Splenic arterial interventions: anatomy, indications, technical considerations, and potential complications.

Splenic arterial interventions are increasingly performed to treat various clinical conditions, including abdominal trauma, hypersplenism, splenic arterial aneurysm, portal hypertension, and splenic neoplasm. When clinically appropriate, these procedures may provide an alternative to open surgery. They may help to salvage splenic function in patients with posttraumatic injuries or hypersplenism and to improve hematologic parameters in those who otherwise would be unable to undergo high-dose chemotherapy or immunosuppressive therapy. Splenic arterial interventions also may be performed to exclude splenic artery aneurysms from the parent vessel lumen and prevent aneurysm rupture; to reduce portal pressure and prevent sequelae in patients with portal hypertension; to treat splenic artery steal syndrome and improve liver perfusion in liver transplant recipients; and to administer targeted treatment to areas of neoplastic disease in the splenic parenchyma. As the use of splenic arterial interventions increases in interventional radiology practice, clinicians must be familiar with the splenic vascular anatomy, the indications and contraindications for performing interventional procedures, the technical considerations involved, and the potential use of other interventional procedures, such as radiofrequency ablation, in combination with splenic arterial interventions. Familiarity with the complications that can result from these interventional procedures, including abscess formation and pancreatitis, also is important.

Sensitive and rapid detection of ganciclovir resistance by PCR based MALDI-TOF analysis.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with significant morbidity and mortality in transplant recipients. Resistance against ganciclovir is increasingly observed. According to current guidelines, direct drug resistance testing is not always performed due to high costs and work effort, even when resistance is suspected. OBJECTIVES: To develop a more sensitive, easy applicable and cost-effective assay as proof of concept for direct drug resistance testing in CMV surveillance of post-transplant patients. STUDY DESIGN: Five consecutive plasma samples from a heart transplant patient with a primary CMV infection were analyzed by quantitative real-time polymerase chain reaction (rtPCR) as a surrogate marker for therapy failure, and by direct drug resistance detection assays such as Sanger sequencing and the novel primer extension (PEX) reaction matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) based method. RESULTS: This report demonstrates that PEX reaction followed by MALDI-TOF analysis detects the A594V mutation, encoding ganciclovir resistance, ten days earlier compared to Sanger sequencing and more than 30 days prior to an increase in viral load. CONCLUSION: The greatly increased sensitivity and rapid turnaround-time combined with easy handling and moderate costs indicate that this procedure could make a major contribution to improve transplantation outcomes.

Opposing roles for calcineurin and ATF3 in squamous skin cancer.

Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population. By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent. Here we report that genetic and pharmacological suppression of calcineurin/nuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xenografts, in immune compromised mice, of H-ras(V12) (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the 'enlarged' AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.

Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland.

Different interactions have been described between glucocorticoids and the product of the ob gene leptin. Leptin can inhibit the activation of the hypothalamo-pituitary-adrenal axis by stressful stimuli, whereas adrenal glucocorticoids stimulate leptin production by the adipocyte. The present study was designed to investigate the potential direct effects of leptin to modulate glucocorticoid production by the adrenal. Human adrenal glands from kidney transplant donors were dissociated, and isolated primary cells were studied in vitro. These cells were preincubated with recombinant leptin (10(-10)-10(-7) M) for 6 or 24 h, and basal or ACTH-stimulated cortisol secretion was subsequently measured. Basal cortisol secretion was unaffected by leptin, but a significant and dose-dependent inhibition of ACTH-stimulated cortisol secretion was observed [down by 29 +/- 0.1% of controls with the highest leptin dose, P < 0.01 vs. CT (unrelated positive control)]. This effect of leptin was also observed in rat primary adrenocortical cells, where leptin inhibited stimulated corticosterone secretion in a dose-dependent manner (down by 46 +/- 0.1% of controls with the highest leptin dose, P < 0.001 vs. CT). These effects of leptin in adrenal cells are likely mediated by the long isoform of the leptin receptor (OB-R), because its transcript was found to be expressed in the adrenal tissue and leptin had no inhibitory effect in adrenal glands obtained from db/db mice. Therefore, leptin inhibits directly stimulated cortisol secretion from human and rat adrenal glands, and this may represent an important mechanism to modulate glucocorticoid levels in various metabolic states.

