochromaffin-like (ECL) cell proliferation in vitro. The role of this neurotransmitter during gastrin-mediated ECL cell tumor formation and gastrin-autonomous ECL cell neoplasia is unknown. METHODS AND RESULTS: ECL cell transformation was induced in the Mastomys using 16 wk H2 receptor blockade of acid inhibition. Examination of the epithelial fundic mucosa demonstrated that PACAP-immunoreactivity significantly increased in the tumor mucosa compared to the naïve stomach, and was associated with ECL cells. Naïve and tumor ECL cells were then purified (approximately 95%) from Mastomys and the presence of all three PACAP/VPAC receptor subtypes was demonstrated by polymerase chain-reaction amplification. Thereafter, cells were maintained in short-term (48 h) primary cultures. PACAP significantly (p<0.05) increased 24 h bromo-deoxyuridine uptake (approximately 4-fold) in both cell types with estimated EC(50) values of approximately 4x10(-16) M and approximately 2x10(-16) M, respectively. Specific receptor antagonists (PAC1/VPAC1) of PACAP competitively inhibited these proliferative effects in naïve cells. Oligonucleotide antisense directed against PAC1 significantly inhibited PACAP-stimulated DNA synthesis by approximately 85% (p<0.05) in tumor cells. CONCLUSION: PACAP is a potent and effective modulator of ECL cell proliferation. The expression of this neuropeptide and its receptors, particularly PAC1, suggest the existence of a neural regulatory pathway of ECL cell proliferation and transformation.

Functional donor-site morbidity during level and uphill gait after a gastrocnemius or soleus muscle-flap procedure.

BACKGROUND: There is only limited objective information about functional donor-site morbidity after harvest of one head of the triceps surae muscles to cover a severe soft-tissue defect of the leg. The purpose of the present study was to investigate whether a functional deficit is present during level and uphill walking after such a procedure. METHODS: Five subjects who had completely recovered from the initial injury were studied with use of comprehensive gait analysis during free level, fast level, and uphill walking on a ramp at a 10 degrees inclination. RESULTS: Gait analysis revealed no relevant donor-site morbidity affecting level gait at a free walking speed (mean, 1.27 m/sec; range, 1.18 to 1.40 m/sec). When the subjects walked at a higher velocity (mean, 1.89 m/sec; range, 1.58 to 2.43 m/sec), an asymmetry of the ground-reaction forces was seen. The second vertical peak force during push-off was reduced by a mean of 7.3% (range, 0.94% to 12.24%), and the impulse in the direction of progression was reduced by a mean of 8.7% (range, 0.13% to 17.87%) on the affected side (p = 0.04). During uphill walking, a compensatory strategy to reduce the demand on the posterior calf muscles was seen in all subjects-that is, they shortened the length of the step on the contralateral side by a mean of 3.9 cm (range, 2.2 to 6.2 cm), which corresponded to a mean side-to-side difference of 5.6% (range, 2.18% to 6.18%) (p = 0.04). A calcaneal motion pattern, denoted as increased ankle dorsiflexion, was seen in three of the five subjects during uphill walking as a sign of decreased function of the posterior calf muscles. Two of them (both with a soleus flap) also had a calcaneal pattern during fast gait. CONCLUSIONS: We concluded from this study that the functional donor-site morbidity after harvest of one head of the triceps surae muscles is mild in subjects who have had a complete recovery from their initial injury. Normal level gait is possible. However, deficits are seen in more demanding tasks such as fast walking or uphill walking.

Intrapancreatic accessory spleen. A rare cause of a pancreatic mass.

CONCLUSION: The clinical significance of intrapancreatic accessory spleens resides in the mimicry of pancreatic cancer. Radionuclide tests (Octreotide scan and Tc99m sulfur colloid scan) should be undertaken to distinguish these lesions from neuroendocrine tumors, hypervascular metastases and pancreatic carcinoma. If the tests are equivocal, diagnostic laparotomy or laparoscopy is recommended. BACKGROUND: Despite its relatively common occurrence, intrapancreatic ectopic splenic tissue is rarely detected owing to its asymptomatic nature. METHODS: We report a case of a clinically asymptomatic patient in which abdominal computed tomography (CT) scans revealed a mass of 1.5 cm in diameter in the distal pancreas. The tumor markers CA 19-9 and carcinoembryonic antigen (CEA) were slightly elevated, and pancreatic neoplasm was suspected. RESULTS: Left pancreatic resection and splenectomy were performed. The removed specimen disclosed the presence of an accessory spleen within the pancreatic tail.

