High frequency of Human Cytomegalovirus DNA in the Liver of Infants with Extrahepatic Neonatal Cholestasis

BACKGROUND: Biliary atresia (BA) is the most severe hepatic disorder in newborns and its etiopathogenesis remains unknown. Viral involvement has been proposed, including the human cytomegalovirus (HCMV). The aims of the study were to use the polymerase chain reaction (PCR) to screen the liver tissue of infants with extrahepatic cholestasis for HCMV and to correlate the results with serological antibodies against HCMV and histological findings. METHODS: A retrospective study in a tertiary care setting included 35 patients (31 BA, 1 BA associated with a choledochal cyst, 2 congenital stenosis of the distal common bile duct and 1 hepatic cyst). HCMV serology was determined by ELISA. Liver and porta hepatis were examined histologically. Liver samples from infants and a control group were screened for HCMV DNA. RESULTS: Twelve patients had HCMV negative serology, 9 were positive for IgG antibodies and 14 were positive for IgG and IgM. Nine liver and seven porta hepatis samples were positive for HCMV DNA but none of the control group were positive (general frequency of positivity was 34.3% – 12/35). There was no correlation between HCMV positivity by PCR and the histological findings. The accuracy of serology for detecting HCMV antibodies was low. CONCLUSION: These results indicate an elevated frequency of HCMV in pediatric patients with extrahepatic neonatal cholestasis. They also show the low accuracy of serological tests for detecting active HCMV infection and the lack of correlation between HCMV positivity by PCR and the histopathological changes

Biliary atresia

Biliary atresia (BA) is a rare disease characterised by a biliary obstruction of unknown origin that presents in the neonatal period. It is the most frequent surgical cause of cholestatic jaundice in this age group. BA occurs in approximately 1/18,000 live births in Western Europe. In the world, the reported incidence varies from 5/100,000 to 32/100,000 live births, and is highest in Asia and the Pacific region. Females are affected slightly more often than males. The common histopathological picture is one of inflammatory damage to the intra- and extrahepatic bile ducts with sclerosis and narrowing or even obliteration of the biliary tree. Untreated, this condition leads to cirrhosis and death within the first years of life. BA is not known to be a hereditary condition. No primary medical treatment is relevant for the management of BA. Once BA suspected, surgical intervention (Kasai portoenterostomy) should be performed as soon as possible as operations performed early in life is more likely to be successful. Liver transplantation may be needed later if the Kasai operation fails to restore the biliary flow or if cirrhotic complications occur. At present, approximately 90% of BA patients survive and the majority have normal quality of life

Immunotherapy with FBTA05 (Bi20), a trifunctional bispecific anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion (DLI) in relapsed or refractory B-cell lymphoma after allogeneic stem cell transplantation: study protocol of an investigator-driven, open-label, non-randomized, uncontrolled, dose-escalating Phase I/II-trial

BACKGROUND: Patients with B cell malignancies refractory to allogeneic stem cell transplantation (SCT) can be treated by subsequent immunotherapy with donor lymphocyte infusions (DLI). But unlike myeloid leukemia, B cell leukemia and lymphoma are less sensitive to allogeneic adoptive immunotherapy. Moreover, the beneficial graft-versus-lymphoma (GVL) effect may be associated with moderate to severe graft-versus-host disease (GVHD). Thus, novel therapeutic approaches augmenting the anti-tumor efficacy of DLI and dissociating the GVL effect from GVHD are needed. The anti-CD20 x anti-CD3 trifunctional bispecific antibody (trAb) FBTA05 may improve the targeting of tumor cells by redirecting immune allogeneic effector cells while reducing the risk of undesirable reactivity against normal host cells. Hence, FBTA05 may maximize GVL effects by simultaneously decreasing the incidence and severity of GVHD. METHODS/DESIGN: Based on this underlying treatment concept and on promising data taken from preclinical results and a small pilot study, an open-label, non-randomized, uncontrolled, dose-escalating phase I/II-study is conducted to evaluate safety and preliminary efficacy of the investigational antibody FBTA05 in combination with DLI for patients suffering from rituximab- and/or alemtuzumab-refractory, CD20-positive low- or high-grade lymphoma after allogeneic SCT. During the first trial phase with emphasis on dose escalation a maximum of 24 patients distributed into 4 cohorts will be enrolled. For the evaluation of preliminary efficacy data a maximum of 12 patients (6 patients with low-grade lymphoma and/or Chronic Lymphocytic Leukemia (CLL) / 6 patients with high-grade or aggressive lymphoma) will attend the second phase of this clinical trial. DISCUSSION: Promising data (e.g. induction of cellular immunity; GVL predominance over GVHD; achievement of partial or complete responses; prolongation of time-to-progression) obtained from this phase I/II trial would represent the first milestone in the clinical evaluation of a novel immunotherapeutic concept for treatment-resistant low- and high-grade lymphoma and NHL patients in relapse. TRIAL REGISTRATION: NCT0113857

Crohn disease lympho node homogenates produce murine lymphoma in athymic mice.

To study the putative agent(s) related to Crohn disease, we intraperitoneally in injected mesenteric lymph node homogenates from four patients with active Crohn disease into 10-week-old athymic (nu/nu) mice. Control mice (nu/nu) were injected with homogenates of mesenteric lymph nodes from two patients with ulcerative colitis and four patients undergoing elective cholecystectomy, and with a homogenate of a cervical lymph node containing sarcoid granuloma. Thirty-four mice received filtered or unfiltered homogenates from Crohn disease lymph nodes. Thirty-two mice received homogenates or filtrates from lymph nodes of control patients. Four mice from the group injected with Crohn disease homogenates from four different patients developed generalized lymphadenopathy due to lymphoma 10-28 weeks after th injection. Two additional mice developed lymphadenopathy due to plasma cell hyperplasia. None of the control mice developed lymphomas or lymphadenopathy. Two lymphomas were homogenized, filtered, and injected intraperitoneally into a second group of nu/nu mice, which also developed lymphoma within 8 weeks of injection. Two lymphomas were cultured in vitro and B cell sur?ACE MARKERS WERE IDENTIFIED. Indirect immunofluorescence studies in two lymphomas showed cytoplasmic staining of lymphoma cells with sera from 10 patients with active Crohn disease but not with sera from 13 control subjects, including 6 with ulcerative colitis and 7 with other gastrointestinal disorders. These results suggest that a transmissible factor present in Crohn disease lymph nodes produces lymphoma in nu/nu mice. Furthermore, sera of Crohn disease patients contain an antibody that recognizes an "antigen(s)" in the murine lymphoma