Valganciclovir to prevent or treat cytomegalovirus disease in organ transplantation.

Cytomegalovirus (CMV) is generally considered the most significant pathogen to infect patients following organ transplantation. Significant improvements have been achieved in the management of CMV disease over recent years, especially since the introduction of oral drugs such as oral ganciclovir followed by valganciclovir (VGC), a prodrug of ganciclovir with enhanced bioavailability. Several randomized controlled trials have shown that VGC is an efficacious and convenient oral drug to prevent or treat CMV disease in solid-organ transplant recipients. In this article, we discuss the clinical and pharmacological experience with the use of VGC for the management of CMV in solid-organ transplant recipients. Finally, novel strategies to further reduce the incidence of CMV disease after transplantation are also reviewed.

Influenza vaccination in immunocompromised patients: efficacy and safety.

Yearly administration of the influenza vaccine is the main strategy to prevent influenza in immunocompromised patients. Here, we reviewed the recent literature regarding the clinical significance of the influenza virus infection, as well as the immunogenicity and safety of the influenza vaccine in HIV‑infected individuals, solid-organ and stem-cell transplant recipients and patients receiving biological agents. Epidemiological data produced during the 2009 influenza pandemic have confirmed that immunocompromised patients remain at high risk of influenza-associated complications, namely viral and bacterial pneumonia, hospitalization and even death. The immunogenicity of the influenza vaccine is overall reduced in immunocompromised patients, although a significant clinical protection from influenza is expected to be obtained with vaccination. Influenza vaccination is safe in immunocompromised patients. The efficacy of novel strategies to improve the immunogenicity to the vaccine, such as the use of adjuvanted vaccines, boosting doses and intradermal vaccination, needs to be validated in appropriately powered clinical trials.

The Oncogene ATF3 Is Potentiated by Cyclosporine A and Ultraviolet Light A.

Cutaneous squamous cell carcinoma (SCC) represents the most important cutaneous complication following organ transplantation. It develops mostly on sun-exposed areas. A recent study showed the role of activating transcription factor 3 (ATF3) in SCC development following treatment with calcineurin inhibitors. It has been reported that ATF3, which may act as an oncogene, is under negative calcineurin/nuclear factor of activated T cells (NFAT) control and is upregulated by calcineurin inhibitors. Still, these findings do not fully explain the preferential appearance of SCC on chronically sun-damaged skin. We analyzed the influence of UV radiation on ATF3 expression and its potential role in SCC development. We found that ATF3 is a specifically induced AP1 member in SCC of transplanted patients. Its expression was strongly potentiated by combination of cyclosporine A and UVA treatment. UVA induced ATF3 expression through reactive oxygen species-mediated nuclear factor erythroid 2-related factor 2 (NRF2) activation independently of calcineurin/NFAT inhibition. Activated NRF2 directly binds to ATF3 promoter, thus inducing its expression. These results demonstrate two mechanisms that independently induce and, when combined together, potentiate the expression of ATF3, which may then force SCC development. Taking into account the previously defined role of ATF3 in the SCC development, these findings may provide an explanation and a mechanism for the frequently observed burden on SCCs on sun-exposed areas of the skin in organ transplant recipients treated by calcineurin inhibitors.

Intravenous pamidronate as treatment for osteoporosis after heart transplantation: a prospective study.

