Increased risk of complicated CMV infection with the use of mycophenolate mofetil in allogeneic stem cell transplantation

Mycophenolate mofetil (MMF) is increasingly used for prophylaxis and therapy of GVHD in allogeneic stem cell transplantation. In some recent reports of use of MMF in solid organ transplantation a high incidence of CMV disease has been described. We evaluated the frequency and course of active CMV infection in patients who received MMF compared to those who did not receive MMF after allogeneic stem cell transplantation. We retrospectively analyzed 48 adult patients who consecutively underwent unmanipulated allogeneic bone marrow (n = 15) or peripheral stem cell transplantation (n = 33) from HLA-compatible family donors (n = 30) or unrelated donors (n = 18) from February 1997 to September 2000 at our institution. Only patients who were evaluable for the first 100 days were included in this analysis. Sixteen patients received MMF post transplant (MMF+). CMV-antigenemia was monitored by CMV-pp65 antigen. CMV-antigenemia occurred in 14 patients and was virtually only observed in CMV-IgG+ recipients (13/23, 56%). CMV-IgG+/MMF+ patients developed a higher incidence of CMV-antigenemia (8/9, 89%) compared to the CMV-IgG+/MMF- patients (5/14, 35%; P < 0.05). Moreover, five of six patients with persistent or recurrent CMV-antigenemia received MMF. No patient in either group developed CMV disease or died of CMV-related complications. In multivariate analysis including MMF treatment, unrelated vs related donor, GVHD, CMV-serostatus of the donor and stem cell graft type, only MMF treatment was found to be a significant risk factor for both overall and complicated CMV infection.     

Omeprazole heals duodenal, but not gastric ulcers more rapidly than ranitidine. Results of two German multicentre trials

In two double-blind, randomized German multicentre trials the effects of omeprazole 20 mg mane and ranitidine 150 mg b.i.d. were compared for the first time in 334 outpatients with duodenal ulcer and 184 outpatients with gastric ulcer. In patients with duodenal ulcer endoscopically controlled healing rates after two weeks were 72% with omeprazole and 59% with ranitidine (p = 0.012); after 4 weeks 96 and 92%, resp. were healed (n.s.). In patients with gastric ulcer the healing rates after two, four, and eight weeks were 43, 81, and 95%, respectively, with omeprazole and 45, 80, and 90%, respectively, with ranitidine (n.s.). Smoking impaired healing in duodenal, but not in gastric ulcer. Symptom relief was comparable with both drugs. Serious side effects or clinically relevant changes in laboratory screening results were not detected. - Our results demonstrate for the first time that omeprazole 20 mg mane is superior to ranitidine 150 mg b.i.d. in the short-term treatment of duodenal, but not gastric ulcer.     

Promoter methylation and loss of coding exons of the fragile histidine triad (FHIT) gene in intrahepatic cholangiocarcinomas.

AIMS: About 10-30% of primary liver cancers represent intrahepatic cholangiocarcinomas (IHCC). Since chromosomal losses of 3p are detectable in about 40% of cholangiocarcinomas our study aimed at the identification of mechanisms leading to functional deletion of tumor suppressor genes in this region. Our efforts focussed on genomic losses and epigenetic inactivation of two tumor suppressor genes, the fragile histidine triad (FHIT) and the ras association domain family 1 (RASSF1A) genes, both located on the short arm of chromosome 3. METHODS: Methylation-specific PCR (MSP) and combined bisulfite-dependent restriction analysis (COBRA) were applied to detect epigenetic silencing of gene promoters. Genomic duplex PCR was used to identify exon losses of the FHIT gene. Nineteen paraffin-embedded samples of intrahepatic cholangiocarcinomas were studied. RESULTS: Here we report for the first time that in addition to frequent losses of the exons 5 and 6, hypermethylation of the FHIT promoter occured in a significant portion of IHCC. Methylation specific PCR (MSP) detected epigenetic inactivation of the FHIT/FRA3B locus in 8 of 19 (42%) cases. Combined bisulfite restriction analysis (COBRA) revealed that high levels of methylated FHIT promoter sequences were present in 6 of the 8 methylation positive samples. In agreement with previous reports MSP identified hypermethylation of the RASSF1A gene in 13 of 19 (68%) IHCC specimens examined. CONCLUSIONS: Epigenetic silencing of the FHIT tumor suppressor gene is a novel inactivation mechanism to be considered in the development of intrahepatic cholangiocarcinomas. However, a statistically significant inverse correlation between K-Ras activation and RASSF1A inactivation was not found.     

Genotoxic effects of high dose rate X‐ray and low dose rate gamma radiation in ApcMin/+ mice

Risk estimates for radiation‐induced cancer in humans are based on epidemiological data largely drawn from the Japanese atomic bomb survivor studies, which received an acute high dose rate (HDR) ionising radiation. Limited knowledge exists about the effects of chronic low dose rate (LDR) exposure, particularly with respect to the application of the dose and dose rate effectiveness factor. As part of a study to investigate the development of colon cancer following chronic LDR vs. acute HDR radiation, this study presents the results of genotoxic effects in blood of exposed mice. CBAB6 F1 Apc^+/+ (wild type) and Apc^Min/+ mice were chronically exposed to estimated whole body absorbed doses of 1.7 or 3.2 Gy ⁶⁰Co‐γ‐rays at a LDR (2.2 mGy h^?1) or acutely exposed to 2.6 Gy HDR X‐rays (1.3 Gy min^?1). Genotoxic endpoints assessed in blood included chromosomal damage (flow cytometry based micronuclei (MN) assay), mutation analyses (Pig‐a gene mutation assay), and levels of DNA lesions (Comet assay, single‐strand breaks (ssb), alkali labile sites (als), oxidized DNA bases). Ionising radiation (ca. 3 Gy) induced genotoxic effects dependent on the dose rate. Chromosomal aberrations (MN assay) increased 3‐ and 10‐fold after chronic LDR and acute HDR, respectively. Phenotypic mutation frequencies as well as DNA lesions (ssb/als) were modulated after acute HDR but not after chronic LDR. The Apc^Min/+ genotype did not influence the outcome in any of the investigated endpoints. The results herein will add to the scant data available on genotoxic effects following chronic LDR of ionising radiation. Environ. Mol. Mutagen. 58:560–569, 2017. © 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society     