Review article: current status of gastrointestinal carcinoids.

Carcinoid tumours are enigmatic, slow growing malignancies which occur most frequently (74%) in the gastrointestinal tract. In recent years, it has become apparent that the term 'carcinoid' represents a wide spectrum of different neoplasms originating from a variety of different neuroendocrine cell types. Carcinoid lesions are usually identified histologically by their affinity for silver salts, by general neuroendocrine markers, or more specifically by immunocytochemistry using antibodies against their specific cellular products. Within the gut, the most frequent sites are the small bowel (29%), the appendix (19%) and rectum (13%). Clinical manifestations are often vague or absent. Nevertheless, in approximately 10% of patients the tumours secrete bioactive mediators which may engender various elements of characteristic carcinoid syndrome. In many instances the neoplasms are detected incidentally at the time of surgery for other gastrointestinal disorders. The tendency for metastatic spread correlates with tumour size, and is substantially higher in lesions larger than 2.0 cm. An association with noncarcinoid neoplasms is ascribed in 8-17% of lesions. Treatment consists of radical surgical excision of the tumour, although gastric (type I and II) and rectal carcinoids may be managed with local excision. Overall 5-year survival is excellent for carcinoids of the appendix (86%) and rectum (72%), whereas small intestinal (55%), gastric (49%) and colonic carcinoids (42%) exhibit a far worse prognosis.

Pituitary adenylate cyclase-activating polypeptide modulates gastric enterochromaffin-like cell proliferation in rats.

BACKGROUND & AIMS: Gastric carcinoids (types I and II) involve the transformation of naive enterochromaffin-like (ECL) cells to the neoplastic state and are associated primarily with hypergastrinemia. In this study, we evaluated the effects of two related neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP), on ECL cell proliferation and characterized the receptor subtype(s) and signal transduction pathways that mediate this effect. METHODS: Purified rat ECL cells were analyzed in culture for DNA synthesis as measured by 24-hour 5-bromo-2-deoxyuridine (BrdU) uptake. Reverse-transcription polymerase chain reaction (RT-PCR) with gene-specific oligonucleotide primers was performed to characterize the PACAP/VIP receptor subtype(s). RESULTS: PACAP/VIP neuropeptide-stimulated BrdU uptake was significantly greater (3.4-3.8-fold greater than control) than that at the maximal dose of gastrin (2.2-fold greater than control). PACAP-stimulated ECL cell proliferation (EC50, approximately 3 x 10(-)14 mol/L) was approximately 100-fold more potent than VIP (EC50, approximately 3x 10(-)12 mol/L). The stimulated BrdU uptake by both PACAP and VIP was competitively inhibited by PACAP-receptor antagonist (IC50, 10(-)9 mol/L, 3 x 10(-)9 mol/L, respectively) and VIP-receptor antagonist (IC50, 3 x 10(-)7 mol/L, 5 x 10(-)7 mol/L, respectively). RT-PCR identified the presence of the PACAP-specific but not PACAP/VIP receptor subtypes. The PACAP-stimulated BrdU uptake was inhibited (70%-80%) by inhibitors of adenosine 3',5'-cyclic monophosphate, phosphatidylinositol 3 kinase, and protein tyrosine kinase as well as mitogen-activated protein kinase. CONCLUSIONS: PACAP/VIP-related peptides are more potent modulators of ECL cell proliferation than gastrin, and their effect is mediated by a PACAP-specific receptor whose activation is transduced by multiple intracellular messenger systems.

Multidisciplinary approach to palliation of obstructive jaundice caused by a central hepatocellular carcinoma.

BACKGROUND/AIMS: Obstructive jaundice due to intraductal tumour growth is a rare symptom in association with hepatocellular carcinoma (HCC). METHODS: We report a 65-year-old white male who was admitted to our department with a 2-week history of progressive jaundice. At laparotomy, the liver showed advanced cirrhosis due to long-standing biliary obstruction. Cholangiography confirmed total obstruction of the main bifurcation of the hepatic duct by intraductal tumour growth. Combination treatment with surgical segment III drainage, transcatheter arterial embolization and radioembolization with yttrium-90 resin particles and endoscopic stenting was performed. This form of treatment has never been reported before. RESULTS: With these combined procedures, relief of jaundice and a survival time of 32 months could be achieved. CONCLUSION: The combination of palliative methods may relieve jaundice, ensure a good quality of life and possibly prolong survival in patients with mechanical tumour obstruction of the biliary tree by HCC.