Fractures due to osteoporosis are one of the major complications after heart transplantation, occurring mostly during the first 6 months after the graft, with an incidence ranging from 18% to 50% for vertebral fractures. Bone mineral density (BMD) decreases dramatically following the graft, at trabecular sites as well as cortical sites. This is explained by the relatively high doses of glucocorticoids used during the months following the graft, and by a long-term increase of bone turnover which is probably due to cyclosporine. There is some evidence for a beneficial effect on BMD of antiresorptive treatments after heart transplantation. The aim of this study was to assess prospectively the effect on BMD of a 3-year treatment of quarterly infusions of 60 mg of pamidronate, combined with 1 g calcium and 1000 U vitamin D per day, in osteoporotic heart transplant recipients, and that of a treatment with calcium and vitamin D in heart transplant recipients with no osteoporosis. BMD of the lumbar spine and the femoral neck was measured by dual-energy X-ray absorptiometry in all patients every 6 months for 2 years and after 3 years. Seventeen patients, (1 woman, 16 men) aged 46+/-4 years (mean +/- SEM) received only calcium and vitamin D. A significant decrease in BMD was observed after 6 months following the graft, at the lumbar spine (- 6.6%) as well as at the femoral neck (-7.8%). After 2 years, BMD tended to recover at the lumbar spine, whereas the loss persisted after 3 years at the femoral neck. Eleven patients (1 woman and 10 men) aged 46+/-4 years (mean +/- SEM) started treatment with pamidronate on average 6 months after the graft, because they had osteoporosis of the lumbar spine and/or femoral neck (BMD T-score below -2.5 SD). Over the whole treatment period, a continuous increase in BMD at the lumbar spine was noticed, reaching 18.3% after 3 years (14.3% compared with the BMD at the time of the graft). BMD at the femoral neck was lowered in the first year by -3.4%, but recovered totally after 3 years of treatment. In conclusion, a 3-year study of treatment with pamidronate given every 3 months to patients with existing osteoporosis led to a significant increase in lumbar spine BMD and prevented loss at the femoral neck. However, since some of these patients were treated up to 14 months after the transplant, they may already have passed through the phase of most rapid bone loss. In patients who were not osteoporotic at baseline, treatment with calcium and vitamin D alone was not able to prevent the rapid bone loss that occurs immediately after transplantation.

Respiratory viruses in bronchoalveolar lavage: a hospital-based cohort study in adults.

BACKGROUND: The epidemiology of respiratory viruses and their potential clinical impact when recovered in lower respiratory specimens has not been established in the hospital setting. A study was performed to investigate the association between positive viral detection and respiratory infection in an at-risk population. METHODS: 299 adult patients who underwent bronchoalveolar lavage (BAL) procedures were enrolled in a hospital-based prospective cohort study. Descriptive epidemiology is presented of 17 different respiratory viruses detected by reverse transcription-polymerase chain reaction assays in BAL fluid specimens. Multivariate analysis was conducted to identify the clinical characteristics independently associated with the presence of virus. RESULTS: Of 522 BAL fluid specimens analysed, 81% were collected in adult transplant recipients or other immunocompromised patients. Overall, PCR assays identified viral nucleic acid in 91 BAL fluid samples (17.4%). Similar rates of virus-positive BAL fluid were found in the different subpopulations studied (p = 0.113). Coronaviruses were the most frequent (32.3%), followed by rhinovirus (22.6%), parainfluenza (19.5%), influenza (9.7%), respiratory synctial virus (8.6%), human metapneumovirus (4.2%) and bocavirus (3.1%). Multivariate analysis using mixed models showed that respiratory viral infections were associated with a lack of antibiotic treatment response (OR 2.2, 95% CI 1.2 to 4.1) and the absence of radiological infiltrate (OR 0.3, 95% CI 0.2 to 0.8). In lung transplant recipients in whom a respiratory infection was suspected, the respiratory viral detection rate was 24.4% compared with 13.8% overall in other patients (p = 0.02). CONCLUSIONS: In this cohort of hospitalised adults, respiratory viruses detected in BAL fluid specimens were associated with respiratory symptoms, absence of radiological infiltrates and a poor response to antibiotic therapy.

