The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors

Extent: 11 p.BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary “sludge” in Arms A/B/C was 39%/36%/27%. CONCLUSION: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. Trial registration: ClinicalTrials.gov NCT00448786Lee S. Rosen, Lara Lipton, Timothy J. Price, Neil D. Belman, Ralph V. Boccia, Herbert I. Hurwitz, Joe J. Stephenson Jr., Lori J. Wirth, Sheryl McCoy, Yong-jiang Hei, Cheng-Pang Hsu and Niall C. Tebbut

LUPUS ERITEMATOSO SISTEMICO Y EMBARAZO

Se presenta una revisión de los casos de embarazos asociados a lupus eritematoso sistémico (LES) atendidos en el Hospital base de Valdivia, en un período de 9 años. Se observó que 13 mujeres portadoras de lupus tuvieron un total de 35 embarazos en los que no hubo abortos o patologías obstétricas asociadas. La frecuencia de exacerbación del lupus fue similar a la observada en la literatura. Hubo un caso de bloqueo aurículo ventricular fetal, con resultado en muerte fetal tardía. Se destaca la importancia de la planificación del embarazo y el manejo multidisciplinario de los caso

Successful pregnancy in a liver transplant recipient treated with lamivudine for de novo hepatitis B in the graft.

Pregnancy is often successful after liver transplantation, despite the potentially toxic effects of immunosuppressive drug therapy. Liver transplant recipients with recurrent hepatitis C or hepatitis B nonetheless appear to be at risk of a worse graft function in the event of pregnancy, and antiviral drugs are generally contraindicated in pregnancy because of their teratogenic effects. A 33-year-old woman had undergone liver transplantation for Caroli's disease 6 years previously. Two years later the patient experienced de novo HBV hepatitis. Lamivudine treatment (100 mg/day) was started and clearance of HBsAg was documented 1 year later. Four years after starting antiviral treatment the patient became pregnant, despite of the risk of teratogenic effects; lamivudine, cyclosporine and azathioprine were not discontinued for risk of break-through hepatitis and acute or chronic rejection. The course of gestation was uneventful and caesarean section was performed after 36 weeks. The newborn infant was a healthy male weighing 3,080 g and measuring 50 cm

Combined liver-kidney transplantation in a 15-year-old boy with alpha1-antitrypsin deficiency

Alphal-antitrypsin (alpha1-AT) deficiency is the most common genetic cause of liver disease in infants and children. The major clinical manifestations include liver disease (primarily in children) and emphysema in adults. For patients who progress to cirrhosis and liver failure, liver transplantation provides a metabolic cure for the deficiency and presumably prevents the associated complications. Several case reports in the pediatric literature describe glomerulonephritis in the setting of severe alpha1-AT deficiency, but this association is less well documented in adults. End-stage chronic kidney disease is a rare finding in the literature and kidney transplantation is the treatment of choice. We report on a 15-year-old boy with alpha1-AT deficiency and consequent end-stage liver disease and membranoproliferative glomerulonephritis rapidly progressing to renal failure, who successfully underwent combined liver-kidney transplantation

Different neurological outcome of liver transplantation for Wilson's disease in two homozygotic twins

Wilson's disease is a genetic disorder characterized by accumulation of copper in many organs and tissues. Phenotypic manifestations are wide-ranging from neuropsychiatric disorders, to severe liver disease requiring liver transplantation. Clinical presentation is not often related to the genetic defect and siblings may have different type of disease. Liver transplantation is indicated for all patients with Wilson's disease and decompensated liver cirrhosis unresponsive to medical therapy, but its efficacy in resolving the neurological symptoms is still controversial, because as far now, very different outcomes have been reported. We describe here on the exceptional case of two homozygotic twins, both with liver cirrhosis due to Wilson's disease, one of them with severe neuropsychiatric involvement, who both underwent liver transplantation and subsequently had very different outcome despite same genetic background. The presence of neurological clinical manifestations in Wilson's disease should recommend caution indicating liver transplantation, because irreversible brain damage may exist

Microvascular autonomic dysfunction may justfy false-positive stress myocardial perfusion imaging in patients with liver cirrhosis undergoing liver transplantation.

Abstract: Background. Up to 15% of liver transplant candidates have asymptomatic coronary artery diseases, which increase the risk of cardiac complications during and after transplantation. The aim of this study was to prospectively investigate the usefulness of an integrated cardiological approach in cirrhotic patients undergoing liver transplantation. Methods. Twenty-four consecutive patients undergoing evaluation for liver transplantation were studied by assessing risk factors for coronary artery diseases, electrocardiogram with QTc interval determination, chest X-ray, echocardiography, 24-hour Holter monitor, myocardial perfusion scintigraphy 99-TcMIBI-GSPECT at rest and after dipyridamole infusion. Cardiac I-123-metaiodobenzylguanidine (MIBG) scan and coronarography were performed in patients with myocardial perfusion defects. Twenty three of 24 patients underwent successful liver transplantation; one patient died on the waiting list. Results. Before liver transplantation, 29% of patients were diabetic and 41% were smokers. Eleven of 24 patients had a prolonged QTc interval, and 3/24 had positive myocardioscintigraphy after dipyridamole infusion: in two coronarography was negative, while the I-123-MIBG washout was altered. No cardiac events were recorded during the short-and long-term follow-up after surgery. Conclusions. Predictive value of positive cardiac (MIBI)-M-99Tc-GSPECT in patients with liver cirrhosis is low, and this may be due to alterations of cardiac microvascular tone as showed by cardiac I-123-MIBG scan

Donor livers with steatosis are safe to use in hepatitis C virus-positive recipients.

Whether donor graft steatosis affects liver function and influences survival after liver transplantation is still open to debate. The aim of this study was to assess the impact of donor graft steatosis on long-term liver histology after liver transplantation. One hundred sixteen consecutive liver transplants were performed in 56 hepatitis C virus-positive (HCV+) patients and 60 HCV- patients who had protocol liver biopsies at 6, 12, 24, and 36 months after liver transplantation. Liver biopsies were obtained from all grafts. No steatosis was seen in 50.9% of the biopsies taken at the back table before implantation, whereas steatosis was mild in 39.6% of the samples and moderate/severe in 9.5% of the samples. In the 56 HCV+ recipients, fibrosis stage 3 was seen in 22.2% and stage 4 was seen in 2.2% of 45 biopsies at 36 months after liver transplantation. There was no correlation between donor graft steatosis and fibrosis after liver transplantation, regardless of the etiology of liver disease. No difference in 36-month survival after liver transplantation was seen, regardless of whether the etiology of the patient's liver disease was HCV-related or non-HCV-related (80.3% versus 75%; P = 0.4) and whether the steatosis in the graft was reportedly absent, mild, or moderate/severe (79.7% versus 73.9% versus 81.1%; P = 0.7). In conclusion, nearly one-quarter of HCV+ recipients have precirrhosis/cirrhosis 3 years after liver transplantation. Steatotic grafts do not seem to exacerbate the progression of fibrosis in HCV+ recipients, nor do they seem to negatively affect 3-year patient survival