Biliary cystadenocarcinoma of the liver: the need for complete resection.

We report on a patient with biliary cystadenocarcinoma and review 112 previously published cases of this rare cystic hepatic neoplasm. This tumour mainly occurs in women at a ratio of 62% (female) to 38% (male), and at an average age of 56.2 years (range 18-88 years). The origin of these neoplasms is intrahepatic in 97% of cases and extrahepatic in the remaining 3%. The clinical symptoms are nonspecific and are not distinctive from benign cystic liver lesions unless invasive growth of the tumour occurs or distant metastases are present. Sonography and computed tomography (CT), as well as magnetic resonance imaging (MRI) demonstrate the multilocular nature of the tumour with septal or mural nodules. Discrete soft tissue masses, thick and coarse calcifications and varying density on CT or intensity on MRI within the loculi are additional non-specific imaging findings. The best therapeutic result with a 5-year survival rate of 100% and a recurrence rate of only 13% was achieved by complete excision (n = 16). Surgical removal of the tumour by complete excision is, therefore, the treatment of choice for biliary cystadenocarcinomas.

Choledocholithiasis at the hepatic confluence mimicking a hilar cholangiocarcinoma.

Adenocarcinomas of the bifurcation of the hepatic ducts (Klatskin tumors) are a relatively rare cause of obstructive jaundice. Differential diagnosis includes other neoplastic lesions, sclerosing cholangitis, Mirizzi's syndrome and benign strictures. We present a 46 year-old white female with a 2 month history of epigastric pain and progressive jaundice. Endoscopic retrograde cholangiopancreaticography (ERCP) revealed a filiform stenosis of the right hepatic duct and an obstructed left hepatic duct, an image strongly suggestive of a Klatskin tumor. The correct diagnosis was achieved, however, by percutaneous transhepatic cholangiography (PTC), which disclosed a gallstone at the common hepatic duct bifurcation and multiple small concrements in the left hepatic duct. After endoscopic removal of the gallstones in the biliary tree and laparoscopic cholecystectomy, the patient was discharged on the third post-operative day. Protuberant tumors and round biliary stones may be confused at ERCP.

Clinical manifestations of lost gallstones after laparoscopic cholecystectomy: a case report with review of the literature.

Laparoscopic cholecystectomy has become the preferred treatment for patients with symptomatic gallstones. During this procedure, perforation of the gallbladder with spillage of stones into the peritoneal cavity is not uncommon. Finding and removing all of the spilled gallstones can be laborious and is often avoided. Left in the peritoneal cavity, however, the stones may lead to intraperitoneal abscess formation, which may require a second procedure. We report here on a patient with an intraperitoneal abscess located between the right liver lobe and the anterior abdominal wall, which contained a large gallstone (4 cm3), found 3 months after an undetected stone spillage during laparoscopic cholecystectomy. Healing was achieved after conventional laparotomy, removal of the gallstone, and surgical drainage of the abscess cavity. The review of the literature emphasizes the clinical manifestations of this rare laparoscopic complication.

Epithelioid hemangioendothelioma of the liver. A rare hepatic tumor.

BACKGROUND: Epithelioid hemangioendothelioma (EH) is a rare neoplasm of vascular origin that may develop at different sites, such as in soft tissue, the lungs, or the liver. It usually affects adult females, and its unpredictable malignant potential has a range between benign hemangioma and clearly malignant hemangioendotheliosarcoma. METHODS: In the current study, the authors describe 2 patients with primary EH of the liver and review 127 previously published cases found in the literature. RESULTS: Most patients presented with nonspecific symptoms, such as right upper quadrant abdominal pain or weight loss. The tumors usually presented as multiple nodular lesions involving both lobes of the liver. Overall metastasis rate was 45.1%, with preferential involvement of the lungs and bones. In general, the key to diagnosis was the demonstration of cells containing factor-VIII-related antigen. CONCLUSIONS: EH of the liver is a very rare clinical entity. The primary treatments of choice are radical hepatic resection or orthotopic liver transplantation. The 5-year survival of 55.5% is significantly better than for other hepatic malignancies.