Emerging viral infections after hematopoietic cell transplantation.

This overview summarizes recent data on emerging viruses after hematopoietic cell transplantation (HCT), including adenovirus, BK virus, human metapneumovirus (hMPV), and human herpesvirus (HHV) 6. The increased recognition of these infections is due to improved molecular detection methods, increased surveillance and more profound immunosuppression in the host. Adenovirus can cause serious disease especially in T-cell depleted transplant recipients. Adenovirus viremia is an important risk factor for disease in this setting. BK virus has been associated with hemorrhagic cystitis in HCT recipients. BK viremia is significantly associated with hemorrhagic cystitis. hMPV shows a seasonal distribution and can cause fatal pneumonia in HCT recipients. hMPV may be the etiology of some cases previously categorized as idiopathic pneumonia syndrome. HHV-6 commonly leads to viremia in HCT recipients. HHV-6 has been strongly associated with encephalitis and delayed platelet engraftment. Prospective studies are needed to further examine epidemiology, disease associations, and management strategies for these viruses.

Limited telomere shortening in hematopoietic stem cells after transplantation.

The number of cell divisions in hematopoietic stem cells (HSCs) following transplantation of bone marrow or mobilized peripheral blood into myelo-ablated recipients is unknown. This number is expected to depend primarily on the number of transplanted stem cells, assuming that stem cells do not differ in engraftment potential and other functional properties. In a previous study, we found that the telomere length in circulating granulocytes in normal individuals shows a biphasic decline with age, most likely reflecting age-related changes in the turnover of HSCs. In order to study HSCs' proliferation kinetics following stem cells transplantation, we analyzed the telomere length in donor-derived nucleated blood cells in four HLA-matched bone marrow transplant recipients relative to comparable cells from the sibling donors. In each case, the telomeres in granulocytes were shorter in the recipient than in the donor. This difference was established in the first year post transplantation and did not change after that. The telomere length in naïve and memory T cells showed marked differences after transplantation, complicating the interpretation of telomere length data using unseparated nucleated blood cells. Interestingly, the telomere length in naïve T cells that were first observed six months post transplantation was very similar in donor and recipient pairs. Our observations are compatible with a limited number of additional cell divisions in stem cell populations after bone marrow transplantations and support the idea that different populations of stem cells contribute to short-term myeloid and long-term lympho myeloid hematopoiesis.

Heart transplantation: current practice and outlook to the future.

QUESTIONS UNDER STUDY: The field of heart transplantation has seen substantial progress in the last 40 years. The breakthroughs in long-term survival were followed by a period of stagnation in the last decade. This review summarises current recommendations for the identification of candidates for heart transplantation and their immunological and non-immunological postoperative follow-up. RESULTS: The progress made in the treatment of patients with advanced heart failure has considerably changed the profile of candidates for heart transplantation. Patients are older, and the load of co-morbidities is more important requiring careful evaluation for candidacy. Long-standing research in the field of immunosuppression made available various drugs, which decrease the risk of acute allograft rejection and prolong survival after heart transplantation. Powerful new molecules are entering early phase clinical studies, suggesting further improvement in the near future. As a consequence, treatment of non-immunological co-morbidity after heart transplantation will gain in importance, however, the base of evidence guiding current recommendations is poor. CONCLUSIONS: The substantial progress in heart failure treatment and immunosuppression after heart transplantation has changed the profile of heart transplant recipients. The arrival of new molecules will provide additional alternatives for immunosuppressive treatment while studies have to address non-immunological treatment in order to improve long-term survival after heart transplantation.

Fatal Outcome of Multiple Clinical Presentations of Human Herpesvirus 8-related Disease After Solid Organ Transplantation.