Expansion of recipient‐derived antiviral T cells may influence donor chimerism after allogeneic stem cell transplantation

Donor chimerism (DC) analysis is an important marker in the hematopoietic stem cell transplant follow‐up. Here, we present evidence for a possible relationship of infectious complications and declines in DC. We analyzed the DC in patients experiencing cytomegalovirus (CMV) reactivation. In addition, in some patients chimerism analyses of T‐cell subsets were performed. CMV‐specific cytotoxic T‐lymphocytes (CMV‐CTL) were monitored using human leukocyte antigen‐restricted multimer staining. Interestingly, CMV reactivation was accompanied by changes in DC in 11 of 67 patients transplanted. For example, DC declined in a cord blood recipient, in both total leukocytes and CD4 and CD8 T‐cell subsets upon CMV reactivation. The latter was controlled after only 5 days through expanding CMV‐CTL of 96% recipient origin, according to chimerism analysis of CMV‐CTL (enriched beyond 50%). In another patient, transplanted after reduced‐intensity conditioning from a DQB1 mismatched, CMV seronegative donor, incipient CMV reactivation was completely aborted by CMV‐CTL of recipient origin. However, at the same time, mixed chimerism dropped from 51% to 0% donor type, resulting in late graft rejection. Our data indicate that chimerism analyses in subset populations lead to a better understanding of declining total leukocyte chimerism. Furthermore, recipient‐derived CMV‐CTL may be able to control CMV reactivation after reduced‐intensity conditioning. We speculate that autologous CMV‐CTL may be instrumental to overcome recurrent CMV reactivations, especially in patients transplanted from CMV‐seronegative donors. In addition, the expansion of recipient‐derived CMV‐CTL may contribute to both, graft failure or to conversion to full DC.     

Computer-assisted surgical treatment of orbitozygomatic fractures

Orbitozygomatic fractures pertain to the most common injuries in craniofacial trauma patients. Accurate fracture reduction is of high importance for a successful outcome. This pilot study was performed to assess the potential benefit of surgical navigation to aid in orbitozygomatic fracture reduction. A non-comparative series of five consecutive patients with severely displaced orbitozygomatic fractures was treated using the guidance of computed tomography (CT)-based surgical navigation. Using a previously developed software platform, the fracture was reduced virtually by a three-dimensional shifting of the orbitozygomatic complex within the patient's preoperative multimodal CT data set. This treatment plan was transferred to a navigation system. Fracture reduction was performed according to the treatment plan using surgical navigation. Intraoperative control of fracture reduction by comparing the real with the virtual bone position using surgical navigation showed up as a helpful tool. Accurate treatment planning and immediate evaluation of craniofacial surgery outcome are the benefits of the new approach demonstrated. A major drawback of the presented approach is a high consumption of human and financial resources. A larger clinical series with long-term follow-up will be needed to determine reproducibility and cost-effectiveness. In addition to bone repositioning, a future application may include simulation of craniofacial osteotomies.     

Neuregulin-1, the fetal endothelium,and brain damage in preterm newborns

ObjectiveTo assess the potential role for Neuregulin-1 (NRG1) as a systemic endogenous protector in the setting of perinatal inflammatory brain damage.MethodsWe measured NRG1-protein and mRNA levels in human umbilical venous endothelial cells (HUVECs) of different gestational ages at various durations of exposure to lipopolysaccharide (LPS). In parallel, we genotyped the donor individuals for SNP8NRG221533, a disease-related single nucleotide polymorphism in the 5′ region upstream of the NRG1 sequence. Intracellular NRG1 localization was visualized by confocal microscopy. Furthermore we analyzed the relationship between SNP8NRG221533 genotype and neurodevelopmental outcome in children born preterm.ResultsWe observed a positive dose–response-relationship between NRG1-mRNA and intracellular protein levels with both advancing gestational age and duration of LPS exposure in HUVECs. The presence of allele C at the SNP8NRG221533 locus was associated with an increased cellular production of NRG1 in HUVECs, and with a significantly reduced risk for cerebral palsy and developmental delay in children born preterm.InterpretationIn conclusion, our data indicate that gestational age, duration of LPS exposure, and the SNP8NRG221533 genotype affect NRG1 levels. Our results support the hypothesis that NRG1 may qualify as an endogenous protector during fetal development.     

Imaging of paranasal sinuses today

CT is accepted as the gold standard for pathological-anatomical evaluation of paranasal sinus disease, CT is especially considered an obligatory part of planning surgical procedures. Indications for paranasal sinus CT include trauma, malignant disease, and chronic sinusitis, which accounts for the major part of examinations. Due to the benign character of the disease and the relatively moderate age of the patients involved, the radiation dose of paranasal sinus CT plays an important role. The use of a low-dose spiral CT technique and the reformation of coronal images out of the axial CT data instead of an additional direct coronal scan allow the effective dose of paranasal sinus CT to be reduced to the order of a chest radiogram. MRI is the preferred imaging modality in malignant disease or complications of inflammatory sinus disease that extend beyond the limits of the paranasal sinuses. The clinical value of other imaging modalities, including plain film radiography, ultrasound, or scintigraphy, is limited to special indications.