Kaposi sarcoma is the most common human herpesvirus 8 (HHV-8)-related disease described after solid organ transplantation. Multicentric Castleman disease and hemophagocytic syndrome are other potential HHV-8-induced entities but are less frequently reported. We describe the case of a liver transplant recipient who presented with an acute febrile illness 1 year after transplantation with a rapidly fatal outcome. Autopsy revealed 3 distinct HHV-8-related entities: Kaposi sarcoma, HHV-8-associated multicentric Castleman disease with microlymphomas and a severe hemophagocytic syndrome. Retrospective serologic tests suggested that HHV-8 was likely transmitted by the seropositive donor at the time of transplantation. To our knowledge, this is the first case of copresentation of 3 clinical presentations of HHV-8-mediated human disease in the post-transplant setting. Considering the absence of systematic screening of organ donors/recipients for HHV-8 infection, HHV-8-related illness should be suspected in transplant recipients who present with acute febrile illness, systemic symptoms, lymphadenopathies, and/or multiorgan failure to rapidly document the diagnosis and provide timely an adequate treatment.

Quality of life and menopausal symptoms in women with liver transplants

PURPOSE: To assess quality of life and climacteric symptoms in women with and without liver transplants. METHODS: This was a cross-sectional study of 52 women undergoing follow-up at a university hospital in southeastern Brazil from February 4th, 2009 to January 5th, 2011. Twenty-four of these women were 35 years old or older and had undergone liver transplantation at least one year before study entry. The remaining 28 women had no liver disease and were matched by age and menstrual patterns to the patients with transplants. The abbreviated version of the World Health Organization (WHOQOL-BREF) questionnaire was used to assess quality of life. Menopausal symptoms were assessed using the Menopause Rating Scale (MRS). Statistical analysis was carried out by Student's t-test, Mann-Whitney test and analysis of variance. Correlations between MRS and the WHOQOL-BREF were established by correlation coefficients. RESULTS: The mean age of the women included in the study was 52.2 (±10.4) years and the mean time since transplantation was 6.1 (±3.3) years. Women with liver transplants had better quality of life scores in the environment domain (p=0.01). No difference was noted between the two groups in any domain of the MRS. For women in the comparison group, there was a strongly negative correlation between somatic symptoms in the MRS and the physical domain of the WHOQOL-BREF (p<0.01; r=-0.8). In contrast, there was only a moderate association for women with liver transplants (p<0.01; r=-0.5). CONCLUSIONS: Women with liver transplants had better quality of life scores in the domain related to environment and did not exhibit more intense climacteric symptoms than did those with no liver disease. Climacteric symptoms negatively influenced quality of life in liver transplant recipients, although less intensely than in women without a history of liver disease.

Expression of CD40 ligand, interferon-gamma and Fas ligand genes in endomyocardial biopsies of human cardiac allografts: correlation with acute rejection

The purpose of the present study was to investigate the expression (mRNA) of CD40 ligand (CD40L), interferon-gamma (IFN-gamma) and Fas ligand (FasL) genes in human cardiac allografts in relation to the occurrence of acute cardiac allograft rejection as well as its possible value in predicting acute rejection. The mRNA levels were determined by a semiquantitative reverse transcriptase-polymerase chain reaction method in 39 samples of endomyocardial biopsies obtained from 10 adult cardiac transplant recipients within the first six months after transplantation. Biopsies with ongoing acute rejection showed significantly higher CD40L, IFN-gamma and FasL mRNA expression than biopsies without rejection. The median values of mRNA expression in biopsies with and without rejection were 0.116 and zero for CD40L (P<0.003), 0.080 and zero for IFN-gamma (P<0.0009), and 0.156 and zero for FasL (P<0.002), respectively. In addition, the levels of IFN-gamma mRNA were significantly increased 7 to 15 days before the appearance of histological evidence of rejection (median of 0.086 in pre-rejection biopsies), i.e., they presented a predictive value. This study provides further evidence of heightened expression of immune activation genes during rejection and shows that some of these markers may present predictive value for the occurrence of acute